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“Trong cuốn sách sâu sắc và kích thích suy nghĩ này, đặt ra những câu hỏi về cách chúng ta già đi,”

và liệu con người có thể vượt qua sự suy tàn và thoái hóa, Sinclair vật lộn

với một số câu hỏi cơ bản nhất xung quanh khoa học về quá trình lão hóa.

Kết quả là một cuốn sách tinh tế và thú vị xứng đáng được đọc rộng rãi và

sâu sắc

—Siddhartha Mukherjee, người đoạt giải Pulitzer và là tác giả sách bán chạy nhất của New York Times

tác giả bán chạy nhất

"Nếu bạn từng tự hỏi chúng ta già đi như thế nào, liệu chúng ta có thể làm chậm hoặc thậm chí đảo ngược quá trình lão hóa hay không,"

Có thể sống khỏe mạnh hơn 100 năm, thì cuốn sách mới của David Sinclair, "Tuổi thọ" . . .

Tôi sẽ hướng dẫn bạn qua khoa học và các chiến lược thực tiễn để thực hiện điều đó.

"Thời gian khỏe mạnh của bạn bằng với tuổi thọ của bạn, và làm cho tuổi thọ của bạn dài và đầy sức sống."

—Mark Hyman, MD Giám đốc, Trung tâm Chức năng Cleveland Clinic

Y học và tác giả sách bán chạy số 1 của New York Times

"Đây là cuốn sách đầy tầm nhìn nhất về sự già đi mà tôi từng đọc. Hãy nắm bắt cơ hội—"

"và bắt lấy cuốn sách này!"

—Dean Ornish, MD, người sáng lập và tổng thống, Nghiên cứu Y học Phòng ngừa

Viện và tác giả sách bán chạy của New York Times của UnDo It!

"Trong cuốn sách Lifespan, David Sinclair một cách suôn sẻ cho chúng ta biết bí mật mà mọi người đều muốn biết."

Biết: cách sống lâu hơn và lão hóa chậm hơn. Sinclair thuyết phục chúng ta rằng không chỉ...

Có thể sống vượt qua một trăm năm, thì khó tránh khỏi rằng chúng ta sẽ có thể.

Một ngày nào đó hãy làm như vậy. Nếu bạn là người muốn biết cách đánh bại sự lão hóa,

"Sự sống còn là một cuốn sách cần đọc."

—William W. Li, MD, tác giả sách bán chạy nhất của New York Times, Eat to Beat

Bệnh

“Sáng suốt, truyền cảm hứng và đầy thông tin. [Sinclair] đã chuyển ngữ một khối lượng lớn”

chi tiết phân tử thành một chương trình mà chúng ta có thể sử dụng để sống lâu hơn và khỏe mạnh hơn.

Đối với bất kỳ ai quan tâm đến việc hiểu quá trình lão hóa, sống lâu hơn, và

"Tránh xa các bệnh tật của lão hóa, đây là cuốn sách nên đọc."

—Dale Bredesen, MD, tác giả sách bán chạy của New York Times với cuốn The End of

Bệnh Alzheimer

“Một cuốn sách đầy tầm nhìn từ một trong những nhà khoa học về tuổi thọ tài ba nhất của chúng ta”

thời gian. Tuổi thọ trao quyền cho chúng ta thay đổi sức khỏe của mình hôm nay trong khi tiết lộ một

"tiềm năng tương lai khi chúng ta sống trẻ lâu hơn."

—Sara Gottfried, MD, tác giả ăn khách của New York Times của cuốn The Hormone

Chữa trị

"Sẵn sàng để tâm trí bạn bị chấn động. Bạn đang cầm trong tay món quý giá"

kết quả của hàng thập kỷ làm việc, như được chia sẻ bởi Tiến sĩ David Sinclair, ngôi sao sáng trong lĩnh vực lão hóa

và tuổi thọ con người.

—Dave Asprey, nhà sáng lập và CEO của Bulletproof và New York Times

tác giả bán chạy nhất của Cuộc sống không khổ sở

"Hãy tưởng tượng một thế giới trong đó chúng ta có thể sống đủ lâu để gặp gỡ không chỉ riêng chúng ta"

cháu chắt, nhưng là chắt của chúng ta. Đây là tầm nhìn của Sinclair cho

tương lai của nhân loại, một tầm nhìn hướng tới khoa học, thiên nhiên, lịch sử, và thậm chí

chính trị để lập luận rằng điều này là có thể sống khỏe mạnh đến cả trăm tuổi.

“Thời gian sống đang dẫn đầu một cách mạnh mẽ.”

—Jason Fung, MD, tác giả của The Diabetes Code và The Obesity Code

"Trong cuốn sách Lifespan, Tiến sĩ David Sinclair . . . cung cấp cho chúng ta những công cụ hàng ngày mà chúng ta cần."

Bạn có thể sử dụng để ngăn chặn cái mà anh ấy hiện gọi là "căn bệnh của sự lão hóa."... Bạn nợ điều đó cho

bạn và những người thân yêu của bạn hãy đọc và làm theo lời khuyên của ông ấy, như tôi đã làm trong suốt thời gian qua.

15 năm!

—Steven R. Gundry, MD, tác giả bán chạy nhất của New York Times với cuốn sách The

Nghịch lý tuổi thọ và giám đốc y khoa của Hội Tim mạch Quốc tế

Viện Phổi

"Tuổi thọ vượt qua mọi điều chúng ta biết về sự lão hóa và tuổi thọ."

sự kết hợp giữa công trình khoa học xuất sắc, tư duy tiên phong và ước mơ về một

cuộc sống dài hơn, khỏe mạnh hơn và hạnh phúc hơn. Tuổi thọ mang đến một tầm nhìn cho tương lai của chúng ta và

l roadmap về cách để đến đó, kết hợp các đột phá khoa học và sự đơn giản

“Những thay đổi lối sống không chỉ giúp chúng ta cảm thấy trẻ hơn, mà còn thực sự giúp trẻ hóa.”

—Naomi Whittel, tác giả sách bán chạy của New York Times với tác phẩm Glow15

“David Sinclair tài ba trình bày một tầm nhìn táo bạo về tương lai trong đó”

Nhân loại có khả năng làm chậm hoặc đảo ngược quá trình lão hóa và sống trẻ hơn, khỏe mạnh hơn.

sống lâu hơn

—Victor J. Dzau, MD, chủ tịch Viện Hàn lâm Y học Hoa Kỳ

và Giám đốc điều hành của Trung tâm Y tế Đại học Duke

"Có rất ít cuốn sách khiến tôi suy nghĩ về khoa học theo một"

cách tiếp cận cơ bản và mới. Cuốn sách của David Sinclair đã làm điều đó cho tôi về lão hóa. Đây là một

"Cuốn sách mà ai cũng phải đọc khi trưởng thành."

—Leroy Hood, Tiến sĩ, giáo sư tại Viện Công nghệ California,

nhà phát minh, doanh nhân, thành viên của cả ba Học viện Quốc gia Hoa Kỳ, và

đồng tác giả của Bộ quy tắc các quy tắc

Trong "Lifespan", sức mạnh đầy đủ của [Sinclair's] lạc quan, hài hước và giọng nói nhẹ nhàng.

tài năng hùng biện như một nhà khoa học kể chuyện xuất hiện. Tôi hy vọng chúng ta có David.

Sinclair với chúng tôi và tiến hành khoa học cũng như viết sách trong 500 năm nữa.

khoảng một thế kỷ nữa.

—David Ewing Duncan, nhà báo đoạt giải, tác giả bán chạy, và

người điều hành Arc Fusion

“Tuổi thọ mang lại cho chúng ta hy vọng về một cuộc sống phi thường. Như bác sĩ xuất sắc David.”

Sinclair giải thích, lão hóa là một căn bệnh, và căn bệnh đó có thể được điều trị. Điều này thật sự mở mang tầm mắt.

Cuốn sách đưa bạn đến những mặt trận của những đột phá đáng kinh ngạc. Hãy tận hưởng tác phẩm này.

kiệt tác!

—Peter H. Diamandis, MD, tác giả sách bán chạy nhất của New York Times

Sự phong phú và Táo bạo

“Mô tả khoa học thực sự sẽ đặt câu hỏi về nền tảng của mọi thứ chúng ta”

"giả định về cuộc sống và xã hội của chúng ta."

—Salman Khan, người sáng lập Khan Academy

“David là một người tiên phong sẵn sàng thay đổi cách mà chúng ta suy nghĩ và hiểu.”

lão hóa

—Stephanie Lederman, Giám đốc điều hành của Liên đoàn Người cao tuổi Hoa Kỳ

Nghiên cứu (AFAR), New York

"Thông điệp và ưu tiên quan trọng nhất của thời đại chúng ta. Trong nhiều năm tới,"

"Nhân loại sẽ suy ngẫm về cuốn sách này với sự kinh ngạc và tôn trọng. Hãy đọc nó... Cuộc đời của bạn."

phụ thuộc vào điều đó.

—Marc Hodosh, cựu chủ sở hữu và đồng sáng lập TEDMED

Một cuộc trình diễn xuất sắc. Cuốn sách của Sinclair, và công trình cả đời của ông, đứng ngang hàng với nhân loại.

các đóng góp lớn nhất để giúp nâng cao niềm vui và hạnh phúc trong cuộc sống, xếp hạng

với các công trình của Jenner, Pasteur, Salk, Locke, Gandhi và Edison. A

kiệt tác.

—Martine Rothblatt, người sáng lập, Chủ tịch Hội đồng quản trị và Giám đốc điều hành của

"United Therapeutics và người sáng lập SiriusXM Đài Phát Thanh Vệ Tinh"

"Chạm chân lên mặt trăng đã thay đổi nhân loại. Trong Lifespan, Sinclair nói về"

bước cuối cùng cho nhân loại sẽ biến đổi cuộc sống của chúng ta vượt xa bất cứ điều gì chúng ta đã biết.

chưa từng có thể tưởng tượng. Tác giả táo bạo, khoa học sâu sắc, và chúng ta

Tương lai đã đến.

—Henry Markram, tiến sĩ, giáo sư tại EPFL, Thụy Sĩ, giám đốc của

Dự án Blue Brain và người sáng lập các tạp chí mở Frontiers

" Một cuốn sách trí thức và hấp dẫn với những cái nhìn kích thích về những điều nhất"

"vấn đề quan trọng về tương lai của bạn và mọi người."

—Andrew Scott, Tiến sĩ, giáo sư kinh tế tại Trường Kinh doanh London

Trường và tác giả của cuốn sách Cuộc sống 100 năm

Cảm ơn bạn đã tải xuống

cái này Simon & Schuster

sách điện tử

Nhận một sách điện tử MIỄN PHÍ khi bạn tham gia danh sách gửi thư của chúng tôi. Thêm vào đó, nhận thông tin cập nhật về những điều mới.

các bản phát hành, giao dịch, sách đọc được khuyên dùng và nhiều hơn nữa từ Simon & Schuster.

Nhấp vào bên dưới để đăng ký và xem các điều khoản và điều kiện.

NHẤN VÀO ĐÂY ĐỂ ĐĂNG KÝ

Bạn đã là người đăng ký? Vui lòng cung cấp email của bạn một lần nữa để chúng tôi có thể đăng ký ebook này.

và gửi cho bạn nhiều hơn những gì bạn thích đọc. Bạn sẽ tiếp tục nhận được

các ưu đãi độc quyền trong hộp thư của bạn.

Gửi bà nội Vera của tôi, người đã dạy tôi nhìn thế giới theo cách mà nó có thể.

là

Đến mẹ tôi, Diana, người đã chăm sóc cho con cái nhiều hơn cho bản thân.

Đến vợ tôi, Sandra, nền tảng vững chắc của tôi.

Và đến những đứa chắt chắt của tôi; Tôi rất mong được gặp gỡ.

bạn

HÀNH RỪNG. Trong thế giới hoang dã và kỳ diệu của tộc Garigal, thác nước và nước mặn

các cửa sông gió thổi qua những mỏm đá sa thạch cổ xưa, dưới những tán cây tối tăm của những chỗ bị cháy.

các cây máu, angophora và bạch đàn gai mà những chú kookaburra, currawong và walabies ăn

nhà

GIỚI THIỆU

LỜI CẦU NGUYỆN CỦA MỘT BÀ NGOẠI

Tôi lớn lên ở rìa của rừng. Về nghĩa bóng, sân sau của tôi là một...

rừng trăm mẫu. Về mặt nghĩa đen, nó lớn hơn nhiều so với điều đó. Nó tiếp tục như

đến mức mắt trẻ tuổi của tôi có thể nhìn thấy, và tôi chưa bao giờ cảm thấy chán khi khám phá nó. Tôi sẽ

leo núi và leo núi, dừng lại để nghiên cứu những con chim, những loài côn trùng, những loài bò sát. Tôi đã kéo

những thứ tách rời. Tôi xoa bụi giữa các ngón tay. Tôi nghe những âm thanh của...

hoang dã và cố gắng kết nối chúng với nguồn gốc của chúng.

Và tôi đã chơi. Tôi đã làm kiếm từ que và pháo đài từ đá. Tôi đã leo cây.

và đu trên các nhành cây, để chân qua những vách đá dốc và nhảy xuống

o của những điều mà có lẽ tôi không nên nhảy vào. Tôi hình dung mình như một

nhà du hành vũ trụ trên một hành tinh xa xôi. Tôi đã giả vờ là một thợ săn trong safari. Tôi nâng cao chiếc của mình

Giọng nói cho động vật như thể chúng là một khán giả tại nhà hát opera.

“Coooeey!” tôi sẽ gọi, có nghĩa là “Đến đây” trong ngôn ngữ của

Người Garigal, những cư dân bản địa.

Tôi không phải là người đặc biệt trong bất kỳ điều gì này, tất nhiên. Có rất nhiều đứa trẻ trong đó.

các vùng ngoại ô phía bắc của Sydney, những người chia sẻ niềm đam mê phiêu lưu và khám phá của tôi

và trí tưởng tượng. Chúng ta mong đợi điều này ở trẻ em. Chúng ta muốn chúng chơi theo cách này.

Cho đến khi, tất nhiên, họ “quá lớn” cho những thứ như vậy. Khi đó, chúng ta lại muốn họ.

đi học. Sau đó, chúng tôi muốn họ đi làm. Tìm một người bạn đời. Tiết kiệm tiền.

Mua một ngôi nhà.

Bởi vì, bạn biết đấy, thời gian đang trôi.

Bà của tôi là người đầu tiên nói với tôi rằng không nhất thiết phải như vậy.

Theo cách đó. Hoặc, tôi đoán, cô ấy không nói với tôi nhiều như là chỉ cho tôi thấy.

Cô đã lớn lên ở Hungary, nơi cô đã trải qua những mùa hè Bohemian.

bơi trong làn nước mát của hồ Balaton và đi bộ đường dài ở những ngọn núi của nó

bờ biển phía bắc tại một khu nghỉ dưỡng phục vụ cho các diễn viên, họa sĩ và nhà thơ.

các tháng mùa đông, cô ấy đã giúp quản lý một khách sạn ở Buda Hills trước khi người Đức Quốc xã đến.

đã tiếp quản và chuyển đổi nó thành bộ chỉ huy trung tâm của Schutzsta el, hoặc

"SS." in Vietnamese is typically translated as "SS." (the abbreviation remains the same). If you need a specific context, please provide more details.

Mười năm sau chiến tranh, trong những ngày đầu của sự chiếm đóng của Liên Xô,

Cộng sản bắt đầu đóng cửa biên giới. Khi mẹ của cô ấy cố gắng vượt qua.

Cô ấy đã bị bắt, giam giữ và bị kết án hai năm tù.

và đã qua đời ngay sau đó. Trong cuộc nổi dậy Hungary năm 1956, tôi

Bà ngoại đã viết và phát hành các bản tin chống Cộng sản trên đường phố.

của Budapest. Sau khi cuộc cách mạng bị đàn áp, người Soviet bắt đầu bắt giữ hàng chục

của hàng ngàn những người bất đồng chính kiến, và bà đã di cư sang Úc cùng với con trai của bà, cha tôi,

lý do là đây là nơi xa nhất họ có thể tới từ châu Âu.

Cô ấy không bao giờ đặt chân tới châu Âu nữa, nhưng cô ấy đã mang theo mọi thứ của Bohemia.

cô ấy. Tôi đã được nghe nói, cô là một trong những người phụ nữ đầu tiên mặc bikini tại

Nước Úc và bị đuổi khỏi bãi biển Bondi vì điều đó. Cô đã sống ở đây nhiều năm.

New Guinea—mà ngay cả ngày nay vẫn là một trong những nơi gồ ghề nhất trên thế giới.

hành tinh của chúng ta—một mình cô ấy.

Mặc dù dòng máu của cô ấy là người Do Thái Ashkenazi và cô đã được nuôi dạy một cách...

"Lutheran, bà ngoại tôi là một người rất thế tục. Chúng tôi có tương đương của"

Lời cầu nguyện của Chúa là bài thơ “Bây Giờ Chúng Ta” của tác giả người Anh Alan Alexander Milne.

Là sáu, kết thúc:

Nhưng bây giờ tôi sáu tuổi.

Tôi thông minh như người thông minh.

Vậy tôi nghĩ tôi sẽ được sáu tuổi bây giờ.

mãi mãi và mãi mãi

Cô ấy đã đọc bài thơ đó cho anh trai và tôi nghe đi nghe lại nhiều lần. Cô ấy nói, "sáu".

đó là độ tuổi tuyệt vời nhất, và cô ấy đã nỗ lực hết mình để sống cuộc đời với tinh thần và

sự ngưỡng mộ của một đứa trẻ ở độ tuổi đó.

Ngay cả khi chúng tôi còn rất trẻ, bà tôi không muốn chúng tôi gọi bà là...

“bà ngoại.” Cô cũng không thích thuật ngữ tiếng Hungary “nagymama,” hoặc bất kỳ từ nào khác.

các thuật ngữ thân mật ấm áp khác như “bubbie,” “bà,” và “nana.”

Đối với chúng tôi, những cậu bé, và mọi người khác, cô ấy đơn giản chỉ là Vera.

Vera đã dạy tôi lái xe, lạng lách và nghiêng ngả qua tất cả các làn đường.

“nhảy múa” theo bất kỳ bản nhạc nào trên đài radio của xe. Cô ấy bảo tôi hãy tận hưởng điều đó.

tuổi trẻ, để thưởng thức cảm giác được trẻ. Người lớn, cô ấy nói, luôn làm hỏng mọi thứ.

"Đừng lớn lên, cô ấy nói. Đừng bao giờ lớn lên."

Khi vào những năm 60 và 70 của bà, bà vẫn là người mà chúng ta gọi là "trẻ trung trong tâm hồn."

uống rượu vang với bạn bè và gia đình, ăn món ngon, kể những câu chuyện thú vị

giúp đỡ người nghèo, người ốm, và những người kém may mắn, giả vờ chỉ huy các buổi hòa nhạc

cười khuya đến tận đêm. Theo tiêu chuẩn của hầu hết mọi người, đó là dấu hiệu của một

"Cuộc sống sống đẹp."

Nhưng đúng vậy, thời gian đang trôi.

Vào giữa những năm 80 tuổi, Vera chỉ còn là một cái bóng của chính mình, và thập kỷ cuối cùng của bà.

Cuộc sống thật khó chịu khi chứng kiến. Cô ấy yếu ớt và ốm đau. Cô vẫn còn đủ sự khôn ngoan để

nhấn mạnh rằng tôi phải kết hôn với vị hôn thê của mình, Sandra, nhưng đến lúc đó âm nhạc không còn mang lại niềm vui cho cô ấy nữa và cô ấy

hầu như không ra khỏi ghế; sự năng động từng định hình cô ấy đã biến mất.

Cuối cùng, cô ấy đã từ bỏ hy vọng. “Chỉ đơn giản là vậy thôi,” cô ấy nói với tôi.

Cô ấy đã qua đời ở tuổi 92. Và, theo cách mà chúng ta đã được dạy để suy nghĩ về điều đó.

những điều này, cô ấy đã có một cuộc sống dài và tốt đẹp. Nhưng càng nghĩ về điều đó,

Càng ngày tôi càng tin rằng người mà cô ấy thực sự là đã chết rồi.

nhiều năm vào thời điểm đó.

Việc già đi có thể có vẻ là một sự kiện xa vời, nhưng mỗi chúng ta sẽ trải qua điều đó.

cuối đời. Sau khi chúng ta thở hơi thở cuối cùng, các tế bào của chúng ta sẽ kêu gào đòi oxy, chất độc.

sẽ tích lũy, năng lượng hóa học sẽ bị cạn kiệt, và cấu trúc tế bào sẽ

vỡ vụn. Vài phút sau, tất cả kiến thức, trí tuệ và kỷ niệm

những thứ mà chúng tôi trân quý, và tất cả tiềm năng tương lai của chúng ta, sẽ bị xóa sổ một cách không thể đảo ngược.

Tôi đã học được điều này một cách trực tiếp khi mẹ tôi, Diana, qua đời. Cha tôi, người mà tôi...

Anh trai và tôi đã ở đó. Đó là một cái chết nhanh chóng, may mắn, do sự tích tụ gây ra.

của dịch trong phổi còn lại của cô ấy. Chúng tôi vừa mới cười đùa cùng nhau về việc

điếu văn tôi đã viết trên chuyến đi từ Hoa Kỳ đến Úc, và sau đó

đột ngột cô ấy quằn quại trên giường, thở hổn hển tìm kiếm không khí mà không thể làm thoả mãn được cô.

"Nhu cầu oxy của cơ thể, nhìn chúng ta với sự tuyệt vọng trong ánh mắt."

Tôi nghiêng người vào và thì thầm vào tai cô ấy rằng cô là người mẹ tuyệt vời nhất mà tôi có thể có.

mong muốn. Chỉ trong vài phút, các nơ-ron của cô ấy đang chết đi, xóa đi không chỉ sự

kỷ niệm của những lời cuối cùng tôi dành cho cô ấy nhưng tất cả những kỷ niệm của cô ấy. Tôi biết một số người

"chết yên bình. Nhưng đó không phải là những gì xảy ra với mẹ tôi. Trong những khoảnh khắc đó"

Cô ấy đã biến đổi từ người đã nuôi dưỡng tôi thành một người co giật.

đám tế bào nghẹt thở, chiến đấu vì những dấu vết cuối cùng của năng lượng đang được tạo ra tại

cấp độ nguyên tử của sự tồn tại của cô ấy.

Mọi điều tôi có thể nghĩ là “Không ai nói cho bạn biết cái cảm giác chết đi như thế nào. Tại sao không…”

Có ai nói với bạn không?

Có rất ít người đã nghiên cứu cái chết một cách sâu sắc như Thế chiến II.

nhà làm phim tài liệu Claude Lanzmann. Và đánh giá của ông—thật vậy, sự

Cảnh báo—đang gây rùng mình. “Mỗi cái chết đều bạo lực,” ông nói vào năm 2010. “Không có...

cái chết tự nhiên, khác với hình ảnh chúng ta thường vẽ về người cha qua đời một cách yên tĩnh trong

"giấc ngủ của anh, được bao quanh bởi những người thân yêu. Tôi không tin vào điều đó."

Ngay cả khi chúng không nhận ra bạo lực của nó, trẻ em cũng đến để hiểu điều đó.

bi kịch của cái chết đến một cách bất ngờ khi còn quá trẻ. Đến tuổi bốn hoặc năm, họ

biết rằng cái chết xảy ra và là không thể đảo ngược. Đó là một suy nghĩ chấn động đối với họ, một

cơn ác mộng có thật

“MỘT CUỘC SỐNG TỐT ĐẸP, DÀI LÂU.” Bà của tôi “Vera” đã che chở cho người Do Thái trong Thế chiến II, sống trong điều kiện sơ sài.

New Guinea, và đã bị đuổi khỏi bãi biển Bondi vì mặc bikini. Cuộc đời của cô kết thúc là

khó nhìn. “Đây chỉ là cách mọi chuyện diễn ra,” cô ấy nói. Nhưng người mà cô thực sự là đã chết.

nhiều năm vào lúc đó.

Trước tiên, vì nó mang lại sự bình yên, hầu hết trẻ em thích nghĩ rằng có

các nhóm người nhất định được bảo vệ khỏi cái chết: cha mẹ, giáo viên và

chúng. Giữa 5 và 7 tuổi, tuy nhiên, tất cả trẻ em bắt đầu hiểu rõ về điều này.

Tính phổ quát của cái chết. Mỗi thành viên trong gia đình sẽ chết. Mỗi thú cưng. Mỗi cây cối.

Mọi thứ họ yêu. Cả chính họ nữa. Tôi nhớ lần đầu tiên học điều này. Tôi có thể.

cũng rất nhớ con trai lớn của chúng tôi, Alex, đã học nó.

"Ba, con sẽ không luôn có ba ở đây sao?"

“Thật buồn, không có,” tôi nói.

Alex đã khóc trong vài ngày, rồi ngừng lại, và không bao giờ hỏi tôi về điều đó.

Một lần nữa. Và tôi cũng chưa bao giờ nhắc đến nó nữa.

Nó không mất nhiều thời gian để suy nghĩ bi thảm bị chôn vùi sâu trong những ngóc ngách của

tiềm thức của chúng ta. Khi được hỏi liệu chúng có lo lắng về cái chết hay không, trẻ em thường nói

rằng họ không nghĩ về nó. Nếu được hỏi họ nghĩ gì về điều đó, họ sẽ nói rằng đó là

không phải mối bận tâm vì nó chỉ xảy ra trong tương lai xa, khi họ già đi.

Đó là quan điểm mà hầu hết chúng ta duy trì cho đến giữa tuổi năm mươi. Cái chết chỉ đơn giản là

Quá buồn và tê liệt để suy nghĩ về mỗi ngày. Thường thì, chúng ta nhận ra điều đó quá muộn. Khi mà

Khi nó gõ cửa, và chúng ta không chuẩn bị, điều đó có thể là thảm khốc.

Đối với Robin Marantz Henig, một cây bút của New York Times, “cay đắng”.

"Sự thật" về cái chết đến muộn trong cuộc đời, sau khi bà trở thành ông bà.

"Dưới tất cả những khoảnh khắc tuyệt vời mà bạn may mắn được chia sẻ và"

"Hãy tận hưởng," cô ấy viết, "cuộc sống của cháu bạn sẽ là một chuỗi dài những ngày sinh nhật."

"không sống để thấy."

Cần có sự can đảm để suy nghĩ một cách có ý thức về sự sống chết của những người thân yêu trước.

Nó thực sự xảy ra. Cần có nhiều can đảm hơn nữa để suy ngẫm sâu sắc về chính mình.

Đó là diễn viên hài và diễn viên Robin Williams người đầu tiên yêu cầu điều này.

sự can đảm từ tôi qua hình ảnh của John Keating, người thầy và anh hùng trong

bộ phim Xã Hội Những Poets Chết, người thách thức các học sinh tuổi teen của mình nhìn thẳng vào

gương mặt của những cậu bé đã khuất từ lâu trong bức ảnh phai nhạt. 4

“Chúng không khác bạn nhiều lắm, phải không?” Keating nói. “Bất khả chiến bại,”

Như bạn cảm thấy. . . . Đôi mắt của họ đầy hy vọng . . . Nhưng các quý ông, bạn thấy đấy, những cái này

"Các chàng trai bây giờ đang bón phân cho hoa đào."

Keating khuyến khích các cậu bé đến gần hơn để lắng nghe một thông điệp từ.

mộ. Đứng phía sau họ, trong một giọng nói tĩnh lặng, ma quái, anh thì thầm, “Carpe.

"Hãy nắm bắt từng khoảnh khắc. Hãy tận dụng ngày hôm nay, các chàng trai. Hãy làm cho cuộc sống của các bạn trở nên phi thường."

Cảnh đó đã có ảnh hưởng vô cùng lớn đến tôi. Có lẽ tôi sẽ không...

có động lực để trở thành giáo sư tại Harvard nếu không vì điều đó

Bộ phim. Ở độ tuổi 20, tôi cuối cùng đã nghe ai đó nói về điều mà tôi

"Bà ngoại đã dạy tôi từ khi còn nhỏ: Hãy làm phần của mình để nhân loại tồn tại."

Tốt nhất có thể. Đừng lãng phí một khoảnh khắc nào. Hãy ôm lấy tuổi trẻ của bạn; giữ chặt nó lại.

Cố gắng hết sức có thể. Chiến đấu vì điều đó. Chiến đấu vì điều đó. Đừng bao giờ ngừng chiến đấu vì điều đó.

Nhưng thay vì chiến đấu cho tuổi trẻ, chúng ta chiến đấu cho cuộc sống. Hoặc, cụ thể hơn, chúng ta...

đấu tranh chống lại cái chết.

Như một loài, chúng ta đang sống lâu hơn bao giờ hết. Nhưng không khỏe mạnh hơn. Không.

trong thế kỷ qua, chúng ta đã có thêm những năm tháng, nhưng không có thêm

cuộc sống—không phải là cuộc sống đáng sống. 5

Và vì vậy, hầu hết chúng ta, khi nghĩ về việc sống đến 100 tuổi, vẫn nghĩ rằng "Chúa".

"Cấm," vì chúng ta đã thấy những thập kỷ cuối cùng trông như thế nào, và đối với hầu hết.

Mọi người, hầu hết thời gian, họ không trông hấp dẫn chút nào. Máy thở và thuốc.

cocktail. Xương hông gãy và tã. Hóa trị và xạ trị. Phẫu thuật sau.

phẫu thuật sau phẫu thuật. Và hóa đơn bệnh viện; ôi trời ơi, những hóa đơn bệnh viện.

Chúng tôi đang chết dần và đau đớn. Người dân ở các nước giàu thường chi tiêu một cách...

một thập kỷ hoặc hơn chịu đựng bệnh tật sau những căn bệnh ở những giai đoạn cuối của cuộc sống.

nghĩ rằng điều này là bình thường. Khi tuổi thọ tiếp tục tăng ở các quốc gia nghèo hơn, điều này sẽ

trở thành số phận của hàng tỷ người khác. Những thành công của chúng ta trong việc kéo dài sự sống,

nhà phẫu thuật và bác sĩ Atul Gawande đã lưu ý, có tác dụng “làm

"tử vong trải nghiệm y tế."

Nhưng nếu điều đó không cần phải như vậy? Nếu chúng ta có thể trẻ hơn?

lâu hơn? Không phải là nhiều năm hơn mà là hàng thập kỷ. Điều gì sẽ xảy ra nếu những năm cuối cùng đó không trông giống như...

thật sự khác biệt đến mức nào so với những năm trước đó? Và nếu như, bằng

"Cứu lấy bản thân, chúng ta cũng có thể cứu thế giới?"

Có thể chúng ta sẽ không bao giờ có thể là sáu lần nữa—nhưng còn hai mươi sáu hoặc ba mươi sáu thì sao?

"Liệu có thể chơi như những đứa trẻ, sâu hơn vào cuộc sống của chúng ta, mà không lo lắng không?"

Về việc chuyển sang những điều mà người lớn phải làm sớm như vậy? Thì sao nếu tất cả điều đó...

Những điều chúng ta cần nén lại trong những năm thanh thiếu niên không cần phải như vậy.

nén lại sau al? Thì sao nếu chúng ta không bị căng thẳng trong độ tuổi 20? Thì sao nếu chúng ta...

không cảm thấy ở tuổi trung niên trong độ tuổi 30 và 40? Liệu có thể, ở tuổi 50, chúng ta muốn

"để tái phát minh bản thân và không thể nghĩ ra một lý do nào tại sao chúng ta không nên?"

Điều gì sẽ xảy ra nếu, ở độ tuổi 60, chúng ta không phải lo lắng về việc để lại di sản mà bắt đầu?

Một? Thì sao nếu chúng ta không phải lo lắng rằng thời gian đang trôi qua? Và nếu như tôi...

"Tôi đã nói với bạn rằng sớm thôi—thực ra là rất sớm, chúng ta sẽ không?"

Vâng, đó là điều tôi đang nói với bạn.

Tôi thật may mắn vì sau ba mươi năm tìm kiếm sự thật về con người.

Sinh học, tôi thấy mình ở trong một vị trí độc đáo. Nếu bạn đến thăm tôi ở Boston,

Bạn sẽ thấy tôi thường xuyên ở trong phòng thí nghiệm của mình tại Trường Y Harvard.

nơi tôi là giáo sư tại Khoa Di truyền và là đồng giám đốc của Paul

Trung tâm F. Glenn về Cơ chế Sinh học của Lão hóa. Tôi cũng điều hành một phòng thí nghiệm chị em tại

trường đại học của tôi, Đại học New South Wales ở Sydney. Trong các phòng thí nghiệm của tôi, các đội

của những sinh viên xuất sắc và tiến sĩ đã cả tăng tốc và đảo ngược lão hóa trong mô hình

các sinh vật và đã chịu trách nhiệm cho một số nghiên cứu được trích dẫn nhiều nhất trong lĩnh vực này

eld, đã được công bố trong một số tạp chí khoa học hàng đầu thế giới. Tôi cũng là một

người đồng sáng lập một tạp chí, Aging, cung cấp không gian cho các nhà khoa học khác để công bố bài viết.

Nghiên cứu của họ về một trong những câu hỏi thách thức và thú vị nhất của thời đại chúng ta.

và là một đồng sáng lập của Học viện Nghiên cứu Sức khỏe và Tuổi thọ, một nhóm các

hai mươi nhà nghiên cứu hàng đầu về lão hóa trên toàn thế giới.

Trong quá trình cố gắng áp dụng những phát hiện của mình vào thực tiễn, tôi đã giúp bắt đầu một số dự án.

các công ty công nghệ sinh học và ngồi ở vị trí chủ tịch của các hội đồng cố vấn khoa học

của nhiều công ty khác. Những công ty này làm việc với hàng trăm học giả hàng đầu trong

các lĩnh vực khoa học từ nguồn gốc của sự sống đến hệ gen học đến dược phẩm. 7 Tôi

Tôi tất nhiên biết về những phát hiện của phòng thí nghiệm của mình nhiều năm trước khi chúng được thực hiện.

công khai, nhưng qua những mối liên hệ này, tôi cũng nhận thức được nhiều điều khác

những khám phá chuyển mình trước thời gian, đôi khi trước cả một thập kỷ.

Các trang tiếp theo sẽ là thẻ backstage của bạn và chỗ ngồi hàng đầu của bạn.

Đã nhận được sự công nhận tương đương với tước hiệp sĩ ở Úc và đảm nhận

Vai trò của một đại sứ, tôi đã dành khá nhiều thời gian để tóm tắt.

các nhà lãnh đạo chính trị và kinh doanh trên thế giới về những cách mà chúng ta

Sự hiểu biết về lão hóa đang thay đổi - và điều đó có nghĩa gì cho nhân loại trong tương lai.

tiến tới. 8

Tôi đã áp dụng nhiều phát hiện khoa học của mình vào cuộc sống của chính mình, như nhiều người khác cũng vậy.

các thành viên trong gia đình, bạn bè, và đồng nghiệp. Kết quả—mà, nên được

được ghi nhận, hoàn toàn là giai thoại - đang khích lệ. Tôi hiện tại 50 tuổi, và tôi cảm thấy như một

Nhóc. Vợ và bọn trẻ của tôi sẽ nói với bạn rằng tôi cũng hành xử như một đứa trẻ.

Điều đó bao gồm cả việc tò mò, thuật ngữ của Úc chỉ người thích xía vào chuyện người khác.

có phần thắc mắc quá nhiều, có lẽ được bắt nguồn từ những con quạ currawong thường hay đấm

qua các nắp nhôm của những chai sữa được giao đến nhà chúng ta và uống cái đó

Vắt sữa từ chúng. Những người bạn cũ ở trường trung học vẫn thích trêu chọc tôi về việc này.

Mỗi khi họ đến nhà bố mẹ tôi, họ đều thấy tôi đang kéo.

một cái gì đó riêng biệt: kén của một con bướm cưng, nơi trú ngụ cuộn lại của một con nhện, một cái cũ

máy tính, công cụ của cha tôi, một chiếc xe hơi. Tôi đã trở nên khá giỏi trong việc đó. Tôi chỉ không được quá

Giỏi trong việc lắp ráp những thứ này lại với nhau.

Tôi không thể chịu đựng được việc không biết một thứ gì đó hoạt động ra sao hoặc nó đến từ đâu.

Vẫn không thể - nhưng ít nhất bây giờ tôi được trả tiền cho điều đó.

Ngôi nhà thời thơ ấu của tôi nằm chênh vênh trên sườn núi đá. Phía dưới là một con sông mà

chảy vào cảng Sydney. Arthur Philip, thống đốc đầu tiên của New South

"Wales, đã khám phá những thung lũng này vào tháng 4 năm 1788, chỉ vài tháng sau khi ông ấy và"

Đội hạm đội đầu tiên của lính thủy đánh bộ, tù nhân và gia đình họ đã thành lập một thuộc địa trên...

"bờ biển của cái mà ông gọi là 'bến cảng đẹp nhất và rộng lớn nhất trong vũ trụ.'"

Người có trách nhiệm lớn nhất khiến ông ấy có mặt ở đó là nhà thực vật học Sir Joseph.

"Các ngân hàng, những người đã đi thuyền dọc theo bờ biển Australia mười tám năm trước"

Thuyền trưởng James Cook trong "hành trình vòng quanh thế giới." 9

Sau khi trở về London với hàng trăm mẫu thực vật để gây ấn tượng với ông ấy

Các đồng nghiệp, các ngân hàng đã vận động Vua George III để bắt đầu một thuộc địa hình sự của Anh trên.

lục địa, địa điểm tốt nhất cho điều này, theo ông lập luận, không phải ngẫu nhiên, sẽ là một vịnh

được gọi là "Thực vật học" ở "Mũi Banks." Những người định cư của Đoàn Tàu Đầu Tiên nhanh chóng phát hiện rằng

Vịnh Botany, mặc dù có tên rất xuất sắc, nhưng không có nguồn nước nào.

đã cập bến cảng Sydney và phát hiện một trong những “rias” lớn nhất thế giới, một nơi rất

Một con đường thủy sâu có nhánh hình thành khi hệ thống sông Hawkesbury đã...

bị ngập lụt do mực nước biển dâng lên sau kỷ băng hà cuối cùng.

Lúc 10 tuổi, tôi đã khám phá ra thông qua việc khám phá rằng con sông

Trong vườn sau nhà tôi, chảy xuống Middle Harbor, một nhánh của cảng Sydney.

Nhưng tôi không thể chịu đựng được việc không biết con sông bắt nguồn từ đâu nữa. Tôi cần phải

biết cái gì đó ở đầu nguồn một con sông trông như thế nào.

Tôi đã theo nó ngược dòng, rẽ trái lần đầu tiên nó phân nhánh và rẽ phải lần sau.

đi qua và ra khỏi một vài ngoại ô. Đến lúc hoàng hôn, tôi đã cách xa hàng miles.

nhà, ở phía bên kia ngọn núi cuối cùng trên đường chân trời. Tôi đã phải nhờ một người lạ cho phép tôi

Gọi mẹ tôi để cầu xin bà ấy đến đón tôi. Một vài lần sau đó, tôi đã thử.

Tìm kiếm dòng chảy phía thượng nguồn, nhưng không bao giờ gần đến nguồn. Như Juan.

Ponce de León, nhà thám hiểm người Tây Ban Nha của Florida, nổi tiếng với cuộc tìm kiếm thần thoại của ông.

Để tìm kiếm Suối Nguồn Trẻ, tôi đã thất bại. 11

Kể từ khi tôi còn nhớ, tôi đã muốn hiểu tại sao chúng ta lại già đi.

Nhưng việc tìm nguồn gốc của một quá trình sinh học phức tạp giống như việc tìm kiếm.

mùa xuân ở nguồn một con sông: không dễ dàng.

Trên hành trình của mình, tôi đã đi qua lại và có những ngày tôi muốn.

từ bỏ. Nhưng tôi đã kiên trì. Trên con đường đó, tôi đã thấy nhiều nhánh sông, nhưng

Tôi cũng đã tìm thấy cái mà có thể là nguồn gốc. Trong các trang tiếp theo, tôi sẽ trình bày một cái mới.

ý tưởng về lý do tại sao sự lão hóa phát triển và cách nó phù hợp với những gì tôi gọi là Thông tin

Lý thuyết về Lão hóa. Tôi cũng sẽ cho bạn biết lý do tại sao tôi đã coi lão hóa là một căn bệnh—

bệnh phổ biến nhất—một căn bệnh không chỉ có thể mà còn nên được điều trị tích cực

được điều trị. Đó là phần I.

Trong phần II, tôi sẽ giới thiệu cho bạn những bước có thể thực hiện ngay bây giờ—và

các liệu pháp mới đang được phát triển - có thể làm chậm, ngừng lại hoặc đảo ngược quá trình lão hóa, mang lại

một sự chấm dứt cho sự lão hóa như chúng ta biết đến.

Và vâng, tôi hoàn toàn nhận thức được ý nghĩa của cụm từ "đưa đến sự kết thúc".

“lão hóa như chúng ta biết,” vậy nên, trong phần III, tôi sẽ thừa nhận nhiều tương lai có thể xảy ra.

Những hành động này có thể tạo ra và đề xuất một con đường cho một tương lai mà chúng ta có thể nhìn tới.

về một thế giới mà cách chúng ta có thể đạt được tuổi thọ cao hơn là

thông qua một khoảng thời gian sức khỏe ngày càng tăng, phần đời của chúng ta sống không có bệnh tật

hoặc khuyết tật.

Có rất nhiều người sẽ nói với bạn rằng đó chỉ là một câu chuyện cổ tích—gần giống như cái.

Các tác phẩm của H. G. Wells hơn những tác phẩm của C. R. Darwin. Một số trong số đó rất thông minh.

Một vài người thậm chí là những người hiểu khá rõ sinh học con người và những người mà tôi

tôn trọng

Những người đó sẽ nói với bạn rằng lối sống hiện đại của chúng ta đã nguyền rủa chúng ta với

thời gian sống ngắn lại. Họ sẽ nói bạn khó có khả năng sống đến 100 tuổi và rằng

Con của bạn cũng không có khả năng đạt mốc thế kỷ. Chúng sẽ nói rằng chúng đã

nhìn vào khoa học của mọi thứ và đã thực hiện các dự đoán, và nó chắc chắn không có vẻ gì

Có khả năng rằng các cháu của bạn sẽ không đến được sinh nhật lần thứ 100 của chúng. Và

Họ sẽ nói rằng nếu bạn đạt đến 100 tuổi, có lẽ bạn sẽ không đến đó một cách khỏe mạnh.

Bạn chắc chắn sẽ không ở đó lâu đâu. Và nếu họ cho phép bạn thì mọi người sẽ sống.

dài hơn, họ sẽ nói với bạn rằng đó là điều tồi tệ nhất cho hành tinh này. Con người là

kẻ thù!

Họ có bằng chứng tốt cho tất cả điều này - toàn bộ lịch sử của nhân loại, trong.

Chắc chắn rồi, từng chút một, qua hàng thiên niên kỷ, chúng ta đã thêm năm tháng vào.

"Cuộc sống trung bình của con người, họ sẽ nói. Hầu hết chúng ta không sống qua tuổi 40, và rồi chúng ta lại làm được."

Hầu hết chúng ta không đến được 50, và rồi chúng ta đã đến. Hầu hết chúng ta không đến được 60, và...

sau đó chúng tôi đã làm. 12 Nói chung, những mức tăng này trong tuổi thọ đến khi ngày càng nhiều người trong chúng ta

có được quyền truy cập vào nguồn thực phẩm ổn định và nước sạch. Và chủ yếu là mức trung bình đã

đẩy lên từ dưới; số ca tử vong trong thời kỳ sơ sinh và trẻ em giảm, và

Tuổi thọ trung bình đã tăng. Đây là toán học đơn giản về tỷ lệ tử vong của con người.

Nhưng mặc dù trung bình vẫn tăng lên, giới hạn thì không. Miễn là chúng ta đã

đã ghi chép lịch sử, chúng ta đã biết đến những người đã đạt đến tuổi 100

năm và những người có thể đã sống thêm vài năm nữa. Nhưng rất ít người đạt được

Gần như không ai đạt được 115.

Hành tinh của chúng ta đã là nhà của hơn 100 tỷ người cho đến nay. Chúng ta biết

của chỉ một người, Jeanne Calment ở Pháp, người được cho là đã sống qua tuổi 120.

Hầu hết các nhà khoa học tin rằng bà đã qua đời vào năm 1997 ở tuổi 122, mặc dù cũng có những ý kiến khác.

có thể con gái của cô ấy đã thay thế cô để tránh trả thuế. 13 Dù có hay không

Cô ấy thực sự đã đạt đến độ tuổi đó, thật sự không quan trọng; những người khác đã đến gần trong một...

vài năm ở độ tuổi đó nhưng hầu hết chúng tôi, chính xác là 95 phần trăm, đã chết trước khi đó

100. Vì vậy, điều đó chắc chắn có nghĩa khi mọi người nói rằng chúng ta có thể tiếp tục chạm.

ra khỏi mức trung bình, nhưng chúng tôi không có khả năng thay đổi giới hạn. Họ nói là dễ dàng để

kéo dài tuổi thọ tối đa của chuột hoặc chó, nhưng chúng ta, con người, thì khác.

Chúng ta đang sống quá lâu rồi.

Họ sai.

Cũng có sự khác biệt giữa việc kéo dài cuộc sống và kéo dài sự sống động. Chúng ta

có khả năng cả hai, nhưng chỉ đơn giản là giữ cho mọi người sống—hàng thập kỷ sau khi họ đã sống

trở nên bị chi phối bởi nỗi đau, bệnh tật, sự yếu đuối và bất động—không phải là một đức tính.

Sức sống kéo dài - có nghĩa là không chỉ là thêm nhiều năm sống mà còn là nhiều năm sống tích cực hơn.

Những người khỏe mạnh và hạnh phúc đang đến. Nó sẽ đến sớm hơn hầu hết mọi người.

mong đợi. Khi những đứa trẻ sinh ra hôm nay đến tuổi trung niên,

Jeanne Calment có thể không thậm chí nằm trong danh sách 100 người già nhất thế giới.

thời gian. Và đến đầu thế kỷ tiếp theo, một người 122 tuổi vào ngày của anh ấy

Hoặc có thể nói rằng cái chết của cô ấy đã sống một cuộc đời đầy đủ, mặc dù không đặc biệt dài.

Một trăm hai mươi năm có thể không phải là một trường hợp ngoại lệ mà là một kỳ vọng, vì vậy

nhiều đến nỗi chúng ta thậm chí sẽ không gọi nó là sự sống lâu, mà chúng ta sẽ đơn giản gọi nó là “cuộc sống,” và chúng ta

sẽ nhìn lại với nỗi buồn về khoảng thời gian trong lịch sử của chúng ta mà không như vậy.

Giới hạn tối đa là gì? Tôi không nghĩ có giới hạn nào. Nhiều đồng nghiệp của tôi

Đồng ý. Không có quy luật sinh học nào nói rằng chúng ta phải lão hóa. Những người nói như vậy không biết họ đang nói về điều gì. Chúng ta có thể vẫn còn cách xa điều đó.

từ một thế giới mà cái chết là điều hiếm hoi, nhưng chúng ta không xa việc đẩy nó đi mãi mãi

xa hơn vào tương lai.

Tất cả điều này trên thực tế là không thể tránh khỏi. Sự kéo dài tuổi thọ khỏe mạnh là điều có thể nhìn thấy. Vâng,

Toàn bộ lịch sử của nhân loại gợi ý điều ngược lại. Nhưng khoa học về tuổi thọ

"Sự kéo dài trong thế kỷ này nói rằng những ngõ cụt trước đây là nghèo nàn."

hướng dẫn

Cần có tư duy cấp tiến để bắt đầu tiếp cận điều này sẽ có nghĩa là gì cho

loài của chúng ta. Không có gì trong hàng tỷ năm tiến hóa của chúng ta đã chuẩn bị cho điều này.

Điều này, đó là lý do tại sao nó dễ dàng, và thậm chí hấp dẫn, để tin rằng nó đơn giản không thể.

được hoàn thành.

Nhưng đó là điều mà mọi người đã nghĩ về quyền con người, cho đến khi

"Khoảnh khắc ai đó đã làm điều đó."

Hôm nay, anh em nhà Wright đã trở lại xưởng làm việc của họ và đạt được thành công.

sở hữu những chiếc glider của họ xuống những đụn cát ở Kitty Hawk. Thế giới sắp sửa

thay đổi.

Và cũng giống như đã xảy ra trong những ngày trước 17 tháng 12 năm 1903,

Phần lớn nhân loại không chú ý. Thật sự không có bối cảnh nào để

Xây dựng ý tưởng về ánh sáng có kiểm soát, được cung cấp sức mạnh vào thời điểm đó, vì vậy ý tưởng là.

huyền bí, ma thuật, chất liệu của tiểu thuyết giả tưởng.

Rồi: lifto. Và mọi thứ không còn như xưa nữa.

Chúng ta đang ở một điểm khác của bước ngoặt lịch sử. Những gì trước đây dường như

Ma thuật sẽ trở thành hiện thực. Đây là thời điểm mà nhân loại sẽ định nghĩa lại điều gì là.

có thể; một thời điểm kết thúc điều không thể tránh khỏi.

Thật vậy, đây là thời điểm chúng ta sẽ định nghĩa lại ý nghĩa của việc trở thành con người.

Đây không chỉ là sự khởi đầu của một cuộc cách mạng, mà là sự khởi đầu của một cuộc tiến hóa.

PHẦN I

NHỮNG GÌ CHÚNG TÔI BIẾT

QUÁ KHỨ

MỘT

Sống nguyên thủy

HÃY TƯỞNG TƯỢNG MỘT HÀNH TINH CÓ KÍCH THƯỚC TƯƠI ĐƯỢC VỚI HÀNH TINH CỦA CHÚNG TA, CÁCH SAO CỦA NÓ TƯƠI ĐƯỢC, ĐANG XOAY.

quanh trục của nó nhanh hơn một chút, sao cho một ngày kéo dài khoảng hai mươi giờ. Nó được bao phủ

với một đại dương nông đầy nước mặn và không có lục địa nào đáng nói—chỉ có một số

các chuỗi đảo đen basalt thưa thớt nổi lên trên đường nước.

không khí không có cùng hỗn hợp khí như của chúng ta. Nó là một môi trường ẩm ướt và độc hại.

màng chắn của nitơ, metan và carbon dioxide.

Không có oxy. Không có sự sống.

Bởi vì hành tinh này, hành tinh của chúng ta cách đây 4 tỷ năm, là một nơi tàn nhẫn.

nơi khắc nghiệt. Nóng bức và núi lửa. Điện khí. Dữ dội.

Nhưng điều đó sắp thay đổi. Nước đang tích tụ bên cạnh các lỗ thông hơi nhiệt độ ấm mà

rác một trong những hòn đảo lớn hơn. Các phân tử hữu cơ phủ lên tất cả các bề mặt, có

cưỡi trên lưng của các thiên thạch và sao chổi. Ngồi trên đá núi lửa khô cằn,

các phân tử này sẽ chỉ còn là các phân tử, nhưng khi hòa tan trong những bể nước ấm

nước, qua các chu kỳ ướt và khô ở rìa các hồ, một đặc biệt

Hóa học diễn ra. Khi các axit nucleic tập trung, chúng phát triển thành

polimere, cách mà tinh thể muối hình thành khi một vũng nước bên bờ biển bốc hơi. Những cái này là

các phân tử RNA đầu tiên của thế giới, là tiền thân của DNA. Khi cái ao

vật liệu di truyền nguyên thủy được bao bọc bởi axit béo để hình thành

bong bóng xà phòng siêu nhỏ—màng tế bào đầu tiên. 2

Chẳng bao lâu, có thể chỉ một tuần, trước khi những cái ao nông bị bao phủ.

với một lớp bọt vàng của hàng triệu triệu tế bào tiền thân được lấp đầy bởi các sợi ngắn của

axit nucleic, mà hôm nay chúng ta gọi là gen.

Hầu hết các protocel đều được tái chế, nhưng một số sống sót và bắt đầu tiến hóa.

"các con đường chuyển hóa nguyên thủy, cho đến khi ARN bắt đầu sao chép chính nó."

Điểm này đánh dấu nguồn gốc của sự sống. Giờ đây, khi sự sống đã hình thành - dưới dạng xà phòng axit béo.

các bọt khí chứa vật liệu di truyền—chúng bắt đầu cạnh tranh để giành sự thống trị.

Không có đủ tài nguyên để chia sẻ. Chúc cho kẻ xấu nhất giành chiến thắng.

Ngày này qua ngày khác, những sinh vật siêu nhỏ, mong manh bắt đầu tiến hóa thành

các hình thức tiên tiến hơn, lan tỏa vào các con sông và hồ.

Một mối đe dọa mới xuất hiện: một mùa khô dài. Mức độ của lớp bùn...

mực nước hồ đã giảm vài feet trong mùa khô, nhưng các hồ đã

Luôn luôn dồn lên lại khi những cơn mưa quay trở lại. Nhưng năm nay, nhờ vào sự bất thường.

hoạt động núi lửa mạnh mẽ ở phía bên kia của hành tinh, những cơn mưa hàng năm không

rơi như họ thường làm và những đám mây trôi qua. Các hồ hoàn toàn khô cạn.

Điều còn lại là một lớp vỏ dày, màu vàng phủ lên các đáy hồ. Đó là một hệ sinh thái.

được xác định không phải bởi sự lên xuống hàng năm của nước mà bởi một cách tàn nhẫn

cuộc đấu tranh sinh tồn. Và hơn thế nữa: đó là một cuộc đấu tranh cho tương lai—bởi vì

Các sinh vật sống sót sẽ trở thành tổ tiên của mọi sinh vật sống trong tương lai.

vi khuẩn, nấm, thực vật và động vật.

Trong đám tế bào đang hấp hối này, mỗi tế bào đều cố gắng và vật lộn để sống sót.

tối thiểu nhất về dinh dưỡng và độ ẩm, từng cái đều làm những gì có thể để

trả lời câu đố nguyên thủy để tái tạo, có một loài duy nhất. Hãy gọi nó là Magna.

siêu tồn tại.

Nó không trông khác biệt nhiều so với các sinh vật khác trong ngày, nhưng M.

superstes có một lợi thế rõ ràng: nó đã phát triển một cơ chế di truyền để sinh tồn.

Sẽ có nhiều bước tiến hóa phức tạp hơn trong những kỷ nguyên sắp tới.

"Các thay đổi cực đoan đến mức toàn bộ nhánh sự sống sẽ xuất hiện. Những thay đổi này—"

sản phẩm của đột biến, chèn, tái sắp xếp gen và ngang

chuyển giao gen từ loài này sang loài khác—sẽ tạo ra các sinh vật có

đối xứng hai bên, thị giác lập thể, và thậm chí là ý thức.

So với những điều khác, bước tiến hóa ban đầu này trông có vẻ khá đơn giản.

Đó là một mạch. Một mạch gen.

Mạch bắt đầu với gen A, một người quản lý ngăn cản tế bào sinh sản.

khi thời điểm khó khăn. Điều này rất quan trọng, vì trên hành tinh Trái Đất sơ khai, hầu hết các thời điểm đều là

khó. Mạch này cũng có một gen B, mã hóa cho một protein “im lặng”.

Protein im lặng này tắt gen A khi mọi thứ tốt đẹp, để tế bào có thể tạo ra.

bản sao của chính nó khi và chỉ khi nó và con cái của nó có khả năng sống sót.

Các gen đó không phải là mới. Tất cả đời sống trong hồ đều có hai gen này. Nhưng

Điều làm cho M. superstes trở nên độc đáo là gen ức chế B đã đột biến để mang lại cho nó.

một chức năng thứ hai: nó giúp sửa chữa DNA. Khi DNA của tế bào bị đứt,

Protein tắt mã bởi gen B di chuyển từ gen A để giúp đỡ với DNA.

sửa chữa, làm cho gen A hoạt động. Điều này tạm thời ngừng toàn bộ tình dục và sinh sản.

cho đến khi việc sửa chữa DNA hoàn tất.

Điều này có lý, bởi vì trong khi DNA bị hỏng, tình dục và sinh sản thì vẫn tiếp tục.

những điều cuối cùng mà một sinh vật nên làm. Ở các sinh vật đa bào trong tương lai,

Ví dụ, tế bào mà không ngừng lại khi vượt qua một vết gãy DNA sẽ gần như

chắc chắn mất đi vật chất di truyền. Điều này xảy ra vì DNA bị kéo ra trước khi tế bào

phân chia từ chỉ một vị trí gắn kết trên DNA, kéo theo phần còn lại của

DNA với nó. Nếu DNA bị gãy, một phần của nhiễm sắc thể sẽ bị mất hoặc

Bị lặp lại. Các tế bào sẽ có khả năng chết hoặc nhân lên một cách không kiểm soát thành khối u.

Với một loại bộ giảm âm gen mới có khả năng sửa chữa DNA, M. superstes sở hữu một

Cạnh. Nó co cụm lại khi DNA của nó bị tổn thương, sau đó hồi phục. Nó được siêu chuẩn bị.

để sinh tồn.

SỰ TIẾN HÓA CỦA LÃO HÓA. Một mạch gen 4 tỷ năm tuổi trong các dạng sống đầu tiên sẽ có

đã chuyển sang sinh sản trong khi DNA đang được sửa chữa, cung cấp lợi thế sống sót. Gen A

biến đổi và gene B tạo ra một protein giúp chuyển gene A khi an toàn.

tái sản xuất. Khi DNA bị đứt, protein được tạo ra bởi gen B sẽ rời đi để sửa chữa DNA.

Kết quả là, gen A được kích hoạt để ngừng sinh sản cho đến khi quá trình sửa chữa hoàn tất. Chúng ta đã thừa hưởng

một phiên bản nâng cao của mạch sinh tồn này.

Và điều đó thì tốt, vì bây giờ lại đến một cuộc tấn công nữa vào cuộc sống. Mạnh mẽ.

các tia vũ trụ từ một vụ bùng phát mặt trời xa xôi đang chiếu xuống Trái Đất, xé toạc những

DNA của tất cả các vi sinh vật trong những hồ đang chết. Phần lớn trong số chúng tiếp tục tồn tại.

chia sẻ như thể không có điều gì xảy ra, không biết rằng bộ gen của họ đã bị

Bị hỏng và việc tái tạo sẽ giết chúng. Số lượng DNA không đồng đều là

chia sẻ giữa các tế bào của mẹ và con gái, làm cho cả hai đều bị hỏng.

Cuối cùng, nỗ lực này là vô vọng. Các tế bào sẽ chết, và không còn gì nữa.

Không có gì, nghĩa là, nhưng M. superstes. Bởi vì khi các tia gây ra sự tàn phá, M.

superstes làm điều gì đó khác thường: nhờ vào sự di chuyển của protein B ra xa

từ gen A để giúp sửa chữa các đứt gãy DNA, gen A được kích hoạt và tế bào

dừng hầu như mọi thứ họ đang làm, chuyển hướng năng lượng hạn chế của họ vào

xây dựng lại DNA đã bị đứt. Nhờ vào sự coi thường của nó đối với cổ xưa

"Cần thiết để tái sản xuất, M. superstes đã tồn tại."

Khi thời kỳ khô hạn mới nhất kết thúc và các hồ nước hồi phục, M. superstes tỉnh dậy.

Bây giờ nó có thể tái sản xuất. Lại và lại nó làm như vậy. Nhân lên. Di chuyển đến mới.

hệ sinh thái. Tiến hóa. Tạo ra những thế hệ con cháu mới qua các thế hệ.

Họ là Adam và Eva của chúng ta.

Giống như Adam và Eva, chúng ta không biết liệu M. superstes có từng tồn tại hay không. Nhưng tôi...

Nghiên cứu trong suốt hai mươi lăm năm qua cho thấy rằng mọi sinh vật sống mà chúng ta thấy

Xung quanh chúng ta hôm nay là sản phẩm của một người sống sót vĩ đại, hoặc ít nhất là một nguyên thủy.

Sinh vật rất giống nó. Hồ sơ hóa thạch trong gen của chúng ta đi một chặng đường dài để

chứng minh rằng mọi sinh vật sống chia sẻ hành tinh này với chúng ta vẫn mang theo điều này

mạch di truyền sinh tồn cổ xưa, với hình thức cơ bản gần như giống nhau. Nó vẫn hiện hữu trong

mỗi loại cây. Nó có ở mọi loại nấm. Nó có ở mọi loài động vật.

Nó ở trong chúng ta.

Tôi đề xuất lý do mà mạch gen này được bảo tồn là vì nó khá đơn giản.

và giải pháp thanh thoát cho những thử thách đôi khi thô bạo và đôi khi

thế giới phong phú hơn để đảm bảo sự sống còn của các sinh vật mang nó. Nó

là, về bản chất, một bộ dụng cụ sinh tồn nguyên thủy chuyển hướng năng lượng đến khu vực lớn nhất.

Cần, xing những gì tồn tại trong thời điểm mà những căng thẳng của thế giới đang cấu kết để

Gây ra sự tàn phá trên bộ gen, trong khi cho phép sinh sản chỉ khi nhiều hơn.

Thời điểm thuận lợi sẽ chiếm ưu thế.

Và nó đơn giản và mạnh mẽ đến mức không chỉ đảm bảo sự tiếp tục của cuộc sống.

sự tồn tại trên hành tinh, nó đảm bảo rằng mạch tồn tại hóa học của Trái Đất đã

được truyền từ cha mẹ đến thế hệ sau, biến đổi và cải thiện dần dần, giúp đỡ

Cuộc sống tiếp tục hàng tỷ năm, bất kể vũ trụ mang đến điều gì, và trong

nhiều trường hợp cho phép cuộc sống của cá nhân tiếp tục lâu hơn nhiều so với họ

thực tế và cần thiết phải.

Cơ thể con người, mặc dù còn xa sự hoàn hảo và vẫn đang tiến hóa, mang theo một

phiên bản nâng cao của mạch sinh tồn cho phép nó tồn tại hàng thập kỷ sau đây

thời kỳ sinh sản. Trong khi thật thú vị để suy nghĩ về lý do tại sao chúng ta có tuổi thọ dài.

Nhu cầu cho ông bà giáo dục bộ tộc là một điều thu hút.

thuyết—với sự hỗn loạn tồn tại ở cấp độ phân tử, thật kỳ diệu khi chúng ta

sống sót trong ba mươi giây, chứ chưa nói đến việc đạt đến tuổi sinh sản, chứ chưa nói đến việc đạt đến

80 nhiều hơn là không.

Nhưng chúng tôi làm được. Kỳ diệu thay, chúng tôi làm được. Kỳ tích thay, chúng tôi làm được. Bởi vì chúng tôi là thế hệ kế thừa.

của một dòng dõi rất dài của những người sống sót vĩ đại. Vậy nên, chúng tôi là những người sống sót vĩ đại.

Nhưng có một sự đánh đổi. Đối với mạch này bên trong chúng ta, hậu duệ của một chuỗi

"Các đột biến ở tổ tiên xa xôi nhất của chúng ta cũng là lý do chúng ta lão hóa."

Và đúng rồi, mạo từ xác định số ít đó là chính xác: đó là lý do.

MỌI THỨ ĐỀU CÓ LÝ DO.

Nếu bạn cảm thấy bất ngờ trước quan niệm rằng có một nguyên nhân duy nhất gây lão hóa, bạn...

không phải cô đơn. Nếu bạn chưa bao giờ suy nghĩ về lý do tại sao chúng ta lão hóa, thì đó là

hoàn toàn bình thường, cũng vậy. Nhiều nhà sinh học cũng không nghĩ nhiều về điều đó.

Ngay cả các nhà lão học, những bác sĩ chuyên về lão hóa, thường không hỏi tại sao chúng ta lão hóa.

—họ chỉ đơn giản cố gắng điều trị các hậu quả.

Điều này không phải là một cận thị chỉ dành cho sự lão hóa. Ngay từ cuối những năm 1960, cho...

Ví dụ, cuộc chiến chống lại ung thư là một cuộc chiến chống lại các triệu chứng của nó. Không có.

Giải thích thống nhất về lý do tại sao ung thư xảy ra, vì vậy các bác sĩ đã loại bỏ các khối u một cách tốt nhất.

Họ có thể và đã dành rất nhiều thời gian để bảo bệnh nhân sắp xếp công việc của họ.

Ung thư là “chỉ là cách nó diễn ra,” vì đó là những gì chúng ta nói khi chúng ta không thể.

giải thích điều gì đó.

Sau đó, vào những năm 1970, các gen gây ra ung thư khi bị đột biến đã được phát hiện bởi

các nhà sinh học phân tử Peter Vogt và Peter Duesberg. Những người được gọi là

Các gen ung thư đã thay đổi hoàn toàn mô hình nghiên cứu ung thư. Dược phẩm

các nhà phát triển giờ đây có mục tiêu để theo đuổi: các protein gây khối u được mã hóa bởi

các gen, chẳng hạn như BRAF, HER2 và BCR-ABL. Bằng cách phát minh ra các hóa chất mà

cụ thể nhằm chặn các protein gây ung thư, chúng tôi có thể cuối cùng bắt đầu di chuyển

ra khỏi việc sử dụng bức xạ và các tác nhân hóa trị độc hại để tấn công ung thư

tại nguồn gốc di truyền của chúng, trong khi để các tế bào bình thường không bị ảnh hưởng. Chúng tôi chắc chắn

không chữa được tất cả các loại ung thư trong nhiều thập kỷ kể từ đó, nhưng chúng tôi không còn

tin rằng không thể làm như vậy.

Thật vậy, trong số ngày càng nhiều nhà nghiên cứu ung thư, sự lạc quan

tràn đầy. Và sự hy vọng đó là trung tâm của điều mà có thể nói là nhất

phần đáng nhớ trong bài phát biểu Tình trạng Liên bang cuối cùng của Tổng thống Barack Obama

2016.

“Cho những người thân yêu mà chúng ta đã mất, cho gia đình mà chúng ta vẫn có thể cứu, hãy cùng nhau hành động.”

"Ông Obama nói: 'Mỹ, đất nước chữa trị ung thư một lần và mãi mãi.'"

trong phòng họp của Hạ viện và kêu gọi một “chiến dịch đột phá chống ung thư.”

Khi ông đặt cựu Phó Tổng thống Joe Biden—người có con trai Beau đã qua đời do

ung thư não một năm trước - đảm nhận nỗ lực, ngay cả một số đảng viên Dân chủ

Các kẻ thù chính trị kiên quyết đã gặp khó khăn trong việc ngăn nước mắt rơi.

Trong những ngày và tuần tiếp theo, nhiều chuyên gia ung thư đã nhận thấy rằng điều này sẽ...

cần nhiều hơn một năm còn lại của chính quyền Obama-Biden để

Chấm dứt ung thư. Rất ít trong số những chuyên gia đó, tuy nhiên, đã nói rằng nó hoàn toàn không thể.

Đã xong. Và đó là vì, trong khoảng vài thập kỷ ngắn ngủi, chúng ta đã hoàn toàn

"đã thay đổi cách chúng ta nghĩ về ung thư. Chúng ta không còn chấp nhận nó nữa."

sự không thể tránh khỏi như một phần của điều kiện con người.

Một trong những đột phá hứa hẹn nhất trong thập kỷ qua là

"Liệu pháp điểm kiểm soát miễn dịch, hay đơn giản là “miễn dịch trị liệu.” Tế bào T miễn dịch"

liên tục và tuần tra cơ thể của chúng ta, tìm kiếm các tế bào nổi loạn để xác định và tiêu diệt trước khi

Chúng có thể nhân lên thành một khối u. Nếu không nhờ có các tế bào T, chúng ta sẽ đều phát triển thành ung thư.

Trong độ tuổi đôi mươi của chúng ta. Nhưng các tế bào ung thư bất lương phát triển những cách để đánh lừa các tế bào T phát hiện ung thư.

"điều đó để họ có thể tiếp tục sinh sôi một cách hạnh phúc. Mới nhất và hiệu quả nhất"

Các liệu pháp miễn dịch gắn vào các protein trên bề mặt của tế bào ung thư.

tương đương với việc lấy lớp áo choàng vô hình của tế bào ung thư để tế bào T có thể nhận ra

và giết họ. Mặc dù chưa đến 10 phần trăm tổng số bệnh nhân ung thư hiện tại

"lợi ích từ liệu pháp miễn dịch, số lượng đó nên tăng lên nhờ vào"

Hàng trăm cuộc thử nghiệm hiện đang diễn ra.

Chúng tôi tiếp tục phản đối một căn bệnh mà trước đây chúng tôi từng chấp nhận như số phận, đổ hàng triệu.

mỗi năm vào nghiên cứu, và nỗ lực đang đạt được thành quả. Tỷ lệ sống sót cho

Các loại ung thư chết người đang gia tăng một cách đột ngột. Cảm ơn sự kết hợp của một

Thuốc ức chế BRAF và liệu pháp miễn dịch, sự sống sót của di căn não do melanoma.

Một trong những loại ung thư chết người nhất, đã tăng 91% kể từ năm 2011.

Giữa năm 1991 và 2016, tổng số ca tử vong do ung thư ở Hoa Kỳ.

giảm 27 phần trăm và tiếp tục giảm. 3 Đó là một chiến thắng được đo bằng hàng triệu sinh mạng.

Nghiên cứu lão hóa ngày nay đang ở giai đoạn tương tự như nghiên cứu ung thư vào những năm 1960.

Chúng tôi có hiểu biết vững chắc về cách lão hóa diễn ra và những tác động của nó đối với chúng ta.

và một thỏa thuận mới nổi về những gì gây ra nó và những gì giữ cho nó không xảy ra.

Như nó trông có vẻ, việc điều trị lão hóa sẽ không quá khó, dễ hơn nhiều so với việc chữa trị.

ung thư

Cho đến nửa sau của thế kỷ hai mươi, nó được chấp nhận chung.

các sinh vật già đi và chết "vì lợi ích của loài"—một ý tưởng rằng

có từ thời Aristotle, nếu không muốn nói là còn xa hơn. Ý tưởng này có vẻ khá trực quan. Đây là

Giải thích được cung cấp bởi hầu hết mọi người ở các bữa tiệc. Nhưng nó hoàn toàn sai. Chúng tôi không làm.

không chết để nhường chỗ cho thế hệ tiếp theo.

Vào thập niên 1950, khái niệm "lựa chọn nhóm" trong tiến hóa đang dần bị lãng quên.

phong cách, gợi ý ba nhà sinh học tiến hóa, J. B. S. Haldane, Peter B.

Medawar và George C. Williams đã đề xuất một số ý tưởng quan trọng về lý do tại sao

Chúng ta già đi. Khi nói đến tuổi thọ, họ đồng ý rằng các cá nhân quan tâm đến

chính họ. Bị thúc đẩy bởi những gen vị kỷ của mình, họ tiếp tục tiến lên và cố gắng sinh sản để đạt được

dài và nhanh nhất có thể, miễn là nó không giết họ. (Trong một số trường hợp,

Tuy nhiên, họ thúc ép quá nhiều, như tổ tiên vĩ đại của tôi, Miklós Vitéz, một

Nhà biên kịch Hungary đã chứng minh cho cô dâu của mình, kém ông bốn mươi lăm tuổi, trong ngày cưới của họ.

đêm tân hôn.)

"Nếu gen của chúng ta không bao giờ muốn chết, tại sao chúng ta không sống mãi mãi? Bộ ba của"

Các nhà sinh vật học lập luận rằng chúng ta trải qua lão hóa vì các lực của chọn lọc tự nhiên.

Cần thiết để xây dựng một cơ thể khỏe mạnh có thể mạnh mẽ khi chúng ta 18 tuổi nhưng sẽ suy giảm.

nhanh chóng khi chúng tôi đạt 40, vì khi đó chúng tôi có thể đã nhân bản các gen sel sh của mình trong

biện pháp đủ để đảm bảo sự tồn tại của họ. Cuối cùng, các lực lượng tự nhiên

Lựa chọn đạt đến số không. Các gen tiếp tục tiến bước. Chúng ta thì không.

Medawar, người có sở thích với lời lẽ dài dòng, đã trình bày về một lý thuyết tinh vi.

được gọi là "đa hình đối kháng." Nói đơn giản, nó nói rằng các gen giúp chúng ta sinh sản

Khi chúng ta trẻ, không chỉ trở nên ít hữu ích hơn khi già đi, họ thực sự có thể...

trở lại cắn chúng ta khi chúng ta già.

Hai mươi năm sau, Thomas Kirkwood tại Đại học Newcastle đã hình thành ý tưởng về

câu hỏi về lý do tại sao chúng ta lão hóa liên quan đến nguồn lực có sẵn của một sinh vật. Được biết đến với tên gọi

Giả thuyết "Soma có thể tiêu hủy," nó dựa trên thực tế rằng luôn luôn có

tài nguyên hạn chế có sẵn cho các loài—năng lượng, dinh dưỡng, nước. Do đó, chúng

tiến hóa đến mức nằm ở đâu đó giữa hai lối sống rất khác biệt: giống nòi

"Sống nhanh và chết trẻ, hoặc sinh sản chậm và bảo vệ soma, hay cơ thể của bạn. Kirkwood"

lập luận rằng các sinh vật không thể sinh sản nhanh và duy trì một cơ thể khỏe mạnh, vững chắc—

Không đủ năng lượng để làm cả hai. Nói cách khác, trong lịch sử.

của cuộc sống, bất kỳ loài sinh vật nào có đột biến khiến nó sống nhanh và cố gắng

"để chết già sớm đã cạn kiệt tài nguyên và do đó đã bị xóa khỏi nguồn gen."

Lý thuyết của Kirkwood được minh họa tốt nhất bằng những tình huống hư cấu nhưng có thể là thực tế.

Ví dụ. Hãy tưởng tượng bạn là một loài gặm nhấm nhỏ có khả năng bị một con chim bắt được.

của con mồi. Vì lý do này, bạn sẽ cần phải truyền lại vật chất di truyền của mình một cách nhanh chóng,

cũng như cha mẹ của bạn và ông bà của họ trước đây. Các tổ hợp gen mà

sẽ cung cấp một cơ thể bền lâu hơn nếu không được làm giàu trong loài của bạn

bởi vì tổ tiên của bạn có thể đã không thoát khỏi sự săn mồi lâu dài (và bạn cũng sẽ không).

hoặc).

Bây giờ hãy tưởng tượng rằng bạn là một loài chim săn mồi ở đỉnh của chuỗi thức ăn.

Vì lý do này, gen của bạn—thực ra là gen của tổ tiên bạn—đã được hưởng lợi.

từ việc xây dựng một cơ thể chắc khỏe, lâu dài hơn có thể sinh sản trong nhiều thập kỷ. Nhưng trong

trở lại, họ chỉ có thể đủ khả năng nuôi chỉ một vài con chim non mỗi năm.

Giả thuyết của Kirkwood giải thích tại sao một con chuột sống được 3 năm trong khi một số loài chim...

có thể sống đến 100,5. Nó cũng giải thích một cách khá tinh tế lý do tại sao tắc kè hoa Mỹ.

Thằn lằn, Anolis carolinensis, đang tiến hóa một tuổi thọ dài hơn ngay khi chúng ta nói, đã tìm thấy

một vài thập kỷ trước trên những hòn đảo xa xôi của Nhật Bản mà không có kẻ săn mồi. 6

Những lý thuyết này phù hợp với các quan sát và được chấp nhận rộng rãi. Các cá nhân

Đừng sống mãi mãi vì chọn lọc tự nhiên không chọn sự bất tử.

thế giới mà một kế hoạch cơ thể hiện có hoạt động hoàn hảo để truyền đạt cơ thể

Chọn các gen sh. Và vì tất cả các loài đều có giới hạn về tài nguyên, chúng đã tiến hóa để...

cung cấp năng lượng có sẵn cho sinh sản hoặc cho tuổi thọ, nhưng không cho

cả hai. Điều đó đúng với M. superstes cũng như với tất cả các loài khác mà

đã từng sống trên hành tinh này.

Al, tức là, ngoại trừ một: Homo sapiens.

Tận dụng bộ não tương đối lớn và một nền văn minh phát triển để

vượt qua bàn tay không may mà tiến hóa đã ban tặng—các chi yếu ớt, nhạy cảm

đến lạnh, khứu giác kém, và đôi mắt chỉ nhìn thấy rõ vào ban ngày và trong

quang phổ nhìn thấy - loài rất đặc biệt này tiếp tục đổi mới. Nó có

đã tự cung cấp cho mình một nguồn thực phẩm, dinh dưỡng và nước dồi dào trong khi

giảm tử vong do bị săn mồi, tiếp xúc, bệnh truyền nhiễm và chiến tranh.

Điều này từng là giới hạn cho sự phát triển của nó thành một tuổi thọ dài hơn. Khi chúng được loại bỏ, một...

Vài triệu năm tiến hóa có thể gấp đôi tuổi thọ của nó, đưa nó lại gần hơn với.

tuổi thọ của một số loài khác ở đỉnh cao của chúng. Nhưng sẽ không phải chờ đợi.

Cái đó dài, không gần như vậy. Bởi vì loài này đang nỗ lực làm việc để phát minh.

thuốc và công nghệ để mang lại độ bền vững như một sản phẩm có tuổi thọ lâu hơn.

nghĩa đen và vượt qua những gì tiến hóa đã không cung cấp.

CHẾ ĐỘ KHỦNG HOẢNG

Wilbur và Orvil e Wright không bao giờ có thể chế tạo một máy bay nếu không có một

kiến thức về dòng khí và áp suất âm cũng như một đường hầm gió. Cũng không thể

Hoa Kỳ đã đặt người lên mặt trăng mà không có sự hiểu biết về

kim loại nóng chảy, sự cháy lỏng, máy tính, và một số mức độ tự tin rằng

Mặt trăng không được làm bằng phô mai xanh. 7

Tương tự, nếu chúng ta muốn đạt được tiến bộ thực sự trong nỗ lực giảm bớt sự...

Đau khổ đi kèm với tuổi tác, cái cần thiết là một lời giải thích thống nhất cho lý do tại sao.

Chúng ta lão hóa, không chỉ ở cấp độ tiến hóa mà còn ở cấp độ cơ bản.

Nhưng việc giải thích quá trình lão hóa ở mức độ cơ bản không phải là một nhiệm vụ dễ dàng. Nó sẽ phải

đáp ứng tất cả các luật đã biết của vật lý và tất cả các quy tắc của hóa học và nhất quán với

"nhiều thế kỷ quan sát sinh học. Nó sẽ cần trải qua những điều ít được hiểu nhất."

thế giới giữa kích thước của một phân tử và kích thước của một hạt cát, 8 và nó nên giải thích đồng thời sự sống đơn giản nhất và phức tạp nhất.

máy móc đã từng tồn tại.

Do đó, không có gì ngạc nhiên khi chưa bao giờ có một sự thống nhất.

Lý thuyết về sự lão hóa, ít nhất là không có một lý thuyết nào được chứng minh - mặc dù không phải vì thiếu sự cố gắng.

Một giả thuyết, được đề xuất độc lập bởi Peter Medawar và Leo Szilard,

là việc lão hóa do tổn thương DNA và mất mát di truyền gây ra.

thông tin. Khác với Medawar, người luôn là một nhà sinh vật học, người đã xây dựng một Giải Nobel

Sự nghiệp đoạt giải thưởng trong lĩnh vực miễn dịch học, Szilard đã đến để học sinh vật học ở một

theo cách vòng. Nhà đa tài và phát minh sinh ra ở Budapest sống một cuộc sống du mục.

cuộc sống không có công việc hoặc địa chỉ cố định, thích dành thời gian ở bên

các đồng nghiệp đã thỏa mãn những tò mò về tâm lý của ông về những câu hỏi lớn mà ông đang đối diện

nhân loại. Đầu sự nghiệp của mình, ông là một nhà vật lý hạt nhân tiên phong và một

nhà hợp tác sáng lập trong Dự án Manhattan, đưa vào kỷ nguyên của

chiến tranh hạt nhân. Kinh hoàng trước vô số sinh mạng mà công việc của ông đã góp phần kết thúc, ông

"xoay đầu óc đau khổ của anh ấy về việc làm cho cuộc sống dài tối đa."

Ý tưởng rằng sự tích lũy đột biến gây ra lão hóa đã được các nhà khoa học chấp nhận.

và công chúng giống nhau vào những năm 1950 và 1960, vào thời điểm khi những ảnh hưởng của

"Bức xạ lên DNA con người đang là mối quan tâm của rất nhiều người."

biết chắc chắn rằng bức xạ có thể gây ra đủ loại vấn đề trong chúng ta

Điều đó chỉ gây ra một tập hợp con của các dấu hiệu và triệu chứng mà chúng ta quan sát trong suốt.

lão hóa, 10 vì vậy nó không thể đóng vai trò như một lý thuyết phổ quát.

Vào năm 1963, nhà sinh học người Anh Leslie Orgel đã tham gia vào cuộc tranh luận với...

"Hypothesis về Thảm họa Lỗi," giả thuyết rằng những sai lầm xảy ra trong quá trình

Quá trình sao chép DNA dẫn đến các đột biến trong gen, bao gồm cả những gen cần thiết để

tạo ra các máy móc protein sao chép DNA. Quá trình này ngày càng gây gián đoạn

các quá trình đó, nhân lên trên chính chúng cho đến khi bộ gen của một người đã

đã bị sao chép sai và rơi vào quên lãng. 11

Vào khoảng thời gian mà Szilard đang tập trung vào bức xạ, Denham

Harman, một nhà hóa học tại Shel Oil, cũng đang suy nghĩ theo cách nguyên tử, mặc dù theo cách khác.

cách. Sau khi dành thời gian hoàn thành trường y tại Đại học Stanford, anh ấy

đã đưa ra "Lý thuyết Tự do gốc của Lão hóa," cho rằng lão hóa là do

các electron đơn lẻ bay xung quanh trong các tế bào, gây hại cho DNA thông qua

Sự oxy hóa, đặc biệt là ở ti thể, vì đó là nơi hầu hết các gốc tự do xuất hiện.

được tạo ra. Harman đã dành phần lớn cuộc đời để thử nghiệm lý thuyết.

Tôi đã có dịp gặp gỡ gia đình Harman vào năm 2013. Vợ anh ấy đã nói với tôi.

Giáo sư Harman đã sử dụng liều cao axit alpha-lipoic trong phần lớn thời gian.

của cuộc sống của anh ấy để làm dịu các gốc tự do. Xét rằng anh ấy đã làm việc không mệt mỏi với

Nghiên cứu thậm chí có thể kéo dài đến những năm 90, tôi đoán, ít nhất thì cũng chẳng hại gì.

Trong những năm 1970 và 1980, Harman và hàng trăm các nhà nghiên cứu khác

đã kiểm tra xem các chất chống oxy hóa có kéo dài tuổi thọ của động vật hay không. Kết quả

Tổng thể đều gây thất vọng. Mặc dù Harman có một số thành công trong việc tăng cường...

tuổi thọ trung bình của gặm nhấm, chẳng hạn như với phụ gia thực phẩm butylated

hydroxytoluene, không có loại nào cho thấy sự gia tăng trong thời gian sống tối đa. Nói cách khác,

một nhóm động vật nghiên cứu có thể sống lâu hơn vài tuần, trung bình, nhưng không ai trong số đó

Các loài động vật đang lập kỷ lục về tuổi thọ cá nhân. Khoa học kể từ đó...

đã chứng minh rằng những tác động tích cực đến sức khỏe có thể đạt được từ một chế độ ăn giàu chất chống oxy hóa

chế độ ăn uống có nhiều khả năng được gây ra bởi việc kích thích các cơ chế phòng thủ tự nhiên của cơ thể chống lại

lão hóa, bao gồm việc tăng cường sản xuất các enzyme của cơ thể làm tiêu diệt

các gốc tự do, không phải do hoạt động của chất chống oxy hóa tự nó.

Nếu thói quen cũ khó bỏ, thì ý tưởng về gốc tự do giống như heroin. Lý thuyết là

bị các nhà khoa học bác bỏ trong các phòng thí nghiệm của tôi hơn một thập kỷ trước

tuy nhiên nó vẫn được duy trì rộng rãi bởi những người cung cấp thuốc viên và đồ uống, những người tiếp tay cho một thị trường trị giá 3 đô la

ngành công nghiệp toàn cầu. 13 Với tất cả những quảng cáo đó, không có gì ngạc nhiên khi nhiều

Hơn 60% người tiêu dùng Mỹ vẫn tìm kiếm thực phẩm và đồ uống tốt cho sức khỏe.

nguồn của chất chống oxy hóa.

Các gốc tự do thực sự gây ra sự đột biến. Chắc chắn là như vậy. Bạn có thể tìm thấy sự đột biến.

trong sự phong phú, đặc biệt là trong các tế bào tiếp xúc với thế giới bên ngoài và trong

genomes ti thể của những cá thể già. Sự suy giảm ti thể chắc chắn

một dấu hiệu lão hóa và có thể dẫn đến suy chức năng cơ quan. Nhưng chỉ riêng các đột biến,

đặc biệt và đột biến trong bộ gen hạt nhân, xung đột với một sự gia tăng không ngừng.

số lượng bằng chứng ngược lại

Arlan Richardson và Holly Van Remmen đã dành khoảng một thập kỷ tại

Đại học Texas tại San Antonio kiểm tra xem việc tăng cường tổn thương gốc tự do có...

Các đột biến ở chuột dẫn đến sự lão hóa; nó đã không. Trong phòng thí nghiệm của tôi và những nơi khác, điều này đã được chứng minh.

thật ngạc nhiên là đơn giản để phục hồi chức năng của ty thể ở chuột già

ngụ ý rằng một phần lớn của quá trình lão hóa không phải do đột biến ở ti thể.

DNA, ít nhất không cho đến cuối đời. 17

Mặc dù cuộc thảo luận về vai trò của đột biến DNA hạt nhân trong quá trình lão hóa

tiếp tục, có một thực tế mâu thuẫn với tất cả những lý thuyết này, một cái mà khó khăn.

bác bỏ

Nghịch lý thay, chính Szilard, vào năm 1960, đã khởi xướng sự sụp đổ của lý thuyết của chính ông.

bằng cách tìm hiểu cách sao chép một tế bào người. 18 Sao chép cung cấp cho chúng ta câu trả lời cho

liệu rằng các đột biến có gây ra sự lão hóa hay không. Nếu các tế bào cũ thực sự đã mất đi những gen quan trọng

Thông tin này là nguyên nhân của sự lão hóa, chúng ta không nên có khả năng sao chép mới.

động vật từ những cá nhân già hơn. Các bản sao sẽ được sinh ra với tuổi già.

Đó là một sự hiểu lầm rằng động vật được nhân bản lão hóa sớm. Nó đã được phổ biến rộng rãi

"được duy trì trong phương tiện truyền thông và ngay cả trang web của Viện Y tế Quốc gia cũng nói"

Vậy, đúng là Dol y, con cừu được nhân bản đầu tiên, được tạo ra bởi Keith Campbell.

và Ian Wilmut tại Viện Roslin thuộc Đại học Edinburgh, đã sống

chỉ sống được nửa tuổi thọ bình thường và đã chết vì một bệnh phổi tiến triển. Nhưng rộng rãi

Phân tích di thể của cô ấy không cho thấy dấu hiệu của sự lão hóa sớm. 20 Trong khi đó, danh sách

các loài động vật đã được nhân bản và được chứng minh là sống khỏe mạnh, bình thường

Tuổi thọ hiện nay bao gồm dê, cừu, chuột và bò. 21

Vì thực tế rằng chuyển giao hạt nhân hoạt động trong nhân bản, chúng ta có thể nói rằng

mức độ tin cậy cao rằng lão hóa không phải do các đột biến trong DNA nhân.

Chắc chắn, có thể một số tế bào trong cơ thể không đột biến và đó là những tế bào.

Điều đó cuối cùng dẫn đến việc tạo ra những bản sao thành công, nhưng điều đó có vẻ rất không chắc xảy ra.

Giải thích đơn giản nhất là những con vật già giữ lại tất cả gen cần thiết.

thông tin để tạo ra một động vật hoàn toàn mới, khỏe mạnh và rằng các đột biến là

không phải là nguyên nhân chính gây lão hóa.22

Chắc chắn không có sự nhục nhã nào đối với những nhà nghiên cứu xuất sắc đó rằng các lý thuyết của họ

không chịu được thử thách của thời gian. Đó là điều xảy ra với hầu hết các ngành khoa học, và

có lẽ tất cả sẽ cuối cùng. Trong Cấu trúc của các cuộc cách mạng khoa học, Thomas

Kuhn đã lưu ý rằng phát hiện khoa học không bao giờ hoàn chỉnh; nó trải qua.

predictable stages of evolution. When a theory succeeds at explaining previously

unexplainable observations about the world, it becomes a tool that scientists can

use to discover even more.

Inevitably, however, new discoveries lead to new questions that are not

entirely answerable by the theory, and those questions beget more questions.

Soon the model enters crisis mode and begins to drift as scientists seek to adjust

it, as little as possible, to account for that which it cannot explain.

Crisis mode is always a fascinating time in science but one that is not for the

faint of heart, as doubts about the views of previous generations continue to

grow against the old guard’s protestations. But the chaos is ultimately replaced

by a paradigm shift, one in which a new consensus model emerges that can

explain more than the previous model.

That’s what happened about a decade ago, as the ideas of leading scientists in

the aging eld began to coalesce around a new model—one that suggested that

the reason so many bril iant people had struggled to identify a single cause of

aging was that there wasn’t one.

In this more nuanced view, aging and the diseases that come with it are the

result of multiple “hal marks” of aging:

• Genomic instability caused by DNA damage

• Attrition of the protective chromosomal endcaps, the telomeres

• Alterations to the epigenome that controls which genes are turned on and

off

• Loss of healthy protein maintenance, known as proteostasis

• Deregulated nutrient sensing caused by metabolic changes

• Mitochondrial dysfunction

• Accumulation of senescent zombielike cel s that inflame healthy cel s

• Exhaustion of stem cel s

• Altered intercel ular communication and the production of inflammatory

molecules

Researchers began to cautiously agree: address these hal marks, and you can

slow down aging. Slow down aging, and you can forestal disease. Forestal

disease, and you can push back death.

Take stem cel s, which have the potential to develop into many other kinds of

cel s: if we can keep these undi erentiated cel s from tiring out, they can

continue to generate al the di erentiated cel s necessary to heal damaged tissues

and battle al kinds of diseases.

Meanwhile, we’re improving the rates of acceptance of bone marrow

transplants, which are the most common form of stem cel therapy, and using

stem cel s for the treatment of arthritic joints, type 1 diabetes, loss of vision, and

neurodegenerative diseases such as Alzheimer’s and Parkinson’s. These stem

cel –based interventions are adding years to people’s lives.

Or take senescent cel s, which have reached the end of their ability to divide

but refuse to die, continuing to spit out panic signals that in ame surrounding

cel s: if we can kil o senescent cel s or keep them from accumulating in the rst

place, we can keep our tissues much healthier for longer.

The same can be said for combating telomere loss, the decline in proteostasis,

and al of the other hal marks. Each can be addressed one by one, a little at a

time, in ways that can help us extend human healthspans.

Over the past quarter century, researchers have increasingly homed their

e orts in on addressing each of these hal marks. A broad consensus formed that

this would be the best way to al eviate the pain and su ering of those who are

aging.

There is little doubt that the list of hal marks, though incomplete, comprises

the beginnings of a rather strong tactical manual for living longer and healthier

lives. Interventions aimed at slowing any one of these hal marks may add a few

years of wel ness to our lives. If we can address al of them, the reward could be

vastly increased average lifespans.

As for pushing way past the maximum limit? Addressing these hal marks

might not be enough.

But the science is moving fast, faster now than ever before, thanks to the

accumulation of many centuries of knowledge, robots that analyze tens of

thousands of potential drugs each day, sequencing machines that read mil ions

of genes a day, and computing power that processes tril ions of bytes of data at

speeds that were unimaginable just a decade ago. Theories on aging, which were

slowly chipped away for decades, are now more easily testable and refutable.

Although it is in its early days, a new shift in thinking is again under way.

Once again we nd ourselves in a period of chaos—stil quite con dent that the

hal marks are accurate indicators of aging and its myriad symptoms but unable

to explain why the hal marks occur in the rst place.

THE HALLMARKS OF AGING. Scientists have settled on eight or nine hal marks of aging. Address

one of these, and you can slow down aging. Address al of them, and you might not age.

It is time for an answer to this very old question.

Now, nding a universal explanation for anything—let alone something as

complicated as aging—doesn’t happen overnight. Any theory that seeks to

explain aging must not just stand up to scienti c scrutiny but provide a rational

explanation for every one of the pil ars of aging. A universal hypothesis that

seems to provide a reason for cel ular senescence but not stem cel exhaustion

would, for example, explain neither.

Yet I believe that such an answer exists—a cause of aging that exists upstream

of al the hal marks. Yes, a singular reason why we age.

Aging, quite simply, is a loss of information.

You might recognize that loss of information was a big part of the ideas that

Szilard and Medawar independently espoused, but it was wrong because it

focused on a loss of genetic information.

But there are two types of information in biology, and they are encoded

entirely di erently. The rst type of information—the type my esteemed

predecessors understood—is digital. Digital information, as you likely know, is

based on a nite set of possible values—in this instance, not in base 2 or binary,

coded as 0s and 1s, but the sort that is quaternary or base 4, coded as adenine,

thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA.

Because DNA is digital, it is a reliable way to store and copy information.

Indeed, it can be copied again and again with tremendous accuracy, no di erent

in principle from digital information stored in computer memory or on a DVD.

DNA is also robust. When I rst worked in a lab, I was shocked by how this

“molecule of life” could survive for hours in boiling water and thril ed that it was

recoverable from Neanderthal remains at least 40,000 years old. 23 The

advantages of digital storage explain why chains of nucleic acids have remained

the go-to biological storage molecule for the past 4 bil ion years.

The other type of information in the body is analog.

We don’t hear as much about analog information in the body. That’s in part

because it’s newer to science, and in part because it’s rarely described in terms of

information, even though that’s how it was rst described when geneticists

noticed strange nongenetic e ects in plants they were breeding.

Today, analog information is more commonly referred to as the epigenome,

meaning traits that are heritable that aren’t transmitted by genetic means.

The term epigenetics was rst coined in 1942 by Conrad H. Waddington, a

British developmental biologist, while working at Cambridge University. In the

past decade, the meaning of the word epigenetics has expanded into other areas

of biology that have less to do with heredity—including embryonic

development, gene switch networks, and chemical modi cations of DNA-

packaging proteins—much to the chagrin of orthodox geneticists in my

department at Harvard Medical School.

In the same way that genetic information is stored as DNA, epigenetic

information is stored in a structure cal ed chromatin. DNA in the cel isn’t

ailing around disorganized, it is wrapped around tiny bal s of protein cal ed

histones. These beads on a string self-assemble to form loops, as when you tidy

your garden hose on your driveway by looping it into a pile. If you were to play

tug-of-war using both ends of a chromosome, you’d end up with a six foot-long

string of DNA punctuated by thousands of histone proteins. If you could

somehow plug one end of the DNA into a power socket and make the histones

ash on and o , a few cel s could do you for holiday lights.

In simple species, like ancient M. superstes and fungi today, epigenetic

information storage and transfer is important for survival. For complex life, it is

essential. By complex life, I mean anything made up of more than a couple of

cel s: slime molds, jel y sh, worms, fruit ies, and of course mammals like us.

Epigenetic information is what orchestrates the assembly of a human newborn

made up of 26 bil ion cel s from a single fertilized egg and what al ows the

genetical y identical cel s in our bodies to assume thousands of di erent

modalities.24

If the genome were a computer, the epigenome would be the software. It

instructs the newly divided cel s on what type of cel s they should be and what

they should remain, sometimes for decades, as in the case of individual brain

neurons and certain immune cel s.

That’s why a neuron doesn’t one day behave like a skin cel and a dividing

kidney cel doesn’t give rise to two liver cel s. Without epigenetic information,

cel s would quickly lose their identity and new cel s would lose their identity,

too. If they did, tissues and organs would eventual y become less and less

functional until they failed.

In the warm ponds of the primordial Earth, a digital chemical system was the

best way to store long-term genetic data. But information storage was also

needed to record and respond to environmental conditions, and this was best

stored in analog format. Analog data are superior for this job because they can be

changed back and forth with relative ease whenever the environment within or

outside the cel demands it, and they can store an almost unlimited number of

possible values, even in response to conditions that have never been encountered

before. 25

The unlimited number of possible values is why many audiophiles stil prefer

the rich sounds of analog storage systems. But even though analog devices have

their advantages, they have a major disadvantage. In fact, it’s the reason we’ve

moved from analog to digital. Unlike digital, analog information degrades over

time—fal ing victim to the conspiring forces of magnetic elds, gravity, cosmic

rays, and oxygen. Worse stil , information is lost as it’s copied.

No one was more acutely disturbed by the problem of information loss than

Claude Shannon, an electrical engineer from the Massachusetts Institute of

Technology (MIT) in Boston. Having lived through World War II, Shannon

knew rsthand how the introduction of “noise” into analog radio transmissions

could cost lives. After the war, he wrote a short but profound scienti c paper

cal ed “The Mathematical Theory of Communication” on how to preserve

information, which many consider the foundation of Information Theory. If

there is one paper that propel ed us into the digital, wireless world in which we

now live, that would be it. 26

Shannon’s primary intention, of course, was to improve the robustness of

electronic and radio communications between two points. His work may

ultimately prove to be even more important than that, for what he discovered

about preserving and restoring information, I believe, can be applied to aging.

Don’t be disheartened by my claim that we are the biological equivalent of an

old DVD player. This is actual y good news. If Szilard had turned out to be right

about mutations causing aging, we would not be able to easily address it, because

when information is lost without a backup, it is lost for good. Ask anyone who’s

tried to play or restore content from a DVD that’s had an edge broken o : what

is gone is gone.

But we can usual y recover information from a scratched DVD. And if I am

right, the same kind of process is what it wil take to reverse aging.

As cloning beautiful y proves, our cel s retain their youthful digital

information even when we are old. To become young again, we just need to nd

some polish to remove the scratches.

This, I believe, is possible.

A TIME TO EVERY PURPOSE

The Information Theory of Aging starts with the primordial survival circuit we

inherited from our distant ancestors.

Over time, as you might expect, the circuit has evolved. Mammals, for

instance, don’t have just a couple of genes that create a survival circuit, such as

those that rst appeared in M. superstes. Scientists have found more than two

dozen of them within our genome. Most of my col eagues cal these “longevity

genes” because they have demonstrated the ability to extend both average and

maximum lifespans in many organisms. But these genes don’t just make life

longer, they make it healthier, which is why they can also be thought of as

“vitality genes.”

Together, these genes form a surveil ance network within our bodies,

communicating with one another between cel s and between organs by releasing

proteins and chemicals into the bloodstream, monitoring and responding to

what we eat, how much we exercise, and what time of day it is. They tel us to

hunker down when the going gets tough, and they tel us to grow fast and

reproduce fast when the going gets easier.

And now that we know these genes are there and what many of them do,

scienti c discovery has given us an opportunity to explore and exploit them; to

imagine their potential; to push them to work for us in di erent ways. Using

molecules both natural and novel, using technology both simple and complex,

using wisdom both new and old, we can read them, turn them up and down,

and even change them altogether.

The longevity genes I work on are cal ed “sirtuins,” named after the yeast

SIR2 gene, the rst one to be discovered. There are seven sirtuins in mammals,

SIRT1 to SIRT7, and they are made by almost every cel in the body. When I

started my research, sirtuins were barely on the scienti c radar. Now this family

of genes is at the forefront of medical research and drug development.

Descended from gene B in M. superstes, sirtuins are enzymes that remove

acetyl tags from histones and other proteins and, by doing so, change the

packaging of the DNA, turning genes o and on when needed. These critical

epigenetic regulators sit at the very top of cel ular control systems, control ing

our reproduction and our DNA repair. After a few bil ion years of advancement

since the days of yeast, they have evolved to control our health, our tness, and

our very survival. They have also evolved to require a molecule cal ed

nicotinamide adenine dinucleotide, or NAD. As we wil see later, the loss of

NAD as we age, and the resulting decline in sirtuin activity, is thought to be a

primary reason our bodies develop diseases when we are old but not when we are

young.

Trading reproduction for repair, the sirtuins order our bodies to “buckle

down” in times of stress and protect us against the major diseases of aging:

diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer.

They mute the chronic, overactive in ammation that drives diseases such as

atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma.

They prevent cel death and boost mitochondria, the power packs of the cel .

They go to battle with muscle wasting, osteoporosis, and macular degeneration.

In studies on mice, activating the sirtuins can improve DNA repair, boost

memory, increase exercise endurance, and help the mice stay thin, regardless of

what they eat. These are not wild guesses as to their power; scientists have

established al of this in peer-reviewed studies published in journals such as

Nature, Cell, and Science.

And in no smal measure, because sirtuins do al of this based on a rather

simple program—the wondrous gene B in the survival circuit—they’re turning

out to be more amenable to manipulation than many other longevity genes.

They are, it would appear, one of the rst dominos in the magni cent Rube

Goldberg machine of life, the key to understanding how our genetic material

protects itself during times of adversity, al owing life to persist and thrive for

bil ions of years.

Sirtuins aren’t the only longevity genes. Two other very wel studied sets of

genes perform similar roles, which also have been proven to be manipulable in

ways that can o er longer and healthier lives.

One of these is cal ed target of rapamycin, or TOR, a complex of proteins

that regulates growth and metabolism. Like sirtuins, scientists have found TOR

—cal ed mTOR in mammals—in every organism in which they’ve looked for it.

Like that of sirtuins, mTOR activity is exquisitely regulated by nutrients. And

like the sirtuins, mTOR can signal cel s in stress to hunker down and improve

survival by boosting such activities as DNA repair, reducing in ammation

caused by senescent cel s, and, perhaps its most important function, digesting

old proteins. 27

When al is wel and ne, TOR is a master driver of cel growth. It senses the

amount of amino acids that is available and dictates how much protein is created

in response. When it is inhibited, though, it forces cel s to hunker down,

dividing less and reusing old cel ular components to maintain energy and extend

survival—sort of like going to the junkyard to nd parts with which to x up an

old car rather than buying a new one, a process cal ed autophagy. When our

ancestors were unsuccessful in bringing down a wool y mammoth and had to

survive on meager rations of protein, it was the shutting down of mTOR that

permitted them to survive.

The other pathway is a metabolic control enzyme known as AMPK, which

evolved to respond to low energy levels. It has also been highly conserved among

species and, as with sirtuins and TOR, we have learned a lot about how to

control it.

These defense systems are al activated in response to biological stress. Clearly,

some stresses are simply too great to overcome—step on a snail, and its days are

over. Acute trauma and uncontrol able infections wil kil an organism without

aging that organism. Sometimes the stress inside a cel , such as a multitude of

DNA breaks, is too much to handle. Even if the cel is able to repair the breaks in

the short term without leaving mutations, there is information loss at the

epigenetic level.

Here’s the important point: there are plenty of stressors that wil activate

longevity genes without damaging the cel , including certain types of exercise,

intermittent fasting, low-protein diets, and exposure to hot and cold

temperatures (I discuss this in chapter 4). That’s cal ed hormesis. 28 Hormesis is

general y good for organisms, especial y when it can be induced without causing

any lasting damage. When hormesis happens, al is wel . And, in fact, al is better

than wel , because the little bit of stress that occurs when the genes are activated

prompts the rest of the system to hunker down, to conserve, to survive a little

longer. That’s the start of longevity.

Complementing these approaches are hormesis-mimicking molecules. Drugs

in development and at least two drugs on the market can turn on the body’s

defenses without creating any damage. It’s like making a prank cal to the

Pentagon. The troops and the Army Corps of Engineers are sent out, but there’s

no war. In this way, we can mimic the bene ts of exercise and intermittent

fasting with a single pil (I discuss this in chapter 5).

Our ability to control al of these genetic pathways wil fundamental y

transform medicine and the shape of our everyday lives. Indeed, it wil change

the way we de ne our species.

And yes, I realize how that sounds. So let me explain why.

TWO

THE DEMENTED PIANIST

ON APRIL 15, 2003, NEWSPAPERS, television programs, and websites around the

world carried the story: the mapping of the human genome was complete.

There was just one pesky problem: it real y wasn’t. There were, in fact, huge

gaps in the sequence.

This wasn’t a case of the mainstream news media blowing things out of

proportion. Highly respected scienti c journals such as Science and Nature told

pretty much the same story. It also wasn’t a case of scientists overstating their

work. The truth is simply that, at the time, most researchers involved in the

thirteen-year, $1 bil ion project agreed that we’d come as close as we possibly

could—given the technology of the time—to identifying each of the 3 bil ion

base pairs in our DNA.

The parts of the genome that were missing, general y overlapping sections of

repetitive nucleotides, were just not considered important. These were areas of

the code of life that were once derided as “junk DNA” and that are now a little

better respected but stil general y disregarded as “noncoding.” From the

perspective of many of the best minds in science at the time, those regions were

little more than the ghosts of genomes past, mostly remnants of dead

hitchhiking viruses that had integrated into the genome hundreds of thousands

of years ago. The stu that makes us who we are, it was thought, had largely

been identi ed, and we had what we needed to propel forward our

understanding of what makes us human.

Yet by some estimates, that genetic dark matter accounts for as much as 69

percent of the total genome, 1 and even within the regions general y regarded as

“coding,” some scientists believe, up to 10 percent has yet to be decoded,

including regions that impact aging. 2

In the relatively short time that has come and gone since 2003, we have come

to nd out that within the famous double helix, there were sequences that were

not just unmapped but essential to our lives. Indeed, many thousands of

sequences had gone undetected because the original algorithms to detect genes

were written to disregard any gene less than 300 base pairs long. In fact, genes

can be as short as 21 base pairs, and today we’re discovering hundreds of them al

over the genome.

These genes tel our cel s to create speci c proteins, and these proteins are the

building blocks of the processes and traits that constitute human biology and

lived experiences. And as we get closer to identifying a complete sequence of our

DNA, we’ve come closer to having a “map” of the genes that control so much of

our existence.

Even once we have a complete code, though, there’s something we stil won’t

be able to nd.

We won’t be able to nd an aging gene.

We have found genes that impact the symptoms of aging. We’ve found

longevity genes that control the body’s defenses against aging and thus o er a

path to slowing aging through natural, pharmaceutical, and technological

interventions. But unlike the oncogenes that were discovered in the 1970s and

that have given us a good target for going to battle against cancer, we haven’t

identi ed a singular gene that causes aging. And we won’t.

Because our genes did not evolve to cause aging.

YEAST OF EDEN

My journey toward formulating the Information Theory of Aging was a long

one. And in no smal part, it can be traced to the work of a scientist who toiled

without fame but whose work helped set the stage for a lot of the longevity

research being done around the world today.

His name was Robert Mortimer, and if there was one adjective that seemed

to come up more than any other about him after he passed away, it was “kind.”

“Visionary” was another. “Bril iant,” “inquisitive,” and “hardworking,” too.

But I’ve long been inspired by the example Mortimer set for his fel ow scientists.

Mortimer, who died in 2007, had played a tremendously important role in

elevating Saccharomyces cerevisiae from a seemingly lowly, single-cel ed yeast with

a sweet tooth (its name means “sugar-loving”) to its rightful place as one of the

world’s most important research organisms.

Mortimer col ected thousands of mutant yeast strains in his lab, many of

which had been developed right there at the University of California, Berkeley.

He could have paid for his research, and then some, by charging the thousands

of scientists he supplied through the university’s Yeast Genetic Stock Center.

But anyone, from impecunious undergraduates to tenured professors at the

world’s best-funded research institutions, could browse the center’s catalog,

request any strain, and have it promptly delivered for the cost of postage. 3

And because he made it so easy and so inexpensive, yeast research bloomed.

When Mortimer began working on S. cerevisiae alongside fel ow biologist

John Johnston4 in the 1950s, hardly anyone was interested in yeast. To most, it

didn’t seem we could learn much about our complex selves by studying a tiny

fungus. It was a struggle to convince the scienti c community that yeast could

be useful for something more than baking bread, brewing beer, and vinting

wine.

What Mortimer and Johnston recognized, and what many others began to

realize in the years to come, was that those tiny yeast cel s are not so di erent

from ourselves. For their size, their genetic and biochemical makeup is

extraordinarily complex, making them an exceptional y good model for

understanding the biological processes that sustain life and control lifespans in

large complex organisms such as ourselves. If you are skeptical that a yeast cel

can tel us anything about cancer, Alzheimer’s disease, rare diseases, or aging,

consider that there have been ve Nobel Prizes in Physiology or Medicine

awarded for genetic studies in yeast, including the 2009 prize for discovering

how cel s counteract telomere shortening, one of the hal marks of aging. 5

The work Mortimer and Johnston did—and, in particular, a seminal paper in

1959 that demonstrated that mother and daughter yeast cel s can have vastly

di erent lifespans—would set the stage for a world-shattering change in the way

we view the limits of life. And by the time of Mortimer’s death in 2007, there

were some 10,000 researchers studying yeast around the globe.

Yes, humans are separated from yeast by a bil ion years of evolution, but we

stil have a lot in common. S. cerevisiae shares some 70 percent of our genes. And

what it does with those genes isn’t so di erent from what we do with them. Like

a whole lot of humans, yeast cel s are almost always trying to do one of two

things: either they’re trying to eat, or they’re trying to reproduce. They’re

hungry or they’re horny. As they age, much like humans, they slow down and

grow larger, rounder, and less fertile. But whereas humans go through this

process over the course of many decades, yeast cel s experience it in a week. That

makes them a pretty good place to start in the quest to understand aging.

Indeed, the potential for a humble yeast to tel us so much about ourselves—

and do so quite quickly relative to other research organisms—was a big part of

the reason I decided to begin my career by studying S. cerevisiae. They also smel

like fresh bread.

I met Mortimer in Vienna in 1992, when I was in my early 20s and attending

the International Yeast Conference—yes, there is such a thing—with my two

PhD supervisors, Professor Ian Dawes, a rule-avoiding Australian from the

University of New South Wales, 6 and Professor Richard Dickinson, a rule-

abiding Briton from the University of Cardi , Wales.

Mortimer was in Vienna to discuss a momentous scienti c endeavor: the

sequencing of the yeast genome. I was there to be inspired. And I was. 7 If I’d

harbored any doubts about my decision to dedicate the opening years of my

scienti c career to a single-cel ed fungus, they al went away when I came face to

face with people who were building great knowledge in a eld that had hardly

existed a few decades before.

It was shortly after that conference that one of the world’s top scientists in

the yeast eld, Leonard Guarente of the Massachusetts Institute of Technology,

came to Sydney on holiday to visit Ian Dawes. Guarente and I ended up at a

dinner together, and I made sure I was sitting opposite him.

I was then a graduate student using yeast to understand an inherited

condition cal ed maple syrup urine disease. As you might imagine from its name,

the disease is not something most polite people discuss over dinner. Guarente,

though, engaged me in a scienti c discussion with a curiosity and enthusiasm

that was nothing short of enchanting. The conversation soon turned to his latest

project—he had begun studying aging in yeast the past few months—work that

had its roots in the workable genetic map that Mortimer had completed in the

mid-1970s.

That was it. I had a passion for understanding aging, and I knew something

about wrangling a yeast cel with a microscope and micromanipulator. Those

were essential skil s needed to gure out why yeast age. That night, Guarente and

I agreed on one thing: if we couldn’t solve the problem of aging in yeast, we had

no chance in humans.

I didn’t just want to work with him. I had to work with him.

Dawes wrote him to tel him that I was keen to join his lab and I was “skil ed

at the bench.”

“It would be a pleasure to work with David,” he replied a few weeks later, the

same way he probably did to so many other enthusiastic applicants. “But he’s got

to come with his own funding.” Later I learned he had been excited only because

he’d thought I was the other student he’d met at dinner.

I had a foot in the door, but my chances were slim. At the time, foreigners

weren’t considered for prestigious postdoctoral awards in the United States, but

I insisted I be interviewed and paid for a ight to Boston myself. I was

interviewed by a giant in the stem cel eld, Douglas Melton, for a Helen Hay

Whitney Foundation Fel owship, which has been providing research support to

postdoctoral biomedical students since 1947. After waiting in line outside his

o ce with the other four candidates, I had my chance. This was my moment. I

don’t remember being nervous. I gured I probably wouldn’t get the award

anyway. So I went for it.

I told Melton about my lifelong quest to understand aging and nd “life-

giving genes,” then sketched out on his whiteboard how the genes work and

what I’d be doing for the next three years if I got the money. To show my

gratitude, I gave him a bottle of red wine that I’d brought from Australia.

Afterward, two things became clear. One, don’t bring wine to an interview

because it can be seen as a bribe. And two, Melton must have liked what I said

and how I said it, because I ew home, got the fel owship, and then got onto a

plane back to Boston. It was, without a doubt, the most life-changing meeting of

my life. 8

At the time of my arrival, in 1995, I had expected to build our understanding

of aging by studying Werner syndrome, a terrible disease that occurs in less than

1 in 100,000 live births, with symptoms that include a loss of body strength,

wrinkles, gray hair, hair loss, cataracts, osteoporosis, heart problems, and many

other tel tale signs of aging—not among folks in their 70s and 80s but rather

among people in their 30s and 40s. Life expectancy for someone with Werner is

46 years.

Within two weeks of my arrival in the United States, though, a research team

at the University of Washington, headed by the wise and supportive grandfather

of aging research, George Martin, announced that they had found the gene that,

when mutated, causes Werner syndrome.9 It was de ating at the time to have

been “scooped,” but the discovery al owed me to take a bigger rst step toward

my ultimate objective. Indeed, it became the key to formulating the Information

Theory of Aging.

Now that the Werner gene, known as WRN, had been identi ed in humans,

the next step was to test if the similar gene in yeast had the same function. If so,

we could use yeast to more rapidly determine the cause of Werner syndrome and

perhaps help us better understand aging in general. I marched into Guarente’s

o ce to tel him I was now studying Werner’s syndrome in yeast and that’s how

we would solve aging.

In yeast, the equivalent of the WRN gene is Slow Growth Suppressor 1, or

SGS1. The gene was already suspected to code for a type of enzyme cal ed a

DNA helicase that untangles tangled strands of DNA before they break.

Helicases are especial y important in repetitive DNA sequences that are

inherently prone to tangling and breaking. Functionality of proteins, such as the

ones coded for by the Werner gene, is therefore vital, since more than half of our

genome is, in fact, repetitive.

Through a gene-swapping process in which cel s are tricked into picking up

extra pieces of DNA, we swapped out the functional SGS1 gene with a mutant

version. In e ect, we were testing to see if it was possible to give the yeast Werner

syndrome.

After the swap, the yeast cel s’ lifespan was cut in half. Ordinarily, this would

not have been news. Many events unrelated to aging—such as being eaten by a

mite, drying out on a grape, or being placed in an oven—can and do shorten the

lifespan of yeast cel s. And here we’d messed with their DNA, which could have

short-circuited the cel s in a thousand di erent ways to cause early death.

But those cel s weren’t just dying. They were dying after a precipitous decline

in health and function. As the SGS1 mutants became older, they slowed down

in their cel cycle. They grew larger. Both male and female “mating-type” genes

(descendants of gene A) were switched on at the same time, so they were sterile

and couldn’t mate. These were al known hal marks of aging in yeast. And it was

happening more quickly in the mutants we’d made. It certainly looked like a

yeast version of Werner’s.

Using specialized stains, we colored the DNA blue and used red for the

nucleolus, which sits inside the nucleus of al eukaryotic cel s. That made it

easier to see under the microscope what was happening at a cel ular level.

And what was happening was fascinating.

The nucleolus is a part of the nucleus in which ribosomal DNA, or rDNA,

resides. rDNA is copied into ribosomal RNA, which is used by ribosome

enzymes to stitch amino acids together to make every new protein.

In the aged SGS1 cel s, the nucleolus looked as if it had exploded. Instead of a

single red crescent swimming in a blue ocean, the nucleolus was scattered into

half a dozen smal islands. It was tragic and beautiful. The picture, which would

later appear in the August 1997 issue of the prestigious journal Science, stil

hangs in my o ce.

What happened next was both enchanting and il uminating. In response to

the damage, like rats to the cal of the Pied Piper, the protein cal ed Sir2—the

rst known sirtuin, which is encoded by the gene SIR2 10 and descended from

gene B—had moved away from the mating genes that control fertility and into

the nucleolus.

That was a beautiful sight to me, but it was a problem for the yeast. Sir2 has

an important job: it is an epigenetic factor, an enzyme that sits on genes, bundles

up the DNA, and keeps them silent. At the molecular level, Sir2 achieves this via

its enzymatic activity, making sure that chemicals cal ed acetyls don’t accumulate

on the histones and loosen the DNA packaging.

When sirtuins left the mating genes—the ones descended from gene A that

control ed fertility and reproduction—the mutant cel s turned on both male

and female genes, causing them to lose their sexual identity, just as in normal old

cel s, but much earlier.

I didn’t understand at rst why the nucleolus was exploding, let alone why

the sirtuins were moving toward it as the cel s grew older. I agonized over the

question for weeks.

And then one night, after a long day in the lab, I woke up with an idea.

It came in the space between sleep-deprived delirium and deep dreaming. The

wisps of a concept. A few words jumbled together. A muddled picture of

something. That was enough, though, to jolt me awake and pul me from my

bed.I grabbed my notebook and went to the kitchen. There, hunched over the

table in the early morning hours of October 28, 1996, I began to write.

I wrote for about an hour, jotting down ideas, drawing pictures, sketching

out graphs, formulating new equations.11 Scienti c observations that had

previously made no sense to me were fal ing perfectly into a larger picture.

Broken DNA causes genome instability, I wrote, which distracts the Sir2

protein, which changes the epigenome, causing the cel s to lose their identity

and become sterile while they xed the damage. Those were the analog scratches

on the digital DVDs. Epigenetic changes cause aging.

There was, I imagined, a singular process that control ed them al . Not a

countless number of separate cel ular changes or diseases. Not even a set of

hal marks that could be addressed one at a time. There was something bigger—

and more singular—than any of that.

This was the foundation for understanding the survival circuit and its role in

aging.

The next day I showed Guarente my notes. I was excited; it felt like the

biggest idea I’d ever had. But I was nervous, too; afraid he would nd a hole in

my logic and tear it apart. Instead, he looked over my notebook quietly, asked a

few questions, and sent me on my way with six words.

“I like it,” he said. “Go prove it.”

THE RECITAL

To understand the Information Theory of Aging, we need to pay another visit to

the epigenome, the part of the cel that the sirtuins help control.

Up close, the epigenome is more complex and wonderful than anything we

humans have invented. It consists of strands of DNA wrapped around spooling

proteins cal ed histones, which are bound up into bigger loops cal ed chromatin,

which are bound up into even bigger loops cal ed chromosomes.

Sirtuins instruct the histone spooling proteins to bind up DNA tightly, while

they leave other regions to ail around. In this way, some genes stay silent, while

others can be accessed by DNA-binding transcription factors that turn genes

on. 12 Accessible genes are said to be in “euchromatin,” while silent genes are in

“heterochromatin.” By removing chemical tags on histones, sirtuins help

prevent transcription factors from binding to genes, converting euchromatin

into heterochromatin.

Every one of our cel s has the same DNA, of course, so what di erentiates a

nerve cel from a skin cel is the epigenome, the col ective term for the control

systems and cel ular structures that tel the cel which genes should be turned on

and which should remain o . And this, far more than our genes, is what actual y

controls much of our lives.

One of the best ways to visualize this is to think of our genome as a grand

piano.13 Each gene is a key. Each key produces a note. And from instrument to

instrument, depending on the maker, the materials, and the circumstances of

manufacturing, each wil sound a bit di erent, even if played the exact same way.

These are our genes. We have about 20,000 of them, give or take a few

thousand.14

Each key can also be played pianissimo (soft) or forte (with force). The notes

can be tenuto (held) or allegretto (played quickly). For master pianists, there are

hundreds of ways to play each individual key and endless ways to play the keys

together, in chords and combinations that create music we know as jazz,

ragtime, rock, reggae, waltzes, whatever.

The pianist that makes this happen is the epigenome. Through a process of

revealing our DNA or bundling it up in tight protein packages, and by marking

genes with chemical tags cal ed methyls and acetyls composed of carbon, oxygen,

and hydrogen, the epigenome uses our genome to make the music of our lives.

Yes, sometimes the size, shape, and condition of a piano dictate what a pianist

can do with it. It’s tough to play a concerto on an eighteen-key toy piano, and

it’s mighty hard to make beautiful music on an instrument that hasn’t been

tuned in fty years. Likewise, the genome certainly dictates what the epigenome

can do. A caterpil ar can’t become a human being, but it can become a butter y

by virtue of changes in epigenetic expression that occur during metamorphosis,

even though its genome never changes. Similarly, the child of two parents from a

long line of people with black hair and brown eyes isn’t likely to develop blond

hair and blue eyes, but twin agouti mice in the lab can turn out brown or

golden, depending on how much the Agouti gene is turned on during gestation

by environmental in uences on the epigenome, such as folic acid, vitamin B12,

genistein from soy, or the toxin bisphenol A. 15

Similarly, among monozygotic human twins, epigenetic forces can drive two

people with the same genome in vastly di erent directions. It can even cause

them to age di erently. You can see this clearly in side-by-side photographs of the

faces of smoking and nonsmoking twins; their DNA is stil largely the same, but

the smokers have bigger bags under their eyes, deeper jowls below their chins,

and more wrinkles around their eyes and mouths. They are not older, but

they’ve clearly aged faster. Studies of identical twins place the genetic in uences

on longevity at between 10 and 25 percent which, by any estimation, is

surprisingly low. 16

Our DNA is not our destiny.

Now imagine you’re in a concert hal . A virtuoso pianist is seated at a

gorgeously polished Steinway grand. The concerto begins. The music is

beautiful, breathtaking. Everything is perfect.

But then, a few minutes into the piece, the pianist misses a key. The rst time

it happens, it’s almost unnoticeable—an extra D, perhaps, in a chord that

doesn’t need that note. Embedded in so many perfectly played notes, hidden

among an otherwise awless chord in an otherwise perfect melody, it’s nothing

to worry about. But then, a few minutes later, it happens again. And then, with

increasing frequency, again and again and again.

It’s important to remember that there is nothing wrong with the piano. And

the pianist is playing most of the notes prescribed by the composer. She’s just

also playing some extra notes. Initial y, this is just annoying. Over time it

becomes unsettling. Eventual y it ruins the concerto. Indeed, we’d assume that

there was something wrong with the pianist. Someone might even rush onto the

stage to make sure she is al right.

Epigenetic noise causes the same kind of chaos. It is driven in large part by

highly disruptive insults to the cel , such as broken DNA, as it was in the original

survival circuit of M. superstes and in the old yeast cel s that lost their fertility.

And this, according to the Information Theory of Aging, is why we age. It’s why

our hair grays. It’s why our skin wrinkles. It’s why our joints begin to ache.

Moreover, it’s why each one of the hal marks of aging occurs, from stem cel

exhaustion and cel ular senescence to mitochondrial dysfunction and rapid

telomere shortening.

This is, I acknowledge, a bold theory. And the strength of a theory is based on

how wel it predicts the results of rigorous experiments, often mil ions of them,

the number of phenomena it can explain, and its simplicity. The theory was

simple, and it explained a lot. As good scientists, what we had left to do was to

try our best to disprove it and see how long it survived.

To get started, Guarente and I had to get our eyes on some yeast DNA.

We used a technique cal ed a Southern blot, a method of separating DNA

based on its size and conformation and lighting it up with a radioactive DNA

probe. In the rst experiment, we noticed something spectacular. Normal y, the

rDNA of a yeast cel that is made visible by a Southern blot is tightly packed, like

a new spool of rope, with a few barely visible wispy loops of supercoiled DNA.

But the rDNA of the yeast cel s we’d created in our lab—the Werner mutants

that seemed to be aging rapidly—were madly unpacking, like a vacuum-sealed

bag of yarn that had been ripped open.

LESSONS FROM YEAST CELLS ABOUT WHY WE AGE. In young yeast cel s, male and female

“mating-type information” (gene A) is kept in the “o ” position by the Sir2 enzyme, the rst

sirtuin (encoded by a descendant of gene B). The highly repetitive ribosomal DNA (rDNA) is

unstable, and toxic DNA circles form; these recombine and eventual y accumulate to toxic levels

in old cel s, kil ing them. In response to DNA circles and the perceived genome instability, Sir2

moves away from silent mating-type genes to help stabilize the genome. Both male and female

genes turn on, causing infertility, the main hal mark of yeast aging.

The rDNA was in a state of chaos. The genome, it seemed, was fragmenting.

DNA was recombining and amplifying, showing up on the Southern blot as

dark spots and wispy circles, depending on how coiled up and twisted they were.

We cal ed those loops extrachromosomal ribosomal DNA circles, or ERCs, and

they were accumulating as the mutants aged.

If we had indeed induced aging, then we would see this same pattern emerge

in yeast cel s that had aged normal y.

We don’t count the age of a single yeast cel with birthday candles. They

simply don’t last that long. Instead, aging in yeast is measured by the number of

times a mother cel divides to produce daughter cel s. In most cases, a yeast cel

gets to about 25 divisions before it dies. That, however, makes obtaining old

yeast cel s an exceptional y chal enging task. Because by the time an average yeast

cel expires, it is surrounded by 225, or 33 mil ion, of its descendants.

It took a week of work, a lot of sleepless nights, and a whole lot of ca einated

beverages to col ect enough regular old cel s. The next day, when I developed the

lm to visualize the rDNA, what I saw astounded me. 17

Just like the mutants, the normal old yeast cel s were packed with ERCs.

That was a “Eureka!” moment. Not proof—a good scientist never has proof

of anything—but the rst substantial con rmation of a theory, the foundation

upon which I and others would build more discoveries in the years to come.

The rst testable prediction was if we put an ERC into very young yeast cel s

—and we devised a genetic trick to do that—the ERCs would multiply and

distract the sirtuins, and the yeast cel s would age prematurely, go sterile, and die

young—and they did. We published that work in December 1997 in the

scienti c journal Cell, and the news broke around the world: “Scientists gured

out a cause of aging.”

It was there and then that Matt Kaeberlein, a PhD student at the time,

arrived at the lab. His rst experiment was to insert an extra copy of SIR2 into

the genome of yeast cel s to see if it could stabilize the yeast genome and delay

aging. When the extra SIR2 was added, ERCs were prevented, and he saw a 30

percent increase in the yeast cel s’ lifespan, as we’d been hoping. Our hypothesis

seemed to be standing up to scrutiny: the fundamental, upstream cause of

sterility and aging in yeast was the inherent instability of the genome.

What emerged from those initial results in yeast, and another decade of

pondering and probing mammalian cel s, was a completely new way to

understand aging, an information theory that would reconcile seemingly

disparate factors of aging into one universal model of life and death. It looked

like this:

Youth → broken DNA → genome instability → disruption of DNA

packaging and gene regulation (the epigenome) → loss of cel identity →

cel ular senescence → disease → death.

The implications were profound: if we could intervene in any of these steps, we

might help people live longer.

But what if we could intervene in al of them? Could we stop aging?

Theories must be tested and tested and tested some more—not just by one

scientist but by many. And to that end, I was fortunate to have been put onto a

research team that included some of the most bril iant and insightful scientists

in the world.

There was Lenny Guarente, our indefatigable mentor. There was also Brian

Kennedy, who started the yeast-aging project in Lenny’s lab and has since played

a tremendously important role in understanding premature aging diseases and

the impact of genes and molecules that increase health and longevity in model

organisms. There were Monica Gotta and Susan Gasser at the University of

Geneva, who are now some of the most in uential researchers in the eld of

gene regulation; Shin-ichiro Imai, now a professor at Washington University,

who discovered that sirtuins are NAD-utilizing enzymes and now does research

into how the body controls sirtuins; Kevin Mil s, who ran a lab in Maine, then

became a cofounder of and chief scienti c o cer at Cyteir Therapeutics, which

develops novel ways to ght cancer and autoimmune diseases; Nicanor

Austriaco, who started the project with Brian, now teacher of biology and

theology at Providence Col ege, a great combo; Tod Smeal, chief scienti c o cer

of cancer biology at the global pharmaceutical company Eli Lil y; David

Lombard, who is now a researcher in the eld of aging at the University of

Michigan; Matt Kaeberlein, a professor at the University of Washington, who is

testing molecules on dog longevity; David McNabb, whose lab at the University

of Arkansas has made key and lifesaving discoveries about fungal pathogens;

Bradley Johnson, an expert on human aging and cancer at the University of

Pennsylvania; and Mala Murthy, a prominent neuroscientist now at Princeton.

Again and again I have been greatly privileged in the matter of those who

work around me. And that was never truer than it was in Guarente’s lab at MIT.

It was a dream team, and I often felt humbled by the people with whom I was

surrounded.

When I began my career in this eld, I dreamt of publishing just one study in

a top-tier journal. During those years, our group was publishing one every few

months.

We demonstrated that the redistribution of Sir2 to the nucleolus is a response

to numerous DNA breakages, which happen as a result of ERCs multiplying

and inserting back into the genome or joining together to form superlarge

ERCs. When Sir2 moves to combat DNA instability, it causes sterility in old,

bloated yeast cel s. That was the rst step of the survival circuit, though at the

time we had no idea that it was as ancient and as essential to our very existence as

it turned out to be.

We told the world that we could give yeast a Werner-like syndrome, causing

exploded nucleoli.18 We described the ways in which mutants of SGS1, those we’d plagued with the yeast equivalent to the Werner syndrome mutation,

accumulated ERCs more rapidly, leading to premature aging and a shortened

lifespan. 19 Crucial y, by demonstrating that if you add an ERC to young cel s

they age prematurely, we had crucial evidence that ERCs don’t just happen

during aging, they cause it. And by arti cial y breaking the DNA in the cel and

watching the cel ular response, we showed why sirtuins move—to help with

DNA repair.20 That turned out to be the second step of the survival circuit.21

The DNA damage that gave rise to the ERCs was distracting Sir2 from the

mating-type genes, causing them to become sterile, a hal mark of yeast aging.

It was epigenomic noise in its purest form.

It took another twenty years to learn if those ndings in yeast were relevant to

organisms more complex than yeast. We mammals have seven sirtuin genes that

have evolved a variety of functions beyond what simple SIR2 can do. Three of

them, SIRT1, SIRT6, and SIRT7, are critical to the control of the epigenome and DNA repair. The others, SIRT3, SIRT4, and SIRT5, reside in

mitochondria, where they control energy metabolism, while SIRT2 buzzes

around the cytoplasm, where it controls cel division and healthy egg

production.

There had been many clues along the way. Brown University’s Stephen

Helfand showed that adding extra copies of the dSir2 gene to fruit ies

suppresses epigenetic noise and extends their lifespan. We found that SIRT1 in

mammals moves from silent genes to help repair broken DNA in mouse and

human cel s. 22 But the true extent to which the survival circuit is conserved between yeast and humans wasn’t ful y known until 2017, when Eva Bober’s

team at the Max Planck Institute for Heart and Lung Research in Bad Nauheim,

Germany, reported that sirtuins stabilize human rDNA. 23 Then, in 2018, Katrin

Chua at Stanford University found that, by stabilizing human rDNA, sirtuins

prevent cel ular senescence—essential y the same antiaging function as we had

found for sirtuins in yeast twenty years earlier.24

That was an astonishing revelation: over a bil ion years of separation between

yeast and us, and, in essence, the circuit hadn’t changed.

By the time those ndings appeared, though, it was clear to me that

epigenomic noise was a likely catalyst of human aging. Two decades of research

had already been leading us in that direction.25

In 1999, I moved from MIT across the river to Harvard Medical School,

where I set up a new lab on aging. There I was hoping to answer a new question

that had increasingly been occupying my thoughts.

I had noticed that yeast cel s fed with lower amounts of sugar were not just

living longer, but their rDNA was exceptional y compact—signi cantly delaying

the inevitable ERC accumulation, catastrophic numbers of DNA breaks,

nucleolar explosion, sterility, and death.

Why was that happening?

THE SURVIVAL CIRCUIT COMES OF AGE

Our DNA is constantly under attack. On average, each of our forty-six

chromosomes is broken in some way every time a cel copies its DNA,

amounting to more than 2 tril ion breaks in our bodies per day. And that’s just

the breaks that occur during replication. Others are caused by natural radiation,

chemicals in our environment, and the X-rays and CT scans that we’re subjected

to. If we didn’t have a way to repair our DNA, we wouldn’t last long. That’s

why, way back in primordium, the ancestors of every living thing on this planet

today evolved to sense DNA damage, slow cel ular growth, and divert energy to

DNA repair until it was xed—what I cal the survival circuit.

Since the yeast work, evidence that yeast aren’t so di erent from us has

continued to accumulate. In 2003, Michael McBurney from the University of

Ottawa in Canada discovered that mouse embryos manipulated to be unable to

produce one of the seven sirtuin enzymes, SIRT1, couldn’t last past the

fourteenth day of development—about two-thirds of the way into a mouse’s

gestation period. 26 Among the reasons, the team reported in the journal Cancer

Cell, was an impaired ability to respond to and repair DNA damage. 27 In 2006,

Frederick Alt, Katrin Chua, and Raul Mostovslavsky at Harvard showed that

mice engineered to lack SIRT6 underwent the typical signs of aging faster along

with shortened lifespans. 28 When the scientists knocked out a cel ’s ability to create this vital protein, the cel lost its ability to repair double-strand DNA

breaks, just as we had showed in yeast back in 1999.

If you are skeptical, and you should be, you might assume these SIRT mutant

mice could just be sick and, therefore, short lived. But adding in more copies of

the sirtuin genes SIRT1 and SIRT6 does just the opposite: it increases the health

and extends the lifespan of mice, just as adding extra copies of the yeast SIR2

gene does in yeast. 29 Credit for these discoveries goes to two of my previous col eagues, Shin-ichiro Imai, my former drinking buddy at the Guarente lab, and

Haim Cohen, my rst postdoc at Harvard.

In yeast, we had shown that DNA breaks cause sirtuins to relocalize away

from silent mating-type genes, causing old cel s to become sterile. That was a

simple system, and we’d gured it out in a few years.

But is the survival circuit causing aging in mammals? What parts of the

system survived the bil ion years, and which are yeast speci c? Those questions

are on the cutting edge of human knowledge right now, but the answers are

beginning to reveal themselves.

What I’m suggesting is that the SIR2 gene in yeast and the SIRT genes in

mammals are al descendants of gene B, the original gene silencer in M.

superstes. 30 Its original job was to silence a gene that control ed reproduction.

In mammals, the sirtuins have since taken on a variety of new roles, not just

as control ers of fertility (which they stil are). They remove acetyls from

hundreds of proteins in the cel : histones, yes, but also proteins that control cel

division, cel survival, DNA repair, in ammation, glucose metabolism,

mitochondria, and many other functions.

I’ve come to think of sirtuins as the directors of a multifaceted disaster

response corps, sending out a variety of specialized emergency teams to address

DNA stability, DNA repair, cel survivability, metabolism, and cel -to-cel

communication. In a way, this is like the command center for the thousands of

utility workers who descended upon Louisiana and Mississippi in the wake of

Hurricane Katrina in 2005. Most of the workers weren’t from the Gulf Coast,

but they came, did their level best to x what was broken, and then went home.

Some were working in the storm-ravaged communities for a few days and others

for a few weeks before returning to their normal lives. And for most, it wasn’t

the rst or last time they had done something like that; anytime there’s a mass

disaster that impacts utilities, they swoop in to help.

When they’re home, those folks take care of the typical business of being at

home: paying bil s, mowing lawns, coaching basebal , whatever. But when

they’re away, helping keep places like the Gulf Coast from descending into

anarchy—a condition that would have had disastrous results for the rest of the

nation—a lot of those things have to be put on hold.

When sirtuins shift from their typical priorities to engage in DNA repair,

their epigenetic function at home ends for a bit. Then, when the damage is xed

and they head back to home base, they get back to doing what they usual y do:

control ing genes and making sure the cel retains its identity and optimal

function.

But what happens when there’s one emergency after another to tend to?

Hurricane after hurricane? Earthquake after earthquake? The repair crews are

away from home a lot. The work they normal y do piles up. The bil s come due,

then overdue, and then the folks from col ections start cal ing. The grass grows

too long, and soon the president of the neighborhood association is sending

nastygrams. The basebal team goes coachless, and the team devolves into the

Bad News Bears. And most of al , one of the most important things they do

while at home—reproducing—doesn’t get done. This form of hormesis, the

original survival circuit, works ne to keep organisms alive in the short term. But

unlike longevity molecules that simply mimic hormesis by tweaking sirtuins,

mTOR, or AMPK, sending out the troops on fake emergencies, these real

emergencies create life-threatening damage.

What could cause so many emergencies? DNA damage. And what causes

that? Wel , over time, life does. Malign chemicals. Radiation. Even normal DNA

copying. These are the things that we’ve come to believe are the causes of aging,

but there is a subtle but vital shift we have to make in that manner of thinking.

It’s not so much that the sirtuins are overwhelmed, though they probably are

when you are sunburned or get an X-ray; what’s happening every day is that the

sirtuins and their coworkers that control the epigenome don’t always nd their

way back to their original gene stations after they are cal ed away. It’s as if a few

emergency workers who came to address the damage done in the Gulf Coast by

Katrina had lost their home address. Then disaster strikes again and again, and

they must redeploy.

Wherever epigenetic factors leave the genome to address damage, genes that

should be o , switch on and vice versa. Wherever they stop on the genome, they

do the same, altering the epigenome in ways that were never intended when we

were born.

Cel s lose their identity and malfunction. Chaos ensues. The chaos

materializes as aging. This is the epigenetic noise that is at the heart of our

uni ed theory.

How does the SIR2 gene actual y turn o genes? SIR2 codes for a specialized

protein cal ed a histone deacetylase, or HDAC, that enzymatical y cleaves the

acetyl chemical tags from histones, which, as you’l recal , causes the DNA to

bundle up, preventing it from being transcribed into RNA.

When the Sir2 enzyme is sitting on the mating-type genes, they remain silent

and the cel continues to mate and reproduce. But when a DNA break occurs,

Sir2 is recruited to the break to remove the acetyl tags from the histones at the

DNA break. This bundles up the histones to prevent the frayed DNA from

being chewed back and to help recruit other repair proteins. Once the DNA

repair is complete, most of the Sir2 protein goes back to the mating-type genes

to silence them and restore fertility. That is, unless there is another emergency,

such as the massive genome instability that occurs when ERCs accumulate in

the nucleoli of old yeast cel s.

For the survival circuit to work and for it to cause aging, Sir2 and other

epigenetic regulators must occur in “limiting amounts.” In other words, the cel

doesn’t make enough Sir2 protein to simultaneously silence the mating-type

genes and repair broken DNA; it has to shuttle Sir2 between the various places

on an “as-needed” basis. This is why adding an extra copy of the SIR2 gene

extends lifespan and delays infertility: cel s have enough Sir2 to repair DNA

breaks and enough Sir2 to silence the mating-type genes.31

Over the past bil ion years, presumably mil ions of yeast cel s have

spontaneously mutated to make more Sir2, but they died out because they had

no advantage over other yeast cel s. Living for 28 divisions was no advantage over

those that lived for 24 and, because Sir2 uses up energy, having more of the

protein may have even been a disadvantage. In the lab, however, we don’t notice

any disadvantage because the yeast are given more sugar than they could possibly

ever eat. By adding extra copies of the SIR2 gene, we gave the yeast cel s what

evolution failed to provide.

If the information theory is correct—that aging is caused by overworked

epigenetic signalers responding to cel ular insult and damage—it doesn’t so

much matter where the damage occurs. What matters is that it is being damaged

and that sirtuins are rushing al over the place to address that damage, leaving

their typical responsibilities and sometimes returning to other places along the

genome where they are silencing genes that aren’t supposed to be silenced. This

is the cel ular equivalent of distracting the cel ular pianist.

To prove that, we needed to break some mouse DNA.

It’s not hard to intentional y break DNA. You can do it with mechanical

shearing. You can do it with chemotherapy. You can do it with X-rays.

But we needed to do it with precision—in a way that wouldn’t create

mutations or impact regions that a ect any cel ular function. In essence, we

needed to attack the wastelands of the genome. To do that, we got our hands on

a gene similar to Cas9, the CRISPR gene-editing tool from bacteria that cuts

DNA at precise places.

The enzyme we chose for our experiments comes from a goopy yel ow slime

mold cal ed Physarum polycephalum, which literal y means “many-headed

slime.” Most scientists believe that this gene, cal ed I- Ppo I, is a parasite that serves

only to copy itself. When it cuts the slime mold genome, another copy of I- Ppo I

is inserted. It is the epitome of a sel sh gene.

That’s in a slime mold, its native habitat. But when I- Ppo I nds itself in a

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mouse cel , it doesn’t have al the slime mold machinery to copy itself. So it oats

around and cuts DNA at just a few places in the mouse genome, and there is no

copying process. Instead, the cel has no problem pasting the DNA strands back

together, leaving no mutations, which is exactly what we were looking for to

engage the survival circuit and distract the sirtuins. DNA-editing genes such as

Cas9 and I- Ppo I are nature’s gifts to science.

To create a mouse to test the information theory, we inserted I- Ppo I into a

circular DNA molecule cal ed a plasmid, along with al the regulatory DNA

elements needed to control the gene, and then inserted that DNA into the

genome of a mouse embryonic stem cel line we were culturing in plastic dishes

in the lab. We then injected the genetical y modi ed stem cel s into a 90-cel

mouse embryo cal ed a blastocyst, implanted it into a female mouse’s uterus, and

waited about twenty days for a baby mouse to show up.

This al sounds complicated, but it’s not. After some training, a col ege

student can do it. It’s such a commodity these days, you can even order a mouse

out of a catalog or pay a company to make you one to your speci cations.

The baby mice were born perfectly normal, as expected, since the cutting

enzyme was switched o at that stage. We cal ed them a ectionately “ICE mice,”

ICE standing for “Inducible Changes to the Epigenome.” The “inducible” part

of the acronym is vital—because there’s nothing di erent about these mice until

we feed them a low dose of tamoxifen. This is an estrogen blocker that is

normal y used to treat human cancers, but in this case, we’d engineered the

mouse so that tamoxifen would turn on the I- Ppo I gene. The enzyme would go

to work, cutting the genome and slightly overwhelming the survival circuit,

without kil ing any cel s. And since tamoxifen has a half-life of only a couple of

days, removing it from the mice’s food would turn o the cutting.

The mice might have died. They might have grown tumors. Or they might

have been perfectly ne, no worse o than if they’d received a dental X-ray.

Nobody had ever done this before in a mouse, so we didn’t know. But if our

hypothesis about epigenetic instability and aging was correct, the tamoxifen

would work like the potion that Fred and George Weasley used to age themselves

in Harry Potter and the Goblet of Fire.

And it worked. Like wizardry, it did.

During the treatment, the mice were ne, oblivious to the DNA cutting and

sirtuin distraction. But a few months later, I got a cal from a postdoc who was

taking care of our lab’s animals while I was on a trip to my lab in Australia.

“One of the mice is real y sick,” she said. “I think we need to put it down.”

I asked her to text me a photo of the mouse she was talking about. When the

photo came over my phone, I couldn’t help but laugh.

“That’s not a sick mouse,” I replied. “That’s an old mouse.”

“David,” she said, “I think you’re mistaken. It says here that it’s the sister of

these other mice in the cage, and they’re perfectly normal.”

Her confusion was understandable. At 16 months old, a regular lab mouse

stil has a thick coat of fur, a sturdy tail, a muscular gure, perky ears, and clear

eyes. A tamoxifen-triggered ICE mouse at the same age has thinning, graying

hair, a bent spine, paper-thin ears, and cloudy eyes.

Remember, we’d done nothing to change the genome. We’d simply broken

the mice’s DNA in places where there aren’t any genes and forced the cel to

paste, or “ligate,” them back together. Just to make sure, later we broke the

DNA in other places, too, with the same results. Those breaks had induced a

sirtuin response. When those xers went to work, their absence from their

normal duties and presence on other parts of the genome altered the ways in

which lots of genes were being expressed at the wrong time.

THE MAKING OF THE ICE MOUSE TO TEST IF THE CAUSE OF AGING MIGHT BE

INFORMATION LOSS. A gene from a slime mold that encodes an enzyme that cuts DNA at a

speci c place was inserted into a stem cel and injected into an embryo to generate the ICE

mouse. Turning on the slime mold gene cut the DNA and distracted the sirtuins, causing the

mouse to undergo aging.

Those ndings were aligned to discoveries being made by Trey Ideker and

Kang Zhang, at UC San Diego, and Steve Horvath, at UCLA. Steve’s name

stuck, and today he’s the namesake of the Horvath Clock—an accurate way of

estimating someone’s biological age by measuring thousands of epigenetic marks

on the DNA, cal ed methylation. We tend to think of aging as something that

begins happening to us at midlife, because that’s when we start to see signi cant

changes to our bodies. But Horvath’s clock begins ticking the moment we are

born. Mice have an epigenetic clock, too. Were the ICE mice older than their

siblings? Yes, they were—about 50 percent older.

We’d found life’s master clock winder.

In another manner of thinking, we’d scratched up the DVD of life about 50

percent faster than it normal y gets scratched. The digital code that is, and was,

the basic blueprint for our mice was the same as it had always been. But the

analog machine built to read that code was able to pick up only bits and pieces

of the data.

Here’s the vital takeaway: we could age mice without a ecting any of the

most commonly assumed causes of aging. We hadn’t made their cel s mutate. We

hadn’t touched their telomeres. We hadn’t messed with their mitochondria. We

hadn’t directly exhausted their stem cel s. Yet the ICE mice were su ering from a

loss of body mass, mitochondria, and muscle strength and an increase in

cataracts, arthritis, dementia, bone loss, and frailty.

Al of the symptoms of aging—the conditions that push mice, like humans,

farther toward the precipice of death—were being caused not by mutation but

by the epigenetic changes that come as a result of DNA damage signals.

We hadn’t given the mice al of those ailments. We had given them aging.

And if you can give something, you can take it away.

FRUIT OF THE SAME TREE

Like the gnarled hands of giant zombies breaking free of the rocky soil, the

ancient bristlecone pine trees of California’s White Mountains strike haunting

silhouettes against the dewy morning sun.

The oldest of these trees have been here since before the pyramids of Egypt

were built, before the construction of Stonehenge, and before the last of the

wool y mammoths left our world. They have shared this planet with Moses,

Jesus, Muhammad, and the rst Buddha. Standing some two miles above sea

level, adding fractions of a mil imeter of growth to their twisted trunks each

year, defying lightning storms and periodic droughts, they are the epitome of

perseverance.

It’s easy to stand in wonder of these great and ancient things. It’s easy to be

swept away by their might and majesty. It’s easy to simply stare at them in awe.

But there’s another way to view these antediluvian patriarchs—a harder way, but

a way in which we should seek to view every living thing on this planet: as our

teachers.

Bristlecones are, after al , our eukaryotic cousins. About half of their genes

are close relatives of ours.

Yet they do not age.

Oh, they add years to their lives—thousands upon thousands of them,

marked by the nearly microscopic rings hidden in their dense heartwood, which

also record in their size, shape, and chemical composition climate events long

past, as when the eruption of Krakatoa sent a cloud of ash around the globe in

1883, leaving a fuzzy ring of growth in 1884 and 1885, barely a centimeter from

the outer ring of bark that marks our current time. 32

Yet even over the course of many thousands of years, their cel s do not appear

to have undergone any decline in function. Scientists cal this “negligible

senescence.” Indeed, when a team from the Institute of Forest Genetics went

looking for signs of cel ular aging—studying bristlecones from 23 to 4,713 years

old—they came up empty-handed. Between young and old trees, their 2001

study found, there were no meaningful di erences in the chemical

transportation systems, in the rate of shoot growth, in the quality of the pol en

they produced, in the size of their seeds, or in the way those seeds germinated.33

The researchers also looked for deleterious mutations—the sorts of which

many scientists at the time expected to be a primary cause of aging. They found

none.34 I expect that if they were to look for epigenetic changes, they would similarly come up empty-handed.

Bristlecones are outliers in the biological world, but they are not unique in

their de ance of aging. The freshwater polyp known as Hydra vulgaris has also

evolved to defy senescence. Under the right conditions, these tiny cnidarians

have demonstrated a remarkable refusal to age. In the wild they might live for

only a few months, subject to the powers of predation, disease, and desiccation.

But in labs around the world they have been kept alive for upward of 40 years—

with no signs that they’l stop there—and indicators of health don’t di er

signi cantly between the very young and the very old.

A couple of species of jel y sh can completely regenerate from adult body

parts, earning them the nickname “immortal jel ies.” Only the elegant moon jel y

Aurelia aurita from the US West Coast and the centimeter-long Turritopsis

dohrnii from the Mediterranean are currently known to regenerate, but I’m

guessing the majority of jel ies do. We just need to look. If you separate one of

these amazing animals into single cel s, the cel s jostle around until they form

clumps that then assemble back into a complete organism, like the T-1000

cyborg in Terminator 2, most likely resetting their aging clock.

Of course, we humans don’t want to be mashed into single cel s to be

immortal. What use is reassembling or spawning if you have no recol ection of

your present life? We may as wel be reincarnated.

What matters is what these biological equivalents of F. Scott Fitzgerald’s

backward-aging Benjamin Button teach us: that cel ular age can be ful y reset,

something I’m convinced we wil be able to do one day without losing our

wisdom, our memories, or our souls.

Though it’s not immortal, the Greenland shark Somniosus microcephalus is

stil an impressive animal and far more closely related to us. About the size of a

great white, it does not even reach sexual maturity until it is 150 years old.

Researchers believe the Arctic Ocean could be home to Greenland sharks that

were born before Columbus got lost in the New World. Radiocarbon dating

estimated that one very large individual may have lived more than 510 years, at

least up until it was caught by scientists so they could measure its age. Whether

this shark’s cel s undergo aging is an open scienti c question; very few biologists

had so much as looked at S. microcephalus until the past few years. At the very

least, this longest-living vertebrate undergoes the process of aging very, very

slowly.

Evolutionarily speaking, al of these life-forms are closer to us than yeast, and

just think of what we’ve learned about human aging from that tiny fungus. But

it is certainly forgivable to consider the distances between pine trees, hydrozoans,

cartilaginous sh, and mammals like ourselves on the enormous tree of life and

say, “No, these things are just too di erent.”

What, then, of another mammal? A warm-blooded, milk-producing, live-

birth-giving cousin?

Back in 2007, aboriginal hunters in Alaska caught a bowhead whale that,

when butchered, was found to have the head of an old harpoon embedded in its

blubber. The weapon, historians would later determine, had been manufactured

in the late 1800s, and they estimated the whale’s age at about 130. That

discovery sparked a new scienti c interest in Balaena mysticetus, and later

research, employing an age-determining method that measures the levels of

aspartic acid in the lens of a whale’s eye, estimated that one bowhead was 211

years old when it was kil ed by native whalers.

That bowheads have been selected for exceptional longevity among mammals

should perhaps not be surprising. They have few predators and can a ord to

build a long-lived body and breed slowly. Most likely they maintain their survival

program on high alert, repairing cel s while maintaining a stable epigenome,

thereby making sure the symphony of the cel s plays on for centuries.

Can these long-lived species teach us how to live healthier and for longer?

In terms of their looks and habitats, pine trees, jel y sh, and whales are

certainly very di erent from humans. But in other ways, we’re very similar.

Consider the bowheads. Like us, they are complex, social, communicative, and

conscious mammals. We share 12,787 known genes, including some interesting

variants in a gene known as FOXO3. Also known as DAF-16, this gene was rst

identi ed as a longevity gene in roundworms by University of California at San

Francisco researcher Cynthia Kenyon. She found it to be essential for defects in

the insulin hormone pathway to double worm lifespan. Playing an integral role

in the survival circuit, DAF-16 encodes a smal transcription factor protein that

latches onto the DNA sequence TTGTTTAC and works with sirtuins to

increase cel ular survival when times are tough. 35

In mammals, there are four DAF-16 genes, cal ed FOXO1, FOXO3, FOXO4,

and FOXO6. If you suspect that we scientists sometimes intentional y

complicate matters, you’d be right, but not in this case. Genes in the same “gene

family” have ended up with di erent names because they were named before

DNA sequences were easily deciphered. It’s similar to the not uncommon

situation in which people have their genome analyzed and learn they have a

sibling on the other side of town. 36 DAF-16 is an acronym for dauer larvae formation. In German, “dauer” means “long lasting,” and this is actual y

relevant to this story. Turns out, worms become dauer when they are starved or

crowded, hunkering down until times improve. Mutations that activate DAF-16

extend lifespan by turning on the worm defense program even when times are

good.

I rst encountered FOXO/DAF-16 in yeast, where it is known as MSN2,

which stands for “multicopy suppressor of SNF1 (AMPK) epigenetic

regulator.” Like DAF-16, MSN2’s job in yeast is to turn on genes that push cel s

away from cel death and toward stress resistance.37 We discovered that when

calories are restricted MSN2 extends yeast lifespan by turning up genes that

recycle NAD, thereby giving the sirtuins a boost. 38

Hidden within the sometimes byzantine way scientists talk about science are

several repeating themes: low energy sensors (SNF1/AMPK), transcription

factors (MSN2/DAF-16/FOXO), NAD and sirtuins, stress resistance, and

longevity. This is no coincidence—these are al key parts of the ancient survival

circuit.

But what about FOXO genes in humans? Certain variants cal ed FOXO3 have

been found in human communities in which people are known to enjoy both

longer lifespans and healthspans, such as the people of China’s Red River

Basin. 39 These FOXO3 variants likely turn on the body’s defenses against diseases and aging, not just when times are tough but throughout life. If you’ve

had your genome analyzed, you can check if you have any of the known

variations of FOXO3 that are associated with a long life. 40 For example, having a C instead of a T variant at position rs2764264 is associated with longer life. Two

of our children, Alex and Natalie, inherited two Cs at this position, one from

Sandra and one from me, so al other genes being equal, and as long as they

don’t live terribly negative lifestyles, they should have greater odds of reaching

age 95 than I do, with my one C and one T, and substantial y greater than

someone with two Ts.

It’s worth pausing to consider how remarkable it is that we nd essential y

the same longevity genes in every organism on the planet: trees, yeast, worms,

whales, and humans. Al living creatures come from the same place in

primordium that we do. When we look through a microscope, we’re al made of

the same stu . We al share the survival circuit, a protective cel ular network that

helps us when times are tough. This same network is our downfal . Severe types

of damage, such as broken strands of DNA, cannot be avoided. They overwork

the survival circuit and change cel ular identity. We’re al subject to epigenetic

noise that should, under the Information Theory of Aging, cause aging.

Yet di erent organisms age at very di erent rates. And sometimes, it appears,

they do not age at al . What al ows a whale to keep the survival circuit on

without disrupting the epigenetic symphony? If the piano player’s skil s are lost,

how is it possible for a jel y sh to restore her ability?

These are the questions that have been guiding my thoughts as I have

considered where our research is headed. What might seem like fanciful ideas, or

concepts straight out of science ction, are rmly rooted in research. Moreover,

they are supported by the knowledge that some of our close relatives have

gured out a workaround to aging.

And if they can, we can, too.

THE LANDSCAPE OF OUR LIVES

Before most people could even fathom the idea of mapping our genome, before

we had the technology to map a cel ’s entire epigenome and understand how it

bundles DNA to turn genes on and o , the developmental biologist Conrad

Waddington was already thinking deeper.

In 1957, the professor of genetics, from the University of Edinburgh, was

trying to understand how an early embryo could possibly be transformed from a

col ection of undi erentiated cel s—each one exactly like the next and with the

exact same DNA—to the thousands of di erent cel types in the human body.

Perhaps not coincidental y, Waddington’s ponderings came in the dawning years

of the digital revolution, at the same time that Grace Hopper, the mother of

computer programming, was laying the foundation for the rst widely used

computer language, COBOL. In essence, what Waddington was seeking to

ascertain was how cel s, al running on the same code, could possibly produce

di erent programs.

There had to be something more than genetics at play: a program that

control ed the code.

Waddington conceived of an “epigenetic landscape,” a three-dimensional

relief map that represents the dynamic world in which our genes exist. More

than half a century later, Waddington’s landscape remains a useful metaphor to

understand why we age.

On the Waddington map, an embryonic stem cel is represented by a marble

at the top of a mountain peak. During embryonic development, the marble rol s

down the hil and comes to rest in one of hundreds of di erent val eys, each

representing a di erent possible cel type in the body. This is cal ed

“di erentiation.” The epigenome guides the marbles, but it also acts as gravity

after the cel s come to rest, ensuring that they don’t move back up the slope or

hop over into another val ey.

The nal resting place is known as the cel ’s “fate.” We used to think this was

a one-way street, an irreversible path. But in biology there is no such thing as

fate. In the last decade, we’ve learned that the marbles in the Waddington

landscape aren’t xed; they have a terrible tendency to move around over time.

At the molecular level, what’s real y going on as the marble rol s down the

slope is that di erent genes are being switched on and o , guided by

transcription factors, sirtuins and other enzymes such as DNA

methyltransferases (DNMTs) and histone methyltransferases (HMTs), which

mark the DNA and its packing proteins with chemical tags that instruct the cel

and its descendants to behave in a certain way.

What’s not general y appreciated, even in scienti c circles, is how important

the stability of this information is for our long-term health. You see, epigenetics

was long the purview of scientists who study the very beginnings of life, not

folks like me who are studying the other end of things.

Once a marble has settled in Waddington’s landscape, it tends to stay there. If

al goes wel with fertilization, the embryo develops into a fetus, then a baby,

then a toddler, then a teenager, then an adult. Things tend to go wel in our

youth. But the clock is ticking.

Every time there’s a radical adjustment to the epigenome, say, after DNA

damage from the sun or an X-ray, the marbles are jostled—envision a smal

earthquake that ever so slightly changes the map. Over time, with repeated

earthquakes and erosion of the mountains, the marbles are moved up the sides

of the slope, toward a new val ey. A cel ’s identity changes. A skin cel starts

behaving di erently, turning on genes that were shut o in the womb and were

meant to stay o . Now it is 90 percent a skin cel and 10 percent other cel types,

al mixed up, with properties of neurons and kidney cel s. The cel becomes inept

at the things skin cel s must do, such as making hair, keeping the skin supple,

and healing when injured.

In my lab we say the cel has ex-differentiated.

Each cel is succumbing to epigenetic noise. The tissue made up of thousands

of cel s is becoming a melange, a medley, a miscel aneous set of cel s.

As you’l recal , the epigenome is inherently unstable because it is analog

information—based on an in nite number of possible values—and thus it’s

di cult to prevent the accumulation of noise and nearly impossible to duplicate

without some information loss. The earthquakes are a fact of life. The landscape

is always changing.

If the epigenome had evolved to be digital rather than analog, the val ey wal s

would be the equivalent of 100 miles high and vertical, and gravity would be

superstrong, so the marbles could never jump over into a new val ey. Cel s would

never lose their identity. If we were built this way, we could be healthy for

thousands of years, perhaps longer.

But we are not built this way. Evolution shapes both genomes and

epigenomes only enough to ensure su cient survival to ensure replacement—

and perhaps, if we are lucky, just a little bit more—but not immortality. So our

val ey wal s are only slightly sloped, and gravity isn’t that strong. A whale that

lives two hundred years has probably evolved steeper val ey wal s and its cel s

maintain their identity for twice as long as ours do. Yet even whales don’t live

forever.

I believe the blame lies with M. superstes and the survival circuit. The

repeated shu ing of sirtuins and other epigenetic factors away from genes to

sites of broken DNA, then back again, while helpful in the short term, is

ultimately what causes us to age. Over time, the wrong genes come on at the

wrong time and in the wrong place.

As we saw in the ICE mice, when you disrupt the epigenome by forcing it to

deal with DNA breaks, you introduce noise, leading to an erosion of the

epigenetic landscape. The mice’s bodies turned into chimeras of misguided,

malfunctioning cel s.

THE CHANGING LANDSCAPE OF OUR LIVES. The Waddington landscape is a metaphor for

how cel s nd their identity. Embryonic cel s, often depicted as marbles, rol downhil and land

in the right val ey that dictates their identity. As we age, threats to survival, such as broken DNA,

activate the survival circuit and rejigger the epigenome in smal ways. Over time, cel s

progressively move towards adjacent val eys and lose their original identity, eventual y

transforming into zombielike senescent cel s in old tissues.

That’s aging. This loss of information is what leads each of us into a world of

heart disease, cancer, pain, frailty, and death.

If the loss of analog information is the singular reason why we age, is there

anything we can do about it? Can we stabilize the marbles, keeping the val ey

wal s high and the gravity strong?

Yes. I can say with con dence that there is.

REVERSAL COMES OF AGE

Regular exercise “is a commitment,” says Benjamin Levine, a professor at the

University of Texas. “But I tel people to think of exercise as part of personal

hygiene, like brushing their teeth. It should be something we do as a matter of

course to keep ourselves healthy. ”41

I’m sure he’s right. Most people would exercise a lot more if going to the gym

were as easy as brushing their teeth.

Perhaps one day it wil be. Experiments in my lab indicate it is possible.

“David, we’ve got a problem,” a postdoctoral researcher named Michael

Bonkowski told me one morning in the fal of 2017 when I arrived at the lab.

That’s seldom a good way to start the day.

“Okay,” I said, taking a deep breath and preparing for the worst. “What is it?”

“The mice,” Bonkowski said. “They won’t stop running.”

The mice he was talking about were 20 months old. That’s roughly the

equivalent of a 65-year-old human. We had been feeding them a molecule

intended to boost the levels of NAD, which we believed would increase the

activity of sirtuins. If the mice were developing a running addiction, that would

be a very good sign.

“But how can that be a problem?” I said. “That’s great news!”

“Wel ,” he said, “it would be if not for the fact that they’ve broken our

treadmil .”

As it turned out, the treadmil tracking program had been set up to record a

mouse running for only up to three kilometers. Once the old mice got to that

point, the treadmil shut down. “We’re going to have to start the experiment

again,” Bonkowski said.

It took a few moments for that to sink in.

A thousand meters is a good, long run for a mouse. Two thousand meters—

ve times around a standard running track—would be a substantial run for a

young mouse.

But there’s a reason why the program was set to three kilometers. Mice simply

don’t run that far. Yet these elderly mice were running ultramarathons.

Why? One of our key ndings, in a study we published in 2018, 42 was that when treated with an NAD-boosting molecule that activated the SIRT1

enzyme, the elderly mice’s endothelial cel s, which line the blood vessels, were

pushing their way into areas of the muscle that weren’t getting very much blood

ow. New tiny blood vessels, capil aries, were formed, supplying badly needed

oxygen, removing lactic acid and toxic metabolites from muscles, and reversing

one of the most signi cant causes of frailty in mice and in humans. That was

how these old mice suddenly became such mighty marathoners.

Because the sirtuins had been activated, the mice’s epigenomes were

becoming more stable. The val ey wal s were growing higher. Gravity was

growing stronger. And Waddington’s marbles were being pushed back to where

they belonged. The lining of the capil aries was responding as if the mice were

exercised. It was an exercise mimetic, the rst of its kind, and a sure sign that

some aspects of age reversal are possible.

We stil don’t know everything about why this happens. We don’t know what

sorts of molecules wil work best for activating sirtuins or in what doses.

Hundreds of di erent NAD precursors have been synthesized, and there are

clinical trials in progress to answer that question and more.

But that doesn’t mean we need to wait to take advantage of al that we’ve

learned about engaging the epigenetic survival circuit and living longer and

healthier lives. We don’t need to wait to take advantage of the Information

Theory of Aging.

There are steps we can take right now to live much longer and much healthier

lives. There are things we can do to slow, stop, and even reverse aspects of aging.

But before we talk about what steps we might take to combat aging, before I

can explain the science-backed interventions that have the greatest promise for

fundamental y changing the way we think about growing old, before we even

begin to talk about the treatments and therapies that wil be game changers for

our species, we need to answer one very important question:

Should we?

THREE

THE BLIND EPIDEMIC

IT WAS MAY 10, 2010, and London was abuzz. Chelsea Footbal Club had just won

its fourth national championship by devastating Wigan Athletic, 8–0, on the

nal day of Premier League play. Meanwhile, Gordon Brown announced that he

would be stepping down as prime minister in response to a disastrous

parliamentary result for his Labour Party, which had lost more than ninety seats

in the previous week’s general election.

With the eyes of the English sports world on one part of London and the

attention of the British political universe on another, the goings-on at Carlton

House Terrace were missed by al but the most attentive observers of the

president, council, and fel ows of the Royal Society of London for Improving

Natural Knowledge.

More simply known as the Royal Society, the world’s oldest national

scienti c organization was established in 1660 to promote and disseminate “new

science” by big thinkers of the day such as Sir Francis Bacon, the

Enlightenment’s promulgator of “the prolongation of life.” 1 Be tting its rich

scienti c history, the society has held annual scienti c events ever since.

Highlights have included lectures by Sir Isaac Newton on gravity, Charles

Babbage on his mechanical computer, and Sir Joseph Banks, who had just

arrived back from Australia with a bounty of more than a thousand preserved

plants that were al new to science.

Even today, in a post-Enlightenment world, most of the events at the society

are fascinating if not world changing. But the two-day meeting that commenced

in the spring of 2010 was nothing short of that, for gathered together on that

Monday and Tuesday was a motley group of researchers who were meeting to

discuss an important “new science.”

The gathering had been cal ed by geneticist Dame Linda Partridge,

bioanalytics pioneer Janet Thornton, and molecular neuroscientist Gil ian

Bates, al luminaries in their respective elds. The attendee list was no less

impressive. Cynthia Kenyon spoke about her landmark work on a single

mutation in the IGF-1 receptor gene that had doubled the lifespan of

roundworms by activating DAF-162—work that was rst suggested by Partridge

to be a worm-speci c aberration3 but soon forced her and other leading

researchers to confront long-held beliefs that aging could be control ed by a

single gene. Thomas Nyström, from the University of Gothenburg, reported his

discovery that Sir2 not only is important for genomic and epigenomic stability

in yeast, it also prevents oxidized proteins from being passed on to young

daughter cel s.

Brian Kennedy, a former Guarente student who was about to assume the

presidency of the Buck Institute for Research on Aging, explained the ways in

which genetic pathways that had been similarly conserved in a diverse array of

species were likely to play similar roles in mammalian aging. Andrzej Bartke

from Southern Il inois University, former PhD adviser to Michael “Marathon

Mouse” Bonkowski, talked about how dwarf mice can live up to twice as long as

normal mice, a record. Molecular biologist María Blasco explained how old

mammalian cel s are more likely than young cel s to lose their identity and

become cancerous. And geneticist Nir Barzilai spoke of genetic variants in long-

lived humans and his belief that al aging-related diseases can be substantial y

prevented and human lives can be considerably extended with one relatively easy

pharmaceutical intervention.

Over the course of those two days, nineteen presenting scientists from some

of the best research institutions in the world moved toward a provocative

consensus and began to build a compel ing case that would chal enge

conventional wisdom about human health and disease. Summarizing the

meeting for the society later that fal , the biogerontologist David Gems would

write that advances in our understanding of organismal senescence are al leading

to a momentous singular conclusion: that aging is not an inevitable part of life

but rather a “disease process with a broad spectrum of pathological

consequences. ”4 In this way of thinking, cancer, heart disease, Alzheimer’s, and

other conditions we commonly associate with getting old are not necessarily

diseases themselves but symptoms of something greater.

Or, put more simply and perhaps even more seditiously: aging itself is a

disease.

THE LAW OF HUMAN MORTALITY

If the idea that aging is a disease sounds strange to you, you’re not alone.

Physicians and researchers have been avoiding saying that for a long time. Aging,

we’ve long been told, is simply the process of growing old. And growing old has

long been seen as an inevitable part of life.

We see aging, after al , in nearly everything around us and, in particular, the

things around us that look anything like us. The cows and pigs in our farms age.

The dogs and cats in our homes do, too. The birds in the sky. The sh in the sea.

The trees in the forest. The cel s in our petri dishes. It always ends the same way:

dust to dust.

The connection between death and aging is so strong that the inevitability of

the former governed the way we came to de ne the latter. When European

societies rst began keeping public death certi cates in the 1600s, aging was a

respected cause of death. Descriptions such as “decrepitude” or “feebleness due

to old age” were commonly accepted explanations for death. But according to

the seventeenth-century English demographer John Graunt, who wrote Natural

and Political Observations Mentioned in a Following Index, and Made upon the

Bills of Mortality, so were “fright,” “grief,” and “vomiting.”

As we’ve moved forward in time, we’ve moved away from blaming death on

old age. No one dies anymore from “getting old.” Over the past century, the

Western medical community has come to believe not only that there is always a

more immediate cause of death than aging but that it is imperative to identify

that cause. In the past few decades, in fact, we’ve become rather fussy about this.

The World Health Organization’s International Classification of Diseases, a

list of il nesses, symptoms, and external causes of injury, was launched in 1893

with 161 headings. Today there are more than 14,000, and in most places where

records of death are kept, doctors and public health o cials use these codes to

record both immediate and underlying causes of disability and death.5 That, in

turn, helps medical leaders and policy makers around the globe make public

health decisions. Broadly speaking, the more often a cause shows up on a death

certi cate, the more attention society gives to ghting it. This is why heart

disease, type 2 diabetes, and dementia are major focuses of research and

interventionary medical care, while aging is not, even though aging is the greatest

cause of al those diseases.

Age is sometimes considered an underlying factor at the end of someone’s life,

but doctors never cite it as an immediate reason for death. Those who do run the

risk of raising the ire of bureaucrats, who are prone to send the certi cate back to

the doctor for further information. Even worse, they are likely to endure the

ridicule of their peers. David Gems, the deputy director of the Institute of

Healthy Ageing at University Col ege London and the same man who wrote the

report from the Royal Society meeting on “the new science of aging,” told

Medical Daily in 2015 that “the idea that people die of pure aging, without

pathology, is nuts. ”6

But this misses the point. Separating aging from disease obfuscates a truth

about how we reach the ends of our lives: though it’s certainly important to

know why someone fel from a cli , it’s equal y important to know what

brought that person to the precipice in the rst place.

Aging brings us to the precipice. Give any of us 100 years or so, and it brings

us al there.

In 1825, the British actuary Benjamin Gompertz, a learned member of the

Royal Society, tried to explain this upward limit with a “Law of Human

Mortality,” essential y a mathematical description of aging. He wrote, “It is

possible that death may be the consequence of two general y co-existing causes;

the one, chance, without previous disposition to death or deterioration; the

other, a deterioration, or an increased inability to withstand destruction. ”7

The rst part of the law says that there is an internal clock that ticks away at

random, like the chance a glass at a restaurant wil break; essential y a rst-order

rate reaction, similar to radioactive decay, with some glasses lasting far longer

than most. The second part says that, as time passes, due to an unknown

runaway process, humans experience an exponential increase in their probability

of death. By adding these two components together, Gompertz could accurately

predict deaths due to aging: the number of people alive after 50 drops

precipitously, but there is a tail at the end where some “lucky” people remain

alive beyond what you’d expect. His equations made his relatives, Sir Moses

Monte ore and Nathan Mayer Rothschild, owners of the Al iance Insurance

Company, a lot of money.

What Gompertz could not have known, but would have appreciated, is that

most organisms obey his law: ies, roundworms, mice, even yeast cel s. For larger

organisms, we don’t know exactly what the two clocks are, but we do know in

yeast cel s: the chance clock is the formation of an rDNA circle, and the

exponential clock is the replication and exponential increase in the numbers of

rDNA circles, with the resulting movement of Sir2 away from the silent mating-

type genes that causes sterility.8

Humans are more complicated, but in the nineteenth century, British

mortality rates were becoming amenable to simple mathematical modeling

because they were increasingly avoiding not-from-aging deaths: childbirth,

accidents, and infections. This increasingly revealed the underlying and

exponential incidence of death due to internal clocks as being the same as it ever

was. During those times, the probability of dying doubled every eight years, an

equation that left very little room for survivors after the age of 100.

That cap has general y held true ever since, even as the global average life

expectancy jumped twenty years between 1960 and today. 9 That’s because al

that doubling adds up quickly. So even though most people who live in

developed nations can now feel con dent that they wil make it to 80, these days

the chances that any of us wil reach a century is just 3 in 100. Getting to 115 is a

1-in-100-mil ion proposition. And reaching 130 is a mathematical improbability

of the highest order.

At least it is right now.

THE MORTAL BREEZE

Back in the mid-1990s, when I was pursuing my PhD at Australia’s University of

New South Wales, my mother, Diana, was found to have a tumor the size of an

orange in her left lung.

As she was a lifelong smoker, I’d suspected it was coming. It was the one

thing we had argued about more than anything else. When I was a young boy, I

used to steal her cigarettes and hide them. It infuriated her. The fact that she

didn’t respond to my pleas to stop smoking infuriated me, too.

“I have lived a good life. The rest is a bonus,” she would say to me in her early

40s.“Do you know how lucky you are to have been born? You’re throwing your

life away! I won’t come visit you in hospital when you get cancer,” I would say.

When the cancer nal y arrived about a decade later, I wasn’t angry. Tragedy

has a way of vanquishing anger. I drove to the hospital, determined to solve any

problem.

My mother was responsible for her own actions, but she was also a victim of

an unscrupulous industry. Tobacco alone doesn’t kil people; it’s the

combination of tobacco, genetics, and time that most often leads to death. She

was diagnosed with cancer at the age of 50. That’s twenty-one years earlier than

the rst diagnosis in the average lung cancer patient. It’s also how old I am now.

In one way of thinking, my mother was unfortunate to develop cancer at

such a young age. After her back was opened up, rows of ribs were cut from her

spine, and major arteries were rerouted, she lived the rest of her life with just one

lung, which certainly impacted her quality of life and ensured that she had only

a few years of good life left.

On the genetics front, my mother was also unfortunate. Everyone in my

family, from my grandmother to my youngest son, has had their genes analyzed

by one of the companies that o er these services. When my mother had hers

done, she learned, albeit after she had cancer, that she had inherited a mutation

in the SERPINA1 gene, which is implicated in chronic obstructive pulmonary

disease or emphysema. That meant her clock was ticking even faster. After her

left lung was removed, her right lung was the sole provider of oxygen, but the

de ciency in SERPINA1 meant that white blood cel s attacked her remaining

lung, destroying the tissue as if it were an invader. Eventual y the lung gave out.10

In another way of thinking, though, my mother was very lucky—she had the

come-to-God moment that many smokers need to go to battle with the

tremendously powerful forces of addiction in time to save herself, and she spent

another two decades on this planet. She traveled the world, visiting eighteen

di erent countries. She met her grandchildren. She saw me give a TED Talk at

the Sydney Opera House. For this we must certainly credit the doctors who

removed her cancerous lung, but we should also acknowledge the positive

impact of her age. One of the best ways to predict whether someone wil survive

a disease, after al , is to take a look at how old he or she is when diagnosed—and

my mother was, relatively speaking, very young.

This is key. We know that smoking accelerates the aging clock and makes you

more likely to die than a nonsmoker—15 years earlier, on average. So, we have

fought it with public health campaigns, class action lawsuits, taxes on tobacco

products, and legislation. We know that cancer makes you more likely to die,

and we’ve fought it with bil ions of dol ars’ worth of research aimed at ending it

once and for al .

We know that aging makes you more likely to die, too, but we’ve accepted it

as part of life.

It’s also worth noting that even before my mother was diagnosed with lung

cancer—indeed, even before the cancerous cel s in her lungs began growing out

of control—she was aging. And in that way, of course, she was hardly unique.

We know that the process of aging begins long before we notice it. And with the

unfortunate exceptions of those whose lives are taken by the early onset of a

hereditary ailment or a deadly pathogen, most people begin to experience at least

some of the e ects of aging long before they are impacted by the accumulation

of diseases we commonly associate with growing old. At the molecular level, this

starts to happen at a time in our lives that many of us stil look and feel young.

Girls who go through puberty earlier than normal, for example, have an

accelerated epigenetic clock. At that age, we can’t hear the mistakes of the

concert pianist.11 But they are there, even as a teenager.

In our 40s and 50s, we don’t often think about what it feels like to grow old.

When I give talks about my research, sometimes I bring an “age suit” and ask a

young volunteer to wear it. A neck brace reduces mobility in the neck, lead-lined

jackets and wraps al over the body simulate weak muscles, earplugs reduce

hearing, and ski goggles simulate cataracts. After a few minutes of walking

around in the suit, the test subject is very relieved to take it o —and fortunately

can do so.

“Imagine wearing it for a decade,” I say.

To put yourself into an aged mind-set, try this little experiment. Using your

nondominant hand, write your name, address, and phone number while circling

your opposite foot counterclockwise. That’s a rough approximation of what it

feels like.

Di erent functions peak at di erent times for di erent people, but physical

tness, in general, begins to decline in our 20s and 30s. Men who run middle-

distance races, for instance, are fastest around the age of 25, no matter how hard

they train after that. The best female marathoners can stay competitive wel into

their late 20s and early 30s, but their times begin to rise quickly after 40.

Occasional y, exceptional y t outliers—such as National Footbal League

quarterback Tom Brady, National Women’s Soccer League defender Christie

Pearce, Major League Basebal out elder Ichiro Suzuki, and tennis legend

Martina Navratilova—demonstrate that professional athletes can stay

competitive into their 40s, but almost no one remains at the highest levels of

these or most other professional sports much past their mid-40s. Even someone

as resilient as Navratilova peaked when she was in her early 20s through her early

30s.There are some simple tests to determine how biologicaly old you probably

are. The number of push-ups you can do is a good indicator. If you are over 45

and can do more than twenty, you are doing wel . The other test of age is the

sitting-rising test (SRT). Sit on the oor, barefooted, with legs crossed. Lean

forward quickly and see if you can get up in one move. A young person can. A

middle-aged person typical y needs to push o with one of their hands. An

elderly person often needs to get onto one knee. A study of people 51 to 80 years

found that 157 out of 159 people who passed away in 75 months had received

less than perfect SRT scores.

Physical changes happen to everyone. Our skin wrinkles. Our hair grays. Our

joints ache. We start groaning when we get up. We begin to lose resilience, not

just to diseases but to al of life’s bumps and bruises.

Fortunately, a hip fracture for a teenager is a very rare event that nearly

everyone is expected to bounce back from. At 50, such an injury could be a life-

altering event but general y not a fatal one. It’s not long after that, though, that

the risk factor for people who su er a broken hip becomes terrifyingly high.

Some reports show that up to half of those over the age of 65 who su er a hip

fracture wil die within six months.12 And those who survive often live the rest

of their lives in pain and with limited mobility. At 88, my grandmother Vera

tripped on a rumpled carpet and broke her upper femur. During surgery to

repair the damage, her heart stopped on the operating table. Though she

survived, her brain had been starved for oxygen. She never walked again and died

a few years later.

Wounds also heal much more slowly with age—a phenomenon rst

scienti cal y studied during World War I by the French biophysicist Pierre

Lecomte du Noüy, who noted a di erence in the rate of healing between

younger and older wounded soldiers. We can see this in even starker relief when

we look at the di erences in the ways children and the elderly heal from wounds.

When a child gets a cut on her foot, a noninfected wound wil heal quite

quickly. The only medicine most kids need when they get hurt like this is a kiss, a

Band-Aid, and some assurance that everything wil be okay. For an elderly

person, a foot injury is not just painful but dangerous. For older diabetics, in

particular, a smal wound can be deadly: The ve-year mortality rate for a foot

ulcer in a diabetic is greater than 50 percent. That’s higher than the death rates

for many kinds of cancer. 13

Chronic foot wounds, by the way, are not rare; we just don’t hear much

about them. They almost always begin with seemingly benign rubbing on

increasingly numb and fragile soles—but not always. My friend David

Armstrong, at the University of Southern California, a passionate advocate for

increasing our focus on preventing diabetic foot injuries, often tel s the story of

one of his patients, who had a nail stuck in his foot for four days. The patient

noticed it only because he wondered where the tapping sound on the oor was

coming from.

Smal and large diabetic foot wounds rarely heal. They can look as though

someone has taken an apple corer to the bal s of both feet. The body doesn’t

have enough blood ow and cel regeneration capacity, and bacteria thrive in this

meaty, moist environment. Right now, 40 mil ion people, bedridden and

waiting for death, are living this nightmare. There’s almost nothing that can be

done for them except to cut back the dead and dying tissue, then cut some more,

and then some more. From there, robbed of upright mobility, misery is your

bedfel ow and thankful y death is nigh. In the United States alone, each year,

82,000 elderly people have a limb amputated. That’s ten every hour. Al this

pain, al this cost, comes from relatively minor initial injuries: foot wounds.

The older we get, the less it takes for an injury or il ness to drive us to our

deaths. We are pushed closer and closer to the precipice until it takes nothing

more than a gentle wind to send us over. This is the very de nition of frailty.

If hepatitis, kidney disease, or melanoma did the sorts of things to us that

aging does, we would put those diseases on a list of the deadliest il nesses in the

world. Instead, scientists cal what happens to us a “loss of resilience,” and we

general y have accepted it as part of the human condition.

There is nothing more dangerous to us than age. Yet we have conceded its

power over us. And we have turned our ght for better health in other

directions.

WHACK-A-MOLE MEDICINE

There are three large hospitals within a few minutes walk of my o ce. Brigham

and Women’s Hospital, Beth Israel Deaconess Medical Center, and Boston

Children’s Hospital are focused on di erent patient populations and medical

specialties, but they’re al set up the same way.

If we were to take a walk into the lobby of Brigham and Women’s and head

over to the sign by the elevator, we’d get a lay of this nearly universal medical

landscape. On the rst oor is wound care. Second oor: orthopedics. Third

oor: gynecology and obstetrics. Fourth oor: pulmonary care.

At Boston Children’s, the di erent medical specialties are similarly separated,

though they are labeled in a way more be tting the young patients at this

amazing hospital. Fol ow the signs with the boats for psychiatry. The owers wil

take you to the cystic brosis center. The sh wil get you to immunology.

And now over to Beth Israel. This way to the cancer center. That way to

dermatology. Over here for infectious diseases.

The research centers that surround these three hospitals are set up in much

the same way. In one lab you’l nd researchers working to cure cancer. In

another they’re ghting diabetes. In yet another they’re working on heart

disease. Sure, there are geriatricians, but they almost always take care of the

already sick, thirty years too late. They treat the aged—not the aging. No

wonder so few doctors today are choosing to specialize in this area of medicine.

There’s a reason why hospitals and research institutions are organized in this

way. Most of our modern medical culture has been built to address medical

problems one by one—a segregation that owes itself in no smal part to our

obsession with classifying the speci c pathologies leading to death.

There was nothing wrong with this setup when it was established hundreds

of years ago. And by and large, it stil works today. But what this approach

ignores is that stopping the progression of one disease doesn’t make it any less

likely that a person wil die of another. Sometimes, in fact, the treatment for one

disease can be an aggravating factor for another. Chemotherapy can cure some

forms of cancer, for instance, but it also makes people’s bodies more susceptible

to other forms of cancer. And as we learned in the case of my grandmother Vera,

something as seemingly routine as orthopedic surgery can make patients more

susceptible to heart failure.

Because the stakes are so exceptional y high for the individual patients being

treated in these places, a lot of people don’t recognize that a battle won on any of

these individual fronts won’t make much of a di erence against the Law of

Human Mortality. Surviving cancer or heart disease doesn’t substantial y

increase the average human lifespan, it just decreases the odds of dying of cancer

or heart disease.

The way doctors treat il ness today “is simple,” wrote S. Jay Olshansky, a

demographer at the University of Il inois. “As soon as a disease appears, attack

that disease as if nothing else is present; beat the disease down, and once you

succeed, push the patient out the door until he or she faces the next chal enge;

then beat that one down. Repeat until failure. ”14

The United States spends hundreds of bil ions of dol ars each year ghting

cardiovascular disease.15 But if we could stop al cardiovascular disease—every

single case, al at once—we wouldn’t add many years to the average lifespan; the

gain would be just 1.5 years. The same is true for cancer; stopping al forms of

that scourge would give us just 2.1 more years of life on average, because al other

causes of death stil increase exponential y. We’re stil aging, after al .

Aging in its nal stages is nothing like a bushwalk, where a bit of rest, a drink

of water, a nutritional bar, and some fresh socks can get you another dozen miles

before sunset. It’s more like a fast sprint over an ever-higher and ever-closer set of

hurdles. One of those hurdles wil eventual y send you for a tumble. And once

you’ve fal en one time, if you do get up, the odds of fal ing again just keep

getting higher. Take away one hurdle, and the path forward is real y no less

precarious. That’s why the current solutions, which are focused on curing

individual diseases, are both very expensive and very ine ective when it comes to

making big advances in prolonging our healthspans. What we need are

medicines that knock down all the hurdles.

WHY TREATING ONE DISEASE AT A TIME HAS LITTLE IMPACT ON LIFESPAN. The graph

shows an exponential increase in disease as each year passes after the age of 20. It’s hard to appreciate exponential graphs. If I were to draw this graph with a linear Y-axis, it would be two

stories tal . What this means is your chance of developing a lethal disease increases by a

thousandfold between the ages of 20 and 70, so preventing one disease makes little di erence to

lifespan.

Source: Adapted from A. Zenin, Y. Tsepilov, S. Sharapov, et al., “Identi cation of 12 Genetic

Loci Associated with Human Healthspan,” Communications Biology 2 (January 2019).

Thanks to statins, triple-bypass surgeries, de bril ators, transplants, and other

medical interventions, our hearts are staying alive longer than ever. But we

haven’t been nearly so attentive to our other organs, including the most

important one of al : our brains. The result is that more of us are spending more

years su ering from brain-related maladies, such as dementia.

Eileen Crimmins, who studies health, mortality, and global aging at the

University of Southern California, has observed that even though average

lifespans in the United States have increased in recent decades, our healthspans

have not kept up. “We have reduced mortality more than we prevented

morbidity,” she wrote in 2015. 16

So prevalent is the combined problem of early mortality and morbidity that

there is a statistic for it: the disability-adjusted life year, or DALY, which

measures the years of life lost from both premature death and poor state of

health. The Russian DALY is the highest in Europe, with twenty- ve lost years

of healthy life per person. In Israel, it is an impressive ten years. In the United

States, the number is a dismal twenty-three. 17

The average age of death can vary rather signi cantly over time, and is

a ected by many factors, including the prevalence of obesity, sedentary lifestyles,

and drug overdoses. Similarly, the very idea of poor health is both subjective and

measured di erently from place to place, and so researchers are divided on

whether the DALY is rising or declining in the United States. But even the more

optimistic assessments suggest that the numbers have largely been static in recent

years. To me, that in itself is an indictment of the US system; like other advanced

countries, we should be making tremendous progress toward reducing the

DALY and other measures of morbidity, yet, at best, it seems we’re treading

water. We need a new approach.

It doesn’t take studies and statistics to know what’s happening, though. It’s

al around us, and the older we get, the more obvious it becomes. We get to 50

and begin to notice we look like our parents, with graying hair and an increasing

number of wrinkles. We get to 65, and if we haven’t faced some form of disease

or disability yet, we consider ourselves fortunate. If we’re stil around at 80, we

are almost guaranteed to be combating an ailment that has made life harder, less

comfortable, and less joyful. One study found that 85-year-old men are

diagnosed with an average of four di erent diseases, with women of that age

su ering from ve. Heart disease and cancer. Arthritis and Alzheimer’s. Kidney

disease and diabetes. Most patients have several additional undiagnosed diseases,

including hypertension, ischemic heart disease, atrial bril ation, and

dementia.18 Yes, these are di erent ailments with di erent pathologies, studied

in di erent buildings at the National Institutes of Health and in di erent

departments within universities.

But aging is a risk factor for al of them.

In fact, it’s the risk factor. Truly, by comparison, little else matters.

The nal years of my mother’s life serve as a good example. Like almost

everyone else, I recognized that smoking would increase my mother’s chances of

getting lung cancer. I also knew why: cigarette smoke contains a chemical cal ed

benzo(a)pyrene, which binds to guanine in DNA, induces double-strand breaks,

and causes mutations. The repair process also causes epigenetic drift and

metabolic changes that cancer cel s thrive on, in a process we’ve cal ed

geroncogenesis.19

The combination of genetic and epigenetic changes induced by years of

exposure to cigarette smoke increases the chances of developing lung cancer

about vefold.

That’s a big increase. And because of it—and the devastatingly high health

costs associated with treating cancer—the majority of the world’s nations

sponsor smoking cessation programs. Most countries also put health warnings

on cigarette packaging, some with horri c color pictures of tumors and

blackened extremities. Most countries have passed laws against certain kinds of

tobacco advertising. And most have sought to decrease consumption through

punitive taxes.20

Al of that to prevent a vefold increase in a few kinds of cancer. And having

watched my mother su er from that kind of cancer, I’l be the rst to say it’s

total y worth it. From both an economic and emotional point of view, these are

good investments.

But consider this: though smoking increases the risk of getting cancer

vefold, being 50 years old increases your cancer risk a hundredfold. By the age

of 70, it is a thousandfold. 21

Such exponential y increasing odds also apply to heart disease. And diabetes.

And dementia. The list goes on and on. Yet there is not a country in the world

that has committed any signi cant resources to help its citizens combat aging. In

a world in which we seem to agree on very little, the feeling that “it’s just the way

it goes” is almost universal.

A GLORIOUS FIGHT

Aging results in physical decline.

It limits the quality of life.

And it has a speci c pathology.

Aging does al this, and in doing so it ful l s every category of what we cal a

disease except one: it impacts more than half the population.

According to The Merck Manual of Geriatrics, a malady that impacts less

than half the population is a disease. But aging, of course, impacts everyone. The

manual therefore cal s aging an “inevitable, irreversible decline in organ function

that occurs over time even in the absence of injury, il ness, environmental risks,

or poor lifestyle choices.”

Can you imagine saying that cancer is inevitable and irreversible? Or

diabetes? Or gangrene?

I can. Because we used to say that.

Al of these may be natural problems, but that doesn’t make them inevitable

and irreversible—and it sure doesn’t make them acceptable. The manual is

wrong about aging.

But being wrong has never stopped conventional wisdom from negatively

impacting public policy. And because aging isn’t a disease by the commonly

accepted de nition, it doesn’t t nicely into the system we’ve built for funding

medical research, drug development, and the reimbursement of medical costs by

insurance companies. Words matter. De nitions matter. Framing matters. And

the words, de nitions, and framing we use to describe aging are al about

inevitability. We didn’t just throw in the towel before the ght began, we threw

it in before we even knew there was a ght to be had.

But there is a ght. A glorious and global one. And, I think, a winnable one.

There’s no good reason why we have to say that something that happens to

49.9 percent of the population is a disease while something that happens to 50.1

percent of the population is not. In fact, that’s a backward way of approaching

problems that lends itself to the whack-a-mole system of medicine we’ve set up

in hospitals and research centers around the world.

Why would we choose to focus on problems that impact smal groups of

people if we could address the problem that impacts everyone—especial y if, in

doing so, we could signi cantly impact al those other, smal er problems?

We can.

I believe that aging is a disease. I believe it is treatable. I believe we can treat it

within our lifetimes. And in doing so, I believe, everything we know about

human health wil be fundamental y changed.

If you are not yet convinced that aging is a disease, I want to let you in on a

secret. I have a window into the future. In 2028, a scientist wil discover a new

virus, cal ed LINE-1. It wil turn out that we are al infected with it. We get it

from our parents. It wil turn out that the LINE-1 virus is responsible for most

other major diseases: diabetes, heart disease, cancer, dementia. It causes a slow,

horrible chronic disorder, and al humans eventual y succumb to it, even if they

have a low-grade infection. Fortunately, the world pours bil ions of dol ars into

nding a cure. In 2033, a company wil succeed in making a vaccine that

prevents LINE-1 infections. New generations who are vaccinated at birth wil

live fty years longer than their parents did—it wil turn out that that’s our

natural lifespan and we had no idea. The new generation of healthy humans wil

pity previous generations, who blindly accepted that physical decline at 50 was

natural and an 80-year life was a life wel lived.

Of course, this is a science ction story I just invented. But it might be truer

than you think.

A few recent studies have suggested that the so-cal ed sel sh genes we al carry

in our genome, actual y cal ed LINE-1 elements, replicate and cause cel ular

havoc as we get older, accelerating our physical demise. We’l discuss them in

more detail later, but for now, it’s the idea I want to focus on because it raises

important questions: Does it matter whether LINE-1 comes from your parents

directly or via a virus? Would you want to eradicate LINE-1 from humanity or

let it grow in your kids and in ict horrible diseases on them? Would you say that

LINE-1 causes a disease or not?

If not, is it simply because more than half of al people carry it?

Whether it’s a virus, a sel sh DNA element, or simply the makeup of our

cel s that causes these health problems, what’s the di erence? The end result is

the same.

The belief that aging is a natural process is deep-rooted. So even if I’ve

somewhat convinced you that aging should be considered a disease, let’s do

another thought experiment.

Imagine that everyone on our planet typical y lives to 150 years in good

health. Your family, though, doesn’t. You become wrinkled, gray-haired,

diabetic, and frail at 80. Upon seeing these poor, unfortunate souls in this poor,

unfortunate state of existence, what doctor would not diagnose your family with

a disease, name it after him- or herself, and publish horrid photos of you with

your eyes blacked out in medical journals? Communities would raise money to

understand and nd a cure for your family’s wretched inheritance.

That was exactly what happened when the German physician Otto Werner

rst described a condition that causes people to look and feel as though they are

80 when they are in their 40s. That’s Werner syndrome, the disease I was

studying when I rst arrived at MIT in the 1990s. Nobody said I was studying

something that is inevitable or irreversible. Nobody said it was crazy to cal

Werner syndrome a disease or to work to nd a breakthrough therapy. Nobody

told me or the Werner patients that “that’s just the way it goes.”

In front of us is the deadliest and costliest disease on the planet, a disease that

almost no one is working on. It is as if the planet is in a stupor. If your rst

thought is “But I don’t want to live past 90,” let me assure you: I don’t want you

to live a year longer than you wish.

But before you make your decision, let’s do one nal thought experiment.

Imagine that a clerk at City Hal has found a mistake on your birth

certi cate. It turns out that you are actual y 92 years old.

“You’l get a new one in the mail,” the clerk says. “Have a nice day.”

Do you feel any di erent now that you are 92? Nothing else has changed in

your life—just a few numbers on your identi cation. Do you suddenly want to

kil yourself?

Of course not. When we stay healthy and vibrant, as long as we feel young

physical y and mental y, our age doesn’t matter. That’s true whether you are 32,

52, or 92. Most middle-aged and older adults in the United States report feeling

ten to twenty years younger than their age, because they stil feel healthy. And

feeling younger than your age predicts lower mortality and better cognitive

abilities later in life.22 It’s a virtuous cycle, as long as you keep pedaling.

But no matter how you feel at this moment in your life, even with a positive

outlook and a healthy lifestyle, you have a disease. And it’s going to catch up to

you, sooner rather than later, unless something is done.

I acknowledge that cal ing aging a disease is a radical departure from the

mainstream view of health and wel -being, which has established an array of

medical interventions addressing the various causes of death. That framework

evolved, however, largely because we didn’t understand why aging occurs. Up

until very recently, the best thing we had was a list of aging hal marks. The

Information Theory of Aging could change that.

There is nothing wrong with using the hal marks to guide interventions. We

can probably have a positive impact on people’s lives by addressing each of them.

It’s possible that interventions aimed at slowing telomere deterioration wil

improve people’s long-term wel -being. Maintaining proteostasis, preventing

deregulation of nutrient sensing, thwarting mitochondrial dysfunction,

stopping senescence, rejuvenating stem cel s, and decreasing in ammation might

al be ways to delay the inevitable. Indeed, I work with students, postdocs, and

companies around the globe that are developing solutions to each one of these

hal marks and hope to continue. 23 Anything we can do to al eviate su ering we

should do.

But we’re stil building nine dams on nine tributaries.

In coming together to tackle the “new science of aging,” as the attendees of

the Royal Society meeting termed this ght in their 2010 meeting, increasing

numbers of scientists are starting to acknowledge the possibility and potential

inherent in heading upstream.

Together we can build a single dam—at the source. Not just intervene when

things go wrong. Not just slow things down. We can eliminate the symptoms of

aging altogether.

This disease is treatable.

PART II

WHAT WE’RE LEARNING

(THE PRESENT)

FOUR

LONGEVITY NOW

EVERY DAY I WAKE UP to an inbox ful of messages from people from al over the

world. The tide ebbs and ows but always takes the form of a ash ood in the

wake of newly announced research from my team or others.

“What should I be taking?” they ask.

“Can you tel me what I need to do to get admitted into one of the human

trials?” they implore.

“Can you extend the lifespan of my daughter’s hamster?” I kid you not.

Some of the letters are much sadder than others. One man recently wrote to

o er to contribute a donation to my lab in honor of his mother, who had passed

away after su ering terribly through many years of age-related il ness. “I feel

compel ed to help, even in some smal way, to prevent this from happening to

someone else,” he wrote. The next day, a woman whose father had been

diagnosed with Alzheimer’s wrote to ask if there were any way to get him

admitted into a study. “I would do anything, take him anywhere, spend every

last cent I have,” she pleaded. “He is the only family I have and I cannot bear the

thought of what is about to happen to him.”

There is great reason for hope on the not-so-distant horizon, but those

battling against the ravages of aging right now must do so in a world in which

most doctors have never even thought about why we age, let alone how to treat

aging.

Some of the medical therapies and life-extending technologies discussed in

this book are already here. Others are a few years away. And there are more to

discuss that are a decade or so down the road; we’l get to those as wel .

But even without access to this developing technology, no matter who you

are, where you live, how old you are, and how much you earn, you can engage

your longevity genes, starting right now.

That’s what people have been doing for centuries—without even knowing it

—in centenarian-heavy places such as Okinawa, Japan; Nicoya, Costa Rica; and

Sardinia, Italy. These are, you might recognize, some of the places the writer Dan

Buettner introduced to the world as so-cal ed Blue Zones starting in the mid-

2000s. Since that time, the primary focus for those seeking to apply lessons from

these and other longevity hot spots has been on what Blue Zone residents eat.

Ultimately this resulted in the distil ation of “longevity diets” that are based on

the commonalities in the foods eaten in places where there are lots of

centenarians. And overwhelmingly that advice comes down to eating more

vegetables, legumes, and whole grains, while consuming less meat, dairy

products, and sugar.

And that’s not a bad place to start—in fact, it’s a great place to start. There is

widespread disagreement, even among the best nutritionists in the world, as to

what constitutes the “best” diet for H. sapiens. That’s likely because there is no

best diet; we’re al di erent enough that our diets need to be subtly and

sometimes substantial y di erent, too. But we’re also al similar enough that

there are some very broad commonalities: more veggies and less meat; fresh food

versus processed food. We al know this stu , though applying it can be a

chal enge.

A big part of the reason so many people aren’t wil ing to face up to that

chal enge is because we’ve always thought of aging as an inevitable part of life. It

might come a little earlier for some and a little later for others, but we’ve always

been told that it’s coming for us al .

That’s what we used to say about pneumonia, in uenza, tuberculosis, and

gastrointestinal conditions, too. In 1900, those four il nesses accounted for

about half of the deaths in the United States and—if you managed to live long

enough—you could be virtual y assured that one of them would get you

eventual y.

Today, deaths among people su ering from tuberculosis and gastrointestinal

conditions are exceedingly rare. And pneumonia and in uenza claim less than 10

percent of the lives taken by those conditions a little more than a century ago—

with most of those deaths now among individuals weakened by aging.

What changed? In no smal part it was framing. Advances in medicine,

innovations in technology, and better information to guide our lifestyle

decisions resulted in a world in which we didn’t have to accept the idea that

these diseases were “just the way it goes.”

We don’t have to accept aging like that, either.

But even among those who wil have the most immediate access to

pharmaceuticals and technologies that wil be emerging to o er longer and

healthier lives in the next few decades, reaching an optimal lifespan and

healthspan won’t be as easy as ipping a switch.

There wil always be good and bad choices. And that starts with what we put

into our bodies.

And what we don’t.

GO, FAST

After twenty- ve years of researching aging and having read thousands of

scienti c papers, if there is one piece of advice I can o er, one sure re way to stay

healthy longer, one thing you can do to maximize your lifespan right now, it’s

this: eat less.

This is nothing revolutionary, of course. As far back as Hippocrates, the

ancient Greek physician, doctors have been espousing the bene ts of limiting

what we eat, not just by rejecting the deadly sin of gluttony, as the Christian

monk Evagrius Ponticus counseled in the fourth century, but through

“intentional asceticism.”

Not malnutrition. Not starvation. These are not pathways to more years, let

alone better years. But fasting—al owing our bodies to exist in a state of want,

more often than most of us al ow in our privileged world of plenty—is

unquestionably good for our health and longevity.

Hippocrates knew this. Ponticus knew this. So, too, did Luigi Cornaro, a

fteenth-century Venetian nobleman who could, and probably should, be

considered the father of the self-help book.

The son of an innkeeper, Cornaro made a fortune as an entrepreneur and

lavishly spent his money on wine and women. By his mid-30s, he was exhausted

by food, drink, and sex—the poor guy—and resolved to limit himself in each

regard. The historical record is a bit vague on the details of his sex life after that

fateful decision,1 but his diet and drinking habits have been wel documented:

he ate no more than twelve ounces of food and drank two glasses of wine each

day.“I accustomed myself to the habit of never fuly satisfying my appetite, either

with eating or drinking,” Cornaro wrote in his First Discourse on the Temperate

Life, “always leaving the table wel able to take more.” 2

Cornaro’s discourses on the bene ts of la vita sobria might have fal en into

obscurity had he not provided such compel ing personal proof that his advice

had merit: he published his guidance when he was in his 80s, and in exceptional

health, no less, and he died in 1566 at nearly (and some sources say more than)

100 years old.

In more recent times, Professor Alexandre Guéniot, the president of the Paris

Medical Academy just after the turn of the twentieth century, was famed for

living on a restricted diet. It is said that his contemporaries mocked him—for

there was no science at that time to back his suspicion that hunger would lead to

good health, just his gut hunch—but he outlived them, one and al . He nal y

succumbed at the age of 102.

The rst modern scienti c explorations of the lifelong e ects of a severely

restricted diet began during the last days of World War I. That’s when the

longtime biochemical col aborators Lafayette Mendel and Thomas Osborne—

the duo who had discovered vitamin A—discovered, along with researcher Edna

Ferry, that female rats whose growth was stunted due to lack of food early in life

lived much longer than those that ate plenty. 3

Picking up on that evidence in 1935, a now-famous Cornel University

professor named Clive McCay demonstrated that rats fed a diet containing 20

percent indigestible cel ulose—cardboard, essential y—lived signi cantly longer

lives than those that were fed a typical lab diet. Studies conducted over the next

eighty years demonstrated again and again that calorie restriction without

malnutrition, or CR, leads to longevity for al sorts of life-forms. Hundreds of

mouse studies have been done since to test the e ects of calories on health and

lifespan, mostly on male mice.

Reducing calories works even in yeast. I rst noticed this in the late 1990s.

Cel s fed with lower doses of glucose were living longer, and their DNA was

exceptional y compact—signi cantly delaying the inevitable ERC

accumulation, nucleolar explosion, and sterility.

If this happened only in yeast, it would merely be interesting. But because we

knew that rodents also lived longer when their food was restricted—and later

learned that this was the case for fruit ies, as wel 4—it was apparent that this

genetic program was very old, perhaps nearly as old as life itself.

In animal studies, the key to engaging the sirtuin program appears to be

keeping things on the razor’s edge through calorie restriction—just enough food

to function in healthy ways and no more. This makes sense. It engages the

survival circuit, tel ing longevity genes to do what they have been doing since

primordial times: boost cel ular defenses, keep organisms alive during times of

adversity, ward o disease and deterioration, minimize epigenetic change, and

slow down aging.

But this has, for obvious reasons, proven a chal enge to test on humans in a

control ed scienti c setting. Sadly, it’s not hard to nd instances in which

humans have had to go without food, but those periods are general y times in

which food insecurity results in malnutrition, and it would be a chal enge to

keep a test group of humans on the razor’s edge for the long periods of time that

would be required for comprehensive control ed studies.

As far back as the 1970s, though, there have been observational studies that

strongly suggested long-term calorie restriction could help humans live longer

and healthier lives, too.

In 1978 on the island of Okinawa, famed for its large number of

centenarians, bioenergetics researcher Yasuo Kagawa learned that the total

number of calories consumed by schoolchildren was less than two-thirds of what

children were getting in mainland Japan. Adult Okinawans were also leaner,

taking in about 20 percent fewer calories than their mainland counterparts.

Kagawa noted that not only were the lifespans of Okinawans longer, but their

healthspans were, too—with signi cantly less cerebral vascular disease,

malignancy, and heart disease.5

In the early 1990s, the Biosphere 2 research experiment provided another

piece of evidence. For two years, from 1991 to 1993, eight people lived inside a

three-acre, closed ecological dome in southern Arizona, where they were

expected to be reliant on the food they were growing inside. Green thumbs they

weren’t, though, and the food they farmed turned out to be insu cient to keep

the participants on a typical diet. The lack of food wasn’t bad enough to result

in malnutrition, but it did mean that the team members were frequently hungry.

One of the prisoners (and by “prisoners” I mean “experimental subjects”)

happened to be Roy Walford, a researcher from California whose studies on

extending life in mice are stil required reading for scientists entering the aging

eld. I have no reason to suspect that Walford sabotaged the crops, but the

coincidence was rather fortuitous for his research; it gave him an opportunity to

test his mouse-based ndings on human subjects. Because they were thoroughly

medical y monitored before, during, and after their two-year stint inside the

dome, the participants gave Walford and other researchers a unique opportunity

to observe the numerous biological e ects of calorie restriction. Tel ingly, the

biochemical changes they saw in their bodies closely mirrored those Walford had

seen in his long-lived calorie-restricted mice, such as decreased body mass (15 to

20 percent), blood pressure (25 percent), blood sugar level (21 percent), and

cholesterol levels (30 percent), among others.6

In recent years, formal human studies have begun, but it has turned out to be

quite di cult to get volunteer human subjects to reduce their food intake and

maintain that level of consumption over long periods. As my col eagues Leonie

Heilbronn and Eric Ravussin wrote in The American Journal of Clinical

Nutrition in 2003, “the absence of adequate information on the e ects of good-

quality, calorie-restricted diets in nonobese humans re ects the di culties

involved in conducting long-term studies in an environment so conducive to

overfeeding. Such studies in free-living persons also raise ethical and

methodologic issues. ”7 In a report published in The Journals of Gerontology in

2017, a Duke University research team described how it sought to limit 145

adults to a diet of 25 percent fewer calories than is typical y recommended for a

healthy lifestyle. People being people, the actual calorie restriction achieved was,

on average, about 12 percent over two years. Even that was enough, however, for

the scientists to see a signi cant improvement in health and a slowdown in

biological aging based on changes in blood biomarkers. 8

These days, there are many people who have embraced a lifestyle that permits

signi cantly reduced caloric intake; about a decade ago, before fasting’s most

recent revival, some of them visited my lab at Harvard.

“Isn’t it hard to do what you do?” I asked Meredith Averil and her husband,

Paul McGlothin, at the time members of CR Society International and stil very

much advocates for calorie restriction, who limit themselves to about 75 percent

of the calories typical y recommended by doctors and sometimes quite a bit less

than that. “Don’t you just feel hungry al the time?”

“Sure, at rst,” McGlothin told me. “But you get used to it. We feel great!”

At lunch that day, McGlothin expounded upon the merits of eating organic

baby food and slurped down something that looked to me like orange mush. I

also noticed that both he and Averil were wearing turtlenecks. It wasn’t winter.

And most folks in my lab are perfectly comfortable in T-shirts. But with so little

fat on their bodies, they needed the extra warmth. Then in his late 60s,

McGlothin showed no signs that his diet might slow him down. He was the

CEO of a successful marketing company and a former New York State chess

champion. He didn’t look much younger than his age, though; in large part, I

suspect this was because a lack of fat exposes wrinkles, but his blood

biochemistry suggested otherwise. On his 70th birthday, his health indicators,

from blood pressure and LDL cholesterol to resting heart rate and visual acuity,

were typical of those of a much younger person. 9 Indeed, they resembled those

seen in the long-lived rats on calorie restriction.

It’s true that what we know about the impact of lifelong calorie restriction in

humans comes down to short-term studies and anecdotal experiences. But one

of our close relatives has o ered us insights into the longitudinal bene ts of this

lifestyle.

Since the 1980s, a long-term study of calorie restriction in rhesus monkeys—

our close genetic cousins—has produced stunningly compel ing results. Before

the study, the maximum known lifespan for any rhesus monkey was 40 years.

But of twenty monkeys in the study that lived on calorie-restricted diets, six

reached that age, which is roughly equivalent to their reaching 120 in human

terms.

To hit that mark, the monkeys didn’t need to live on a calorie-restricted diet

for their entire lives. Some of the test subjects were started on a 30 percent

reduction regimen when they were middle-aged monkeys. 10

CR works to extend the lifespan of mice, even when initiated at 19 months of

age, the equivalent of a 60- to 65-year-old human, but the earlier the mice start

on CR, the greater the lifespan extension.11 What these and other animal studies

tel us is that it’s hard to “age out” of the longevity bene ts of calorie restriction,

but it’s probably better to start earlier than later, perhaps after age 40, when

things real y start to go downhil , molecularly speaking.

That doesn’t make a CR diet a good plan for everyone. Indeed, even Rozalyn

Anderson, a former trainee of mine who’s now a famous professor at the

University of Wisconsin and a lead researcher in the rhesus study, says a 30

percent calorie-reduced diet for humans, long term, amounted in her mind to a

“bonkers diet. ”12

It’s certainly not bonkers for everyone, though, especial y considering that

calorie restriction hasn’t been demonstrated only to lengthen life but also to

forestal cardiac disease, diabetes, stroke, and cancer. It’s not just a longevity

plan; it’s a vitality plan.

It’s nonetheless a hard sel for many people. It takes strong wil power to avoid

the fridge at home or snacks at work. There’s an adage in my eld: if calorie

restriction doesn’t make you live longer, it wil certainly make you feel that way.

But it turns out that’s okay, because research is increasingly demonstrating

that many of the bene ts of a life of strict and uncompromising calorie

restriction can be obtained in another way. In fact, that way might be even better.

THE PERIODIC TABLE

To ensure a genetic response to a lack of food, hunger doesn’t need to be the

status quo. Once we’ve grown accustomed to stress, after al , it’s no longer as

stressful.

Intermittent fasting, or IF—eating normal portions of food but with

periodic episodes without meals—is often portrayed as a new innovation in

health. But long before my friend Valter Longo at the University of California,

Los Angeles, began touting the bene ts of IF, scientists had been studying the

e ects of periodic calorie restriction for the better part of a century.

In 1946, University of Chicago researchers Anton Carlson and Frederick

Hoelzel subjected rats to periodic food restriction and found, when they did,

that those that went hungry every third day lived 15 to 20 percent longer than

their cousins on a regular diet.13

At the time it was believed that fasting provided the body with a “rest. ”14

That’s very much the opposite of what we now know about what happens at a

cel ular level when we subject our bodies to the stress of going without food.

Either way, Carlson and Hoelzel’s work provided valuable information on the

long-term results of irregular calorie restriction.

It’s not clear whether the pair applied what they’d learned to their own lives,

but both lived relatively long lives for their time. Carlson died at the age of 81.

Hoelzel made it to 74, despite having subjected himself over the years to

experiments that included swal owing gravel, glass beads, and bal bearings to

study how long it would take for such objects to pass through his system. And

people say I’m crazy.

Today, human studies are con rming that once-in-a-while calorie restriction

can have tremendous health results, even if the times of fasting are quite

transient.

In one such study, participants ate a normal diet most of the time but turned

to a signi cantly restricted diet consisting primarily of vegetable soup, energy

bars, and supplements for ve days each month. Over the course of just three

months, those who maintained the “fasting mimicking” diet lost weight,

reduced their body fat, and lowered their blood pressure, too. Perhaps most

important, though, the participants had lower levels of a hormone made

primarily in the liver cal ed insulin-like growth factor 1, or IGF-1. Mutations in

IGF-1 and the IGF-1 receptor gene are associated with lower rates of death and

disease and found in abundance in females whose families tend to live past

100.15

Levels of IGF-1 have been closely linked to longevity. The impact is so strong,

in fact, that in some cases it can be used to predict—with great accuracy—how

long someone wil live, according to Nir Barzilai and Yousin Suh, who research

aging at the Albert Einstein Col ege of Medicine at Yeshiva University in New

York.

Barzilai and Suh are geneticists whose research focuses on centenarians who

have made it to 100—and beyond—without su ering from any age-related

diseases. That unique population is a vital study group, because its members

provide a model for aging the way most people say they want to age—not

accepting that additional years of life need to come with additional years of

misery.

When we nd clusters of these people, we see that in some cases it doesn’t

actual y matter what they put into their bodies. They carry gene variants that

seem to put them into a state of fasting no matter what they eat. As anyone who

has ever known a centenarian can attest, it doesn’t take a lifetime of making 100

percent healthy decisions to reach 100. When Barzilai’s team studied nearly 500

Ashkenazi Jews over the age of 95, they saw that many engaged in the same sorts

of behaviors doctors have long been tel ing us to shun: eating fried foods,

smoking, and just sitting around and drinking a little too much. Barzilai once

asked one of his centenarian study subjects why she hadn’t listened to her

doctors over the years when they had strongly advised her to end her lifelong

smoking habit. “I’ve had four doctors tel me smoking would kil me,” she said

with a wry smile, “and wel , al four are dead now, aren’t they?”

Some people are simply winners in the genetic lottery. The rest of us have

some extra work to do. But the good news is that the epigenome is mal eable.

Since it’s not digital, it’s easier to impact. We can control the behavior of this

analog element of our biology by how we live our lives.

The important thing is not just what we eat but the way we eat. As it turns

out, there is a strong correlation between fasting behavior and longevity in Blue

Zones such as Ikaria, Greece, “the island where people forget to die,” where one-

third of the population lives past the age of 90 and almost every older resident is

a staunch disciple of the Greek Orthodox church and adheres to a religious

calendar that cal s for some manner of fasting more than half the year. 16 On many days, that means no meat, dairy products, or eggs and sometimes no wine

or olive oil, either—for some Greeks, that’s just about everything. Additional y,

many Greeks observe periods of total fasting before taking Holy Communion. 17

Other longevity hot spots, such as Bama County in southern China, are

places where people have access to good, healthy food but choose to forgo it for

long periods each day. 18 Many of the centenarians in this region have spent their

lives eschewing a morning meal. They general y eat their rst smal meal of the

day around noon, then share a larger meal with their families at twilight. In this

way, they typical y spend sixteen hours or more of each day without eating.

When we investigate places like this, and as we seek to apply research about

fasting to our modern lives, we nd that there are scores of ways to calorie

restrict that are sustainable, and many take the form of what has come to be

known as periodic fasting—not being hungry al the time but using hunger

some of the time to engage our survival circuit.

Over time, some of these ways of limiting food wil prove to be more e ective

than others. A popular method is to skip breakfast and have a late lunch (the

16:8 diet). Another is to eat 75 percent fewer calories for two days a week (the

5:2 diet). If you’re a bit more adventurous, you can try skipping food a couple of

days a week (Eat Stop Eat), or as the health pundit Peter Attia does, go hungry

for an entire week every quarter. The permutations of these various models for

extending life and health are being worked out in animals and wil be worked

out in people, too. The short-term studies are promising. I suspect the long-term

research wil be, too. In the meantime, however, almost any periodic fasting diet

that does not result in malnutrition is likely to put your longevity genes to work

in ways that wil result in a longer, healthier life.

It doesn’t take any money to eat this way. In fact, it saves money. Moreover,

people who are not accustomed to being able to gorge themselves whenever they

want might be in a better position to be successful at going a few days each

month with a lot less food.

At least at this juncture in the evolution of our customs around food,

though, for many people any form of fasting is a nonstarter.

I’ve tried calorie restriction. I can’t do it. Feeling hungry isn’t fun, and food is

just too pleasurable. Lately, I have taken to periodic fasting—skipping a meal or

two each day—but I admit that it’s mostly unintentional. I simply forget to eat.

So far, though, we’ve talked only about engaging the survival circuit by

limiting how much we eat, but what we eat is also important.

AMINO RIGHT

We’d die quite quickly without amino acids, the organic compounds that serve

as the building blocks for every protein in the human body. Without them—and

in particular the nine essential amino acids that our bodies cannot make on their

own—our cel s can’t assemble the life-giving enzymes needed for life.

Meat contains al nine of the essential amino acids. That’s easy energy, but it

doesn’t come without a cost. Actual y, a lot of costs. Because no matter how you

feel about the morals of the matter, meat is murder—on our bodies. So can we

just avoid protein? Ironical y, protein is what satiates us. Same for mice. Same for

swarming locusts in need of nutrients, which is why they eat each other.19 It would appear that animal life can’t easily limit protein in the diet without some

hunger pains.

There isn’t much debate on the downsides of consumption of animal

protein. Study after study has demonstrated that heavily animal-based diets are

associated with high cardiovascular mortality and cancer risk. Processed red

meats are especial y bad. Hot dogs, sausage, ham, and bacon might be gloriously

delicious, but they’re ingloriously carcinogenic, according to hundreds of

studies that have demonstrated a link between these foods and colorectal,

pancreatic, and prostate cancer.20 Red meat also contains carnitine, which gut

bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is

suspected of causing heart disease.

That doesn’t mean a little red meat wil kil you—the diet of hunter-gatherers

is a mix of plants packed with ber and nutrients, mixed with some red meat and

sh in moderation21—but if you’re interested in a long and healthy life, your

diet probably needs to look a lot more like a rabbit’s lunch than a lion’s dinner.

When we substitute animal protein with more plant protein, studies have

shown, al -cause mortality fal s signi cantly.22

From an energy perspective, the good news is that there isn’t a single amino

acid that can’t be obtained by consuming plant-based protein sources. The bad

news is that, unlike most meats, weight for weight, any given plant usual y

delivers limited amounts of amino acids.

From a vitality perspective, though, that’s great news. Because a body that is

in short supply of amino acids overal , or any single amino acid for a spel , is a

body under the very sort of stress that engages our survival circuits.

You’l recal that when the enzyme known as mTOR is inhibited, it forces

cel s to spend less energy dividing and more energy in the process of autophagy,

which recycles damaged and misfolded proteins. That act of hunkering down

ends up being good for prolonged vitality in every organism we’ve studied. What

we’re coming to learn is that mTOR isn’t impacted only by caloric restriction.23

If you want to keep mTOR from being activated too much or too often,

limiting your intake of amino acids is a good way to start, so inhibiting this

particular longevity gene is real y as simple as limiting your intake of meat and

dairy.

It’s also increasingly clear that al essential amino acids aren’t equal. Rafael de

Cabo at the National Institutes of Health, Richard Mil er at the University of

Michigan, and Jay Mitchel at Harvard Medical School have found over the years

that feeding mice a diet with low levels of the amino acid methionine works

particularly wel to turn on their bodily defenses, to protect organs from hypoxia

during surgery, and to increase healthy lifespan by 20 percent.24 One of my

former students, Dudley Lamming, who now runs a lab at the University of

Wisconsin, demonstrated that methionine restriction causes obese mice to shed

most of their fat—and fast. Even as the mice, which Lamming cal ed “couch

potatoes,” continued to eat as much as they wanted and shun exercise, they stil

lost about 70 percent of their fat in a month, while also lowering their blood

glucose levels.25

We can’t live without methionine. But we can do a better job of restricting

the amount of it we put into our bodies. There’s a lot of methionine in beef,

lamb, poultry, pork, and eggs, whereas plant proteins, in general, tend to contain

low levels of that amino acid—enough to keep the light on, as it were, but not

enough to let biological complacency set in.

The same is true for arginine and the three branched-chain amino acids,

leucine, isoleucine, and valine, al of which can activate mTOR. Low levels of

these amino acids correlate with increased lifespan26 and in human studies, a

decreased consumption of branched-chain amino acids has been shown to

improve markers of metabolic health signi cantly. 27

We can’t live without them, but most of us can de nitely stand to get less of

them, and we can do that by lowering our consumption of foods that many

people consider to be the “good animal proteins,” chicken, sh, and eggs—

particularly when those foods aren’t being used to recover from physical stress or

injury.

Al of this might seem counterintuitive; amino acids, after al , are often

considered helpful. And they can be. Leucine, for instance, is wel known to

boost muscle, which is why it’s found in large quantities in the protein drinks

that bodybuilders often chug before, during, and after workouts. But that

muscle building is coming in part because leucine is activating mTOR, which

essential y cal s out to your body, “Times are good right now, let’s disengage the

survival circuit.” 28 In the long run, however, protein drinks may be preventing

the mTOR pathway from providing its longevity bene ts. Studies in which

leucine is completely eliminated from a mouse’s diet have demonstrated that just

one week without this particular amino acid signi cantly reduces blood glucose

levels, a key marker of improved health. 29 So a little leucine is necessary, of course, but a little goes a long way.

Al of these ndings may explain why vegetarians su er signi cantly lower

rates of cardiovascular disease and cancer than meat eaters.30 The reduction of

amino acids—and thus the inhibition of mTOR—isn’t the only thing at play in

that equation. The lower calorie content, increased polyphenols, and feeling of

superiority over your fel ow human beings are also helpful. Al of these, except

the last, are valid explanations for why vegetarians live longer and stay healthier.

Even if we eat a low-protein, vegetable-rich diet, we may live longer, but we

won’t maximize our lifespans—because putting our bodies into nutritional

adversity isn’t going to maximal y trigger our longevity genes. We need to induce

some physical adversity, too. If that doesn’t happen, we miss a key opportunity

to trigger our survival circuits further. Like a beautiful sports car driven only a

block and back on Sunday mornings, our longevity genes wil go tragical y

underutilized.

With so much horsepower under the hood, we just have to re up the engine

and take it out for a spin.

DO SWEAT IT

There’s a reason why for centuries exercise has been the go-to prescription for

vitality. But that reason isn’t what most people—or even many doctors—think.

In the nearly four hundred years since the English physician Wil iam Harvey

discovered that blood ows around the body in an intricate network of tubes,

doctors thought that exercise improves health by moving blood through the

circulatory system faster, ushing out the buildup of plaque.

That’s not how it works.

Yes, exercise improves blood ow. Yes, it improves lung and heart health. Yes,

it gives us bigger, stronger muscles. But more than any of that—and indeed,

what is responsible for much of that—is a simple thing that happens at a much

smal er scale: the cel ular scale.

When researchers studied the telomeres in the blood cel s of thousands of

adults with al sorts of di erent exercise habits, they saw a striking correlation:

those who exercised more had longer telomeres. And according to one study

funded by the Centers for Disease Control and Prevention and published in

2017, individuals who exercise more—the equivalent of at least a half hour of

jogging ve days a week—have telomeres that appear to be nearly a decade

younger than those who live a more sedentary life. 31 But why would exercising delay the erosion of telomeres?

If you think about how our longevity genes work—employing those ancient

survival circuits—this al makes sense. Limiting food intake and reducing the

heavy load of amino acids in most diets aren’t the only ways to activate longevity

genes that order our cel s to shift into survival mode. Exercise, by de nition, is

the application of stress to our bodies. It raises NAD levels, which in turn

activates the survival network, which turns up energy production and forces

muscles to grow extra oxygen-carrying capil aries. The longevity regulators

AMPK, mTOR, and sirtuins are al modulated in the right direction by exercise,

irrespective of caloric intake, building new blood vessels, improving heart and

lung health, making people stronger, and, yes, extending telomeres. SIRT1 and

SIRT6, for example, help extend telomeres, then package them up so they are

protected from degradation. Because it’s not the absence of food or any

particular nutrient that puts these genes into action; instead it is the hormesis

program governed by the survival circuit, the mild kind of adversity that wakes

up and mobilizes cel ular defenses without causing too much havoc.

There’s real y no way around this. We al need to be pushing ourselves,

especial y as we get older, yet only 10 percent of people over the age of 65 do.32

The good news is that we don’t have to exercise for hours on end. One recent

study found that those who ran four to ve miles a week—for most people,

that’s an amount of exercise that can be done in less than 15 minutes per day—

reduce their chance of death from a heart attack by 40 percent and al -cause

mortality by 45 percent.33 That’s a massive e ect.

In another study, researchers reviewed the medical records of more than

55,000 people and cross-referenced those documents with death certi cates

issued over fteen years. 34 Among 3,500 deaths, they weren’t particularly

surprised to see that those who had told their doctors they were runners were far

less likely to die of heart disease. Even when the researchers adjusted for obesity

and smoking, the runners were less likely to have died during the years of the

study. The big shock was that the health bene ts were remarkably similar no

matter how much running the people had done. Even about ten minutes of

moderate exercise a day added years to their lives. 35

There is a di erence between a leisurely walk and a brisk run, however. To

engage our longevity genes ful y, intensity does matter. Mayo Clinic researchers

studying the e ects of di erent types of exercise on di erent age groups found

that although many forms of exercise have positive health e ects, it’s high-

intensity interval training (HIIT)—the sort that signi cantly raises your heart

and respiration rates—that engages the greatest number of health-promoting

genes, and more of them in older exercisers. 36

You’l know you are doing vigorous activity when it feels chal enging. Your

breathing should be deep and rapid at 70 to 85 percent of your maximum heart

rate. You should sweat and be unable to say more than a few words without

pausing for breath. This is the hypoxic response, and it’s great for inducing just

enough stress to activate your body’s defenses against aging without doing

permanent harm.37

We’re stil working to understand what al of the longevity genes do, but one

thing is already clear: many of the longevity genes that are turned on by exercise

are responsible for the health bene ts of exercise, such as extending telomeres,

growing new microvessels that deliver oxygen to cel s, and boosting the activity

of mitochondria, which burn oxygen to make chemical energy. We’ve known for

a long time that these bodily activities fal as we age. What we also know now is

that the genes most impacted by exercise-induced stress can bring them back to

the levels associated with youth. In other words: exercise turns on the genes to

make us young again at a cel ular level.

Often I’m asked, “Can I just eat what I want and run o the extra calories?”

My answer is “Unlikely.” When you give rats a high-calorie diet and al ow them

to burn o the energy, lifespan extension is minimal. Same for a CR diet. If you

make food l ing but not as calori c, some of the health bene ts are lost. Being

hungry is necessary for CR to work because hunger helps turn on genes in the

brain that release longevity hormones, at least according to a recent study by

Dongsheng Cai at the Albert Einstein Col ege of Medicine. 38

Would a combination of fasting and exercise lengthen your lifespan?

Absolutely. If you manage to do both these things: congratulations, you are wel

on your way.

But there is plenty more you can do.

THE COLD FRONT

Before arriving in Boston in my early 20s, I’d spent my whole life in Australia.

Cultural y, everything worked out just ne. Within a week, I’d gured out which

markets carried Vegemite, the black yeast spread that some might say requires

some pretty signi cant epigenetic programming as a child to enjoy as an adult. It

took a bit longer to track down the best places for meat pies, Violet Crumble,

Tim Tams, and musk sticks, but eventual y I gured out how to get al of those

tastes of home, too. And it didn’t take long before I stopped caring that folks in

the United States seem to have a hard time di erentiating between Australian

and British accents. (It’s not that hard; Aussie accents are sexier.)

The toughest part was the cold.

As a boy, I thought I knew what cold was. When the temperature at

Observatory Hil , Sydney’s o cial weather station for more than a century,

approached freezing (it hasn’t actual y fal en below freezing in modern history),

that was cold.

Boston was a whole di erent world. A real y frigid one.

I invested in coats, sweaters, and long underwear and spent a lot of time

indoors. Like a lot of postdoctoral fel ows, I often worked through the night. I

truly was committed to my work, but the truth is that part of the calculus for

not going home, on many nights, was that I didn’t want to go outside.

These days I wish I’d taken a di erent approach. I wish I’d just told myself to

tough it out. To take a walk in the bitter cold. To dip my toes into the Charles

River in the middle of January. Because as it turns out, exposing your body to

less-than-comfortable temperatures is another very e ective way to turn on your

longevity genes.

When the world takes us out of the thermoneutral zone—the smal range of

temperatures that don’t require our bodies to do any extra work to stay warm or

cool o —al sorts of things happen. Our breathing patterns shift. The blood

ow to and through our skin—the largest organ in our body—changes. Our

heart rates speed up or slow down. These reactions aren’t happening just

“because.” Al of these reactions have genetic roots dating back to M. superstes’s

ght for survival al those bil ions of years ago.

Homeostasis, the tendency for living things to seek a stable equilibrium, is a

universal biological principle. Indeed, it is the guiding force of the survival

circuit. And thus we see it everywhere we look—especial y on the low end of the

thermometer.

As scientists have increasingly turned their attention to the impacts of

reduced food intake on the human body, it has quickly become clear that calorie

restriction has the e ect of reducing core body temperature. It wasn’t at rst

clear whether this contributed to prolonged vitality or was simply a by-product

of al of the changes happening in the bodies of organisms exposed to this

particular sort of stress.

Back in 2006, though, a team from the Scripps Research Institute genetical y

engineered some lab mice to live their lives a half degree cooler than normal—a

feat they accomplished by playing a trick on the mice’s biological thermostat.

The team inserted copies of the mouse UCP2 gene into the mice’s

hypothalamus, which regulates the skin, sweat glands, and blood vessels. UCP2

short-circuited mitochondria in the hypothalamus so they produced less energy

but more heat. That, in turn, caused the mice to cool down about half a degree

Celsius. The result was a 20 percent longer life for female mice, the equivalent of

about seven additional healthy human years, while male mice got an extension of

12 percent. 39

COLD ACTIVATES LONGEVITY GENES. Sirtuins are switched on by cold, which in turn activates

protective brown fat in our back and shoulders. Image: The author enduring “cold therapy” at

the Massachusetts Institute of Technology in 1999.

The gene involved—which has a human analog—wasn’t just a piece of the

complex machinery that tricked the hypothalamus into thinking the mice’s

bodies were warmer than they were. It was also a gene that has been connected

time and time again to longevity. Five years earlier, a joint team of researchers

from Beth Israel Deaconess Medical Center and Harvard Medical School

showed that mice age faster when their UCP2 gene is nul i ed. 40 And in 2005,

Stephen Helfand and his team, then at the University of Connecticut Health

Center, had demonstrated that targeted upregulation of an analogous gene

could extend the lifespans of fruit ies by 28 percent in females and 11 percent

in males.41 Then, in 2017, the connection between the UCP2 gene and aging

came ful circle, thanks to researchers from Université Laval in Quebec: not only

could UCP2 make mice “run cold,” the Canadian team demonstrated, but

colder temperatures could change the way the gene operated, too—through its

ability to rev up brown adipose tissue.42

Also known as “brown fat,” this mitochondria-rich substance was, until

recently, thought to exist only in infants. Now we know that it is found in

adults, too, although the amount of it decreases as we age. Over time, it becomes

harder and harder to nd; it mingles with white fat and is spread out even more

unevenly across the body. It “hangs out” in di erent areas in di erent people,

sometimes in the abdomen, sometimes across the upper back. That makes

researching it in humans a bit of a chal enge: it general y takes a PET scan—

which requires the injection of radioactive glucose—to locate it. Rodent studies,

however, have provided signi cant insights into the correlation between brown

fat and longevity.

One study of genetical y engineered Ames dwarf mice, for instance,

demonstrated that the function of brown fat is enhanced in these remarkably

long-lived animals. 43 Other studies have shown that animals with abundant

brown fat or subjected to shivering cold for three hours a day have much more of

the mitochondrial, UCP-boosting sirtuin, SIRT3, and experience signi cantly

reduced rates of diabetes, obesity, and Alzheimer’s disease. 44

That is why we need to learn more about how to chemical y substitute for

brown adipose tissue thermogenesis.45 Chemicals cal ed mitochondrial

uncouplers can mimic the e ects of UCP2, al owing protons to leak through

mitochondrial membranes, like dril ing holes in a dam at a hydroelectric plant.

The result is not cold but heat as a by-product of the mitochondrial short

circuit.

The sweet-smel ing mitochondrial uncoupler cal ed 2,4-dinitrophenol

(DNP) was used for making explosives in the First World War, and it soon

became apparent that employees exposed to the chemical were rapidly losing

weight, with one employee even dying from overexposure.46 In 1933, doctors

Windsor Cutting and Maurice Tainter, from the Stanford University School of

Medicine, summarized a series of their papers showing that DNP markedly

increases metabolic rate. 47 That same year, despite Tainter and Cutting’s

warnings about “certain potential dangers,” twenty companies started sel ing it

in the United States, as did others in Great Britain, France, Sweden, Italy, and

Australia.

It worked wel —too wel , in fact.

Just one year later, speaking before the American Public Health Association,

Tainter said, “The interest in and enthusiasm for this product were so great that

its wide-spread use has become a matter of some concern in public health. The

total amount of the drug being used is astonishing.”

Moments later he dropped a bombshel : “during the past year, the Stanford

Clinics have supplied . . . over 1,200,000 capsules of dinitrophenol of 0.1 gm.

each.” 48

Over 1 mil ion capsules? From one university? In one year? That is

astonishing. And that was in 1933, when California had an eighth of its present

population. Three pounds of weight per person per week were reportedly being

shed. The public was relieved—something finally worked. Obesity was going to

be a thing of the past.

But the metabolic party didn’t last long. People began to die from overdoses,

and other long-term side e ects showed up. DNP was declared “extremely

dangerous and not t for human consumption” in the United States Federal

Food, Drug, and Cosmetic Act of 1938. As a curious aside, the legislation was

written by Senator Royal Copeland, a homeopathic physician who, only days

before he died, entrenched protections for natural supplements that today fuel a

largely unregulated industry with revenues of $122 bil ion.

The act rightly banned a dangerous substance but dashed hopes that obesity

would be a thing of the past.49 Anecdotal y, DNP continued to be prescribed to

Russian soldiers during World War II to keep them warm, 50 and today some

unscrupulous people sel it on the internet. But they do so at their peril. In 2018,

Bernard Rebelo was sentenced to seven years in prison for the death of a woman

to whom he sold DNP. In the United States, there have been sixty-two

documented deaths since 1918, though there were likely many more than that.51

One thing is clear: DNP is extremely dangerous. Eating less at each meal,

moving more, and focusing on plant-based foods are much safer options.

Another thing you can try is activating the mitochondria in your brown fat

by being a bit cold. The best way to do this might be the simplest—a brisk walk

in a T-shirt on a winter day in a city such as Boston wil do the trick. Exercising

in the cold, in particular, appears to turbocharge the creation of brown adipose

tissue. 52 Leaving a window open overnight or not using a heavy blanket while you sleep could help, too.

This hasn’t gone unnoticed by the health and wel ness industry. Being cold is

hot right now. Cryotherapy—a few minutes in a box superchil ed to −110°C or

−166°F—is an increasingly popular method of inducing a helping of this sort of

stress to our bodies, although the research is stil a ways away from being

conclusive as to how, why, and even whether it truly works. 53 That didn’t stop

me from accepting an invitation from Joe Rogan, the media mogul and

comedian, to go with him to a cryotherapy spa. Three minutes standing in my

underwear at Mars temperatures may have activated my brown fat and al the

great health bene ts that go with that. At the very least, it left me invigorated

and grateful to be alive.

As with most things in life, it’s probably best to change your lifestyle when

you are young, because making brown fat becomes harder as you get older. If

you choose to expose yourself to the cold, moderation wil be key. Similar to

fasting, the greatest bene ts are likely to come for those who get close to, but not

beyond, the edge. Hypothermia is not good for our health. Neither is frostbite.

But goose bumps, chattering teeth, and shivering arms aren’t dangerous

conditions—they’re simply signs that you’re not in Sydney. And when we

experience these conditions often enough, our longevity genes get the stress they

need to order up some additional healthy fat.

What happens on the other side of the thermostat? The picture is a bit less

clear, but we have some promising leads from our friend S. cerevisiae. We know

from work in my lab that raising the temperature of yeast—from 30°C to 37°C,

just below the limits of what those single-cel ed organisms can sustain—turns on

the PNC1 gene and boosts their NAD production, so their Sir2 proteins can

work that much harder. What’s fascinating is not so much that these

temperature-stressed cel s lived 30 percent longer but that the mechanism was

the same as that evoked by calorie restriction.

Is heat good for human bodies, too? Possibly, but not exactly in the same way.

Because we are warm-blooded animals, our enzymes haven’t evolved a tolerance

for large changes in temperature. You can’t just raise your core body temperature

and expect to live longer. But as my northern German wife, Sandra, likes to

point out, there are a lot of bene ts to exposing your skin and lungs to high temperatures, at least temporarily.

Continuing an ancient Roman tradition, many northern and eastern

Europeans regularly partake in “sauna bathing” for relaxation and health

reasons. The Finns are the most dedicated, with the majority of men reporting

using a sauna once a week, year round. Sandra tel s me it’s pronounced “ZOW-

na” not “saw-nah,” and that no home should be without one. I’m sticking with

saw-nah to avoid sounding like a snicklefritz, but when it comes to housing

construction, Sandra may be on to something.

A 2018 study conducted in Helsinki found that “physical function, vitality,

social functioning, and general health were signi cantly better among sauna

users than non-users,” although the researchers were correct to point out that

part of the e ect could be due to the fact that those who are sick or disabled

don’t go to the sauna. 54

A more convincing study fol owed a group of more than 2,300 middle-aged

men from eastern Finland for more than twenty years. 55 Those who used a

sauna with great frequency—up to seven times a week—enjoyed a twofold drop

in heart disease, fatal hearts attacks, and al -cause mortality events over those

who heat bathed once per week.

None of the sauna studies dug deep enough to tel us why temporary heat

exposure may be so good for us. If yeast is any guide, NAMPT, the gene in our

bodies that recycles NAD, may be in on the act. NAMPT is turned on by a

variety of adversity triggers, including fasting and exercise, which makes more

NAD so the sirtuins can work hard at making us healthier.56 We have never

tested if NAMPT is turned on by heat, but that would be something to do.

Either way, one thing is clear: it does us little good to spend our entire lives in the

thermoneutral zone. Our genes didn’t evolve for a life of pampered comfort. A

little stress to induce hormesis once in a while likely goes a long way.

But dealing with biological adversity is one thing. Overwhelming genetic

damage is another.

DON’T ROCK THE LANDSCAPE

A bit of adversity or cel ular stress is good for our epigenome because it

stimulates our longevity genes. It activates AMPK, turns down mTOR, boosts

NAD levels, and activates the sirtuins—the disaster response teams—to keep up

with the normal wear and tear that comes from living on planet Earth.

But “normal” is the operative word, because when it comes to aging,

“normal” is bad enough. When our sirtuins have to respond to many disasters—

especial y those that cause double-strand DNA breaks—these epigenetic

signalers are forced to leave their posts and head to other places on the genome

where DNA breaks have occurred. Sometimes they make their way back home.

Sometimes they don’t.

We can’t prevent al DNA damage—and we wouldn’t want to because it’s

essential for the function of the immune system and even for consolidating our

memories57—but we do want to prevent extra damage.

And there’s a lot of extra damage to be had out there.

Cigarettes, for starters. There aren’t many legal vices out there that are worse

for your epigenome than the deadly concoction of thousands of chemicals

smokers put into their bodies every day. There’s a reason why smokers seem to

age faster: they do age faster. The DNA damage that results from smoking keeps

the DNA repair crews working overtime, and likely the result is the epigenetic

instability that causes aging. And although I’m not likely to be the rst person

you’l hear this from, it nonetheless bears repeating: smoking is not a private,

victimless activity. The levels of DNA-damaging aromatic amines in cigarette

smoke are about fty to sixty times as high in secondhand as in rsthand

smoke. 58 If you do smoke, it is worth trying to quit.

Don’t smoke? That’s great, but even without smoke there’s re. In much of

the developed world—and increasingly in the developing world as wel —we’re

practical y bathing in DNA-damaging chemicals. In some places—cities with

lots of people and lots of cars, especial y—the simple act of breathing is enough

to do extra damage to your DNA. But it would also be wise to be wary of the

PCBs and other chemicals found in plastics, including many plastic bottles and

take-out containers. 59 (Avoid microwaving these; it releases even more PCBs.)

Exposure to azo dyes, such as aniline yel ow, which is used in everything from

reworks to the yel ow ink in home printers, can also damage our DNA.60 And

organohalides—compounds that contain substituted halogen atoms and are

used in solvents, degreasers, pesticides, and hydraulic uid—can also wreak

havoc on our genomes.

Nobody in his right mind would purposeful y ingest solvents, degreasers,

pesticides, and hydraulic uid, of course, but there’s plenty of damage to be had

in some of the things we do intentional y eat and drink. We’ve known for more

than half a century that N-nitroso compounds are present in food treated with

sodium nitrite, including some beers, most cured meats, and especial y cooked

bacon. In the decades since, we’ve learned that these compounds are potent

carcinogens. 61 What we’ve also come to understand is that cancer is just the start

of our nitrate-treated woes, because nitroso compounds can in ict DNA

breakage as wel 62—sending those overworked sirtuins back to work some more.

Then there’s radiation. Any source of natural or human-in icted radiation,

such as UV light, X-rays, gamma rays, and radon in homes (which is the second

most frequent cause of lung cancer besides smoking63) can cause additional

DNA damage, necessitating the cal -up of an epigenetic x-it team. As someone

who ies a lot for work, I think about this quite a bit—every time I go through

security, in fact. Most of the research on the current versions of airport scanners

suggests that they probably don’t do tremendous damage to our DNA, but

there’s been little attention given to their long-term impact on our epigenome

and the aging process. No one has ever tested what a mouse looks like two years

after being repeatedly exposed to these devices. The ICE mice tel us that

chromosome tickling is al that’s needed to accelerate aging. I’m aware the

radiation exposure from mil imeter-wave scanners is lower than that from

previous scanners. The security attendants at the machine tel travelers the

OceanofPDF.com

exposure is about the “same as the ight.” But with mil ions of ight miles under

my belt, why would I want to double the damage? Whenever possible, I take the

pre-check line or ask for a pat down instead.

If al of this makes you feel as if it’s impossible to completely avoid DNA

breaks and the epigenetic consequences of those breaks, wel , that’s true. The

natural and necessary act of replicating DNA causes DNA breaks, tril ions of

them throughout your body every day. You can’t avoid radon particles or cosmic

rays unless you live in a lead box at the bottom of the ocean. And even if you

were to move to a desert island, the sh you’d have to eat would likely contain

mercury, PCBs, PBDEs, dioxins, and chlorinated pesticides, al of which can

damage your DNA. 64 In our modern world, even with the most “natural”

lifestyle you can fol ow, this sort of DNA damage is inevitable.

No matter how old you are, even if you are a teenager, it is already happening

to you. 65 DNA damage has accelerated your clock, with implications at al stages

of life. Embryos and babies experience aging. What, then, of people in their 60s,

70s, and 80s? What of those individuals who are already frail and cannot restrict

their calories, go for a run, or make snow angels in the dead of winter? Is it too

late for them?

Not at al .

But if we’re all going to live longer and healthier lives—regardless of how

much epigenetic drift and aging we have experienced at this moment in time—

we might need some additional help.

FIVE

A BETTER PILL TO SWALLOW

THE DREAM OF EXTENDING HUMAN lives did not begin in the early twenty- rst

century any more than the dream of human ight began in the early twentieth.

Nothing begins with science; it al begins with stories.

From Gilgamesh the Sumerian king, who is said to have reigned over Uruk

for 126 years, to Methuselah the patriarch in Hebrew scriptures, who is said to

have lived to the age of 969, humanity’s sacred stories testify to our deep-seated

fascination with longevity. Outside myths and parables, though, we had little

scienti c evidence of anyone succeeding in extending their life far beyond the

single century mark.

We had little hope of doing so without a deep understanding of how life

works. That is knowledge, albeit stil imperfect, that some of my col eagues and I

believe we nal y possess.

It wasn’t until 1665 that “England’s Leonardo,” Robert Hooke, published

Micrographia, in which he reported seeing cel s in cork bark. That discovery

launched us into the modern era of biology. But centuries would pass before we

had any clue about how cel s work at the molecular scale. That knowledge could

come only from the combination of a series of great leaps in microscopy,

chemistry, physics, genetics, nanoengineering, and computing power.

To understand how aging occurs, we must journey down into the subcel ular

nanoworld, heading down to the cel , piercing the outer membrane, and

traveling into the nucleus. From there, we head down to the scale of amino acids

and DNA. At this size, it is obvious why we don’t live forever.

Until we understood life at the nanoscale, even why we live was a mystery.

The bril iant Austrian theoretical physicist Erwin Schrödinger, the man who

developed quantum physics (and yes, that famous thought experiment involving

a both-dead-and-alive cat) was ummoxed when he tried to explain life. In 1944,

he threw up his hands and declared that living matter “is likely to involve ‘other

laws of physics’ hitherto unknown.” 1 That was the best he could do at the time.

But things moved quickly in the decades to come. And today, the answer to

Schrödinger’s 1944 book, What Is Life? , if not ful y answered, is certainly close

to being so.

Turns out, there is no new law required to explain life. At the nanoscale, it is

merely an ordered set of chemical reactions, concentrating and assembling atoms

that would normal y never assemble, or breaking apart molecules that would

normal y never disintegrate. Life does this using proteinaceous Pac-Men cal ed

enzymes made up of coils and layered mats of amino acid chains.

Enzymes make life possible by taking advantage of fortuitous molecular

movements. Every second you are alive, thousands of glucose molecules are

captured within each of your tril ions of cel s by an enzyme cal ed glucokinase,

which fuses glucose molecules to phosphorus atoms, tagging them for energy

production. Most of the energy created is used by a multicomponent RNA and

protein complex cal ed a ribosome, whose primary job is to capture amino acids

and fuse them with other amino acids to make fresh proteins.

Does this sort of talk make your eyes gloss over? You are not alone, and you

are not to blame. We teachers have done society a great disservice by making cool

science boring. Textbooks and scienti c papers depict biology as a static, two-

dimensional world. Chemicals are drawn as sticks, biochemical pathways are

arrows, DNA is a line, a gene is a rectangle, and enzymes are ovals, drawn

thousands of times larger relative to the cel than they actual y are.

But once you understand how cel s actual y work, they are the most amazing

things. The problem with conveying this wonder in a classroom is that cel s exist

in four dimensions and buzz around with speeds and on scales we humans

cannot perceive or even conceive. To us, the second and the mil imeter are short

divisions of time and space, but to an enzyme about 10 nanometers across and

vibrating every quadril ionth of a second, a mil imeter is the size of a continent

and a second is more than a year.2

Consider catalase, a ubiquitous, regular-sized enzyme that can break apart

and detoxify 10,000 molecules of hydrogen peroxide per second. A mil ion of

them could t inside an E. coli bacterium, a mil ion of which could t on the

head of a pin. 3 These numbers aren’t just hard to imagine; they are

inconceivable.

In each cel are a total of 75,000 enzymes like catalase,4 al thrown together,

jostling around in a slightly salty sea. At the nanoscale, water is gelatinous, and

molecular events are more violent than a category 5 hurricane, with molecules

thrown together at speeds we would perceive as a thousand miles per hour.

Enzymatic reactions are one-in-a-thousand events, but at the nanoscale one-in-a-

thousand events can occur thousands of times a second, enough to sustain life.

If this sounds chaotic, it is, but we need this chaos for order to emerge.

Without it, the molecules that must come together to sustain life would not nd

each other, and they would not fuse. The human sirtuin enzyme cal ed SIRT1

serves as a good example. Precise vibrating sockets on SIRT1 simultaneously

clasp onto an NAD molecule and the protein it wants to strip the acetyls from,

such as a histone or FOXO3. The two captured molecules immediately lock

together, just before SIRT1 rips them apart in a di erent way, producing

vitamin B3 and acetylated adenine ribose as waste products that are recycled back

to NAD.

More important is the fact that the target protein has now been stripped of

the acetyl chemical group that was holding it at bay. Now the histone can pack

DNA more tightly to silence genes, and FOXO3 has had its shackles removed,

al owing it to go turn on a defense program of protective genes.

If the chaos ended and our enzymes suddenly stopped doing what they do,

we would al be dead within a few seconds. Without energy and cel defenses,

there can be no life. M. superstes would never have emerged from the scum and

its descendants would never have been capable of comprehending the words on

this page.

And so, at the fundamental level, life is rather simple: we exist by the grace of

an order created from chaos. When we toast to life, we real y should be toasting

to enzymes.

By studying life at this level, we’ve also learned something rather important—

something the Nobel Prize–winning physicist Richard Feynman expressed

succinctly: “There is nothing in biology yet found that indicates the inevitability

of death. This suggests to me that it is not at al inevitable and that it is only a

matter of time before biologists discover what it is that is causing us the

trouble.” 5

It’s true: there are no biological, chemical, or physical laws that say life must

end. Yes, aging is an increase in entropy, a loss of information leading to disorder.

But living things are not closed systems. Life can potential y last forever, as long

as it can preserve critical biological information and absorb energy from

somewhere in the universe. This doesn’t mean we could be immortal tomorrow

—no more than we could have own to the moon on December 18, 1903.

Science moves forward with smal steps and big steps, but always one step at a

time.

Here’s the remarkable thing: the rst steps have actual y been available to us

since the times of Gilgamesh and Methuselah, and indeed from the time of M.

superstes. And, in the past few centuries, and by accident even earlier than that,

we have discovered ways to chemical y modulate enzymes with molecules we cal

medicines.

Now that we know how life works and have the tools to change it at a genetic

and epigenetic level, we can build upon this very old wisdom. And when it

comes to the goal of extending healthy lifespans, the easiest measures to use are

the various drugs that we already know can impact human aging.

THE WORLD’S GREATEST EASTER EGG

Rapa Nui, a remote volcanic island 2,300 miles west of Chile, is commonly

known as Easter Island and even better known for the nearly nine hundred giant

stone heads that line the island’s perimeter. What should be just as wel known

—and perhaps one day wil be—is the story of how the island came to be the

source of the world’s most e ective lifespan-extending molecule.

Back in the mid-1960s, a team of scientists traveled to the island. The

researchers were not archaeologists seeking answers about the origins of the moai

statues but rather biologists looking for endemic microorganisms.

In the dirt beneath one of the island’s famed stone heads, they discovered a

new actinobacterium. That single-cel ed organism was Streptomyces

hygroscopicus, and when it was isolated by a pharmaceutical researcher, Suren

Sehgal, it soon became clear that the actinobacterium secreted an antifungal

compound. Sehgal named that compound rapamycin, in honor of the island

where it was discovered, and began looking for ways to process it as a potential

remedy for fungal conditions such as athlete’s foot.6 The compound looked

promising for that purpose, but when the Montreal lab where Sehgal worked

was shuttered in 1983, he was directed to destroy the compound.

He couldn’t bring himself to do that, though. Instead he spirited a few vials

of the bacterium out of the lab and kept them in his freezer at home until the

late 1980s, when he convinced his bosses at a new lab in New Jersey to let him

resume studying it.

It wasn’t long before researchers discovered that the compound was an

e ective suppressor of the immune system. That would end its potential as an

antifungal—there are plenty of remedies for athlete’s foot that don’t come at the

cost of lowered immunity—but it gave scientists a new attribute to study.

Even in the 1960s, researchers knew that one of the most common reasons

for an organ transplant to fail is that the recipient patient’s body rejects it. Could

rapamycin lower the immune response enough to ensure the organ would be

accepted? Indeed it could.

It is for this reason that if you were to make a pilgrimage to Rapa Nui, you

might come upon a smal plaque at the site where S. hygroscopicus was

discovered. “At this site,” the plaque reads in Portuguese, “soil samples were

obtained in January 1965 that al owed the production of rapamycin, a substance

that inaugurated a new era for patients who need organ transplants.”

I suspect that a larger plaque may soon be in order, because the discovery of

S. hygroscopicus set into motion a tremendous amount of research, much of

which is stil ongoing and some of which has the potential to prolong vitality for

countless other people. Because in recent years it has become clear that

rapamycin isn’t just an antifungal compound and it isn’t just an immune system

suppressor; it’s also one of the most consistently successful compounds for

extending life.

We know this from experiments on a diverse menagerie of model organisms

in labs around the world. And much as my own research began with

experiments with yeast, much of the initial work that has been done to

understand rapamycin was completed on S. cerevisiae. If you put 2,000 normal

yeast cel s into a culture, a few wil remain viable after six weeks. But if you feed

those yeast cel s rapamycin, in six weeks about half wil stil be healthy. 7 The drug

wil also increase the number of daughter cel s mothers can produce by

stimulating the production of NAD.

Fruit ies fed rapamycin live about 5 percent longer.8 And smal doses of

rapamycin given to mice when they are already in the nal months of their

normal lives results in 9 to 14 percent longer lives, depending on whether they

are male or female, which translates to about a decade of healthy human life. 9

We’ve known for a long time that greater parental age is a risk factor for

disease in the next generation. That’s the power of epigenetics. But mice treated

with rapamycin buck this trend. When researchers from the German Center for

Neurodegenerative Diseases inhibited mTOR in mice born to older fathers, the

negative impact of having an old parent went away. 10

Want to know what the world’s most prominent arbiters of great science

think about the potential of TOR and the molecules that inhibit it to change

the world? The three men who discovered TOR in yeast, Joseph Heitman,

Michael Hal , and Rao Movva, are on a lot of people’s shortlists for the Nobel

Prize in Medicine or Physiology. My col eague across the river at MIT, David

Sabatini, who identi ed mTOR, was named a Clarivate Citation Laureate for

having his work cited most frequently in top-tier peer-reviewed journals; the

Clarivate list has predicted more than forty Nobel Prize winners since 2002.11

Rapamycin isn’t a panacea. Longer-lived animals might not fare as wel on it

as shorter-lived ones do; it’s been shown to be toxic to kidneys at high doses over

extended periods of time; and it might suppress the immune system over time.

That doesn’t mean TOR inhibition is a dead end, though. It might be safe in

smal or intermittent doses—that worked in mice to extend lifespan12 and in

humans dramatical y improved the immune responses of elderly people to a u

vaccine.13

There are hundreds of researchers from the TOR inhibition side of the

family working in universities and biotech companies to identify “rapalogs,”

which are compounds that act on TOR in ways similar to rapamycin but have

greater speci city and less toxicity.14

The quality of the people involved in this line of research and development

makes it hard to bet against TOR inhibition as a pathway to greater human

health and vitality. But even if rapalogs don’t pan out, there’s another

pharmaceutical pathway to prolonged vitality that has already proven to be both

e ective and relatively safe.

PENNIES FOR PROLONGED VITALITY

Galega officinalis is a lovely ower, with stacks of delicate purple petals that seem

locked in a reverent bow to the world.

Also known as goat’s rue, a rather unfortunate name, and French lilac, a far

more charming sobriquet, it has been used as an herbal medicine in Europe for

centuries, owing to a chemical composition rich in guanidine, a smal chemical

in human urine that serves as an indicator of healthy protein metabolism. In the

1920s, doctors began to prescribe guanidine as a way to lower blood glucose

levels in patients with diabetes.

In 1922, a 14-year-old boy named Leonard Thompson, who was dying in a

Toronto hospital, became the rst diabetic patient to be given an injection of a

novel pancreatic peptide hormone that had shown great promise in animal

studies. Two weeks later he was given another, and news of his exceptional

improvement spread quickly around the world. Type 1 diabetes, which occurs

when the pancreas doesn’t produce enough of the hormones needed to alert the

body to sugar, is now widely treated by supplemental insulin. But the ght was

not over.

The type 2 version of the disease, so-cal ed age-associated diabetes, occurs

when the pancreas is able to make enough insulin but the body is deaf to it. The

9 percent of al adults global y with this disease need a drug that restores their

body’s sensitivity to insulin so cel s take up and use the sugar that’s coursing

through their bloodstreams. That’s important for at least two reasons: it gives

the overworked pancreas a rest, and it prevents spikes of freely oating sugar

from essential y caramelizing proteins in the body. Recent results indicate high

blood sugar can also speed up the epigenetic clock.

Thanks to an increasingly sedentary lifestyle and the abundance of sugars and

carbohydrates on every supermarket shelf around the globe, high blood sugar is

causing the premature deaths of 3.8 mil ion people a year. These deaths do not

come quickly and compassionately but in horri c ways, with blindness, kidney

failure, stroke, open foot wounds, and limb amputations.

As they considered this disease in the mid-1950s, the pharmacist Jan Aron

and the physician Jean Sterne—both Frenchmen who would have been

exceptional y familiar with the purple- owering plant so ubiquitous in their

native land—decided to reinvestigate the potential of French lilac derivatives to

ght type 2 diabetes in ways insulin doesn’t. 15

In 1957, Sterne published a paper demonstrating the e ectiveness of oral

dimethyl biguanide to treat type 2 diabetes. The drug, now most commonly

cal ed metformin, has since become one of the most widely taken and e ective

medicines on the globe. It’s among the medications on the World Health

Organization’s Model List of Essential Medicines, a catalog of the most e ective,

safe, and cost-e ective therapies for the world’s most prevalent medical

conditions. As a generic medication, it costs patients less than $5 a month in

most of the world. Except for an extremely rare condition cal ed lactic acidosis,

the most common of the side e ects is some stomach discomfort. Many people

mitigate that side e ect by taking the medication as a coated tablet or with a glass

of milk or a meal, but even when that doesn’t work, the mild upset feeling comes

with a bit of a side bene t: it tends to discourage overeating.

What place does a diabetes medication have in a conversation about

prolonging vitality? Perhaps it would have no place at al if not for the fact that, a

few years ago, researchers noticed a curious phenomenon: people taking

metformin were living notably healthier lives—independent, it seemed, of its

e ect on diabetes. 16

In mice, even a very low dose of metformin has been shown by Rafael de

Cabo’s lab at the National Institutes of Health to increase lifespan by nearly 6

percent, though some have argued that the e ect is due mostly to weight loss.17

Either way, that amounts to the equivalent of ve extra healthy years for

humans, with an emphasis on healthy—the mice showed reduced LDL

cholesterol levels and improved physical performance.18 As the years have gone

by, the evidence has mounted. In twenty-six studies of rodents treated with

metformin, twenty- ve showed protection from cancer. 19

Like rapamycin, metformin mimics aspects of calorie restriction. But instead

of inhibiting TOR, it limits the metabolic reactions in mitochondria, slowing

down the process by which our cel ular powerhouses convert macronutrients

into energy.20 The result is the activation of AMPK, an enzyme known for its

ability to respond to low energy levels and restore the function of mitochondria.

It also activates SIRT1, one of my lab’s favorite proteins. Among other bene cial

e ects, metformin inhibits cancer cel metabolism, increases mitochondrial

activity, and removes misfolded proteins.21

A study of more than 41,000 metformin users between the ages of 68 and 81

concluded that metformin reduced the likelihood of dementia, cardiovascular

disease, cancer, frailty, and depression, and not by a smal amount. In one group

of already frail subjects, metformin use over the course of nine years reduced

dementia by 4 percent, depression by 16 percent, cardiovascular disease by 19

percent, frailty by 24 percent, and cancer by 4 percent. 22 In other studies, the

protective power of metformin against cancer has been far greater than that.

Though not al cancers are suppressed—prostate, bladder, renal, and esophageal

cancer seem recalcitrant—more than twenty- ve studies have shown a powerful

protective e ect, sometimes as great as a 40 percent lower risk, most notably for

lung, colorectal, pancreatic, and breast cancer.23

These aren’t just numbers. These are people whose lives were markedly

improved by using a single, safe drug that costs less than a cup of bad co ee.

If al metformin could do was reduce cancer incidence, it would stil be worth

prescribing widely. In the United States, the lifetime risk of being diagnosed

with cancer is greater than 40 percent. 24 But there’s a dividend beyond preventing cancer directly, a side e ect of living longer that most people don’t

consider: after age 90, your chances of dying of cancer drop considerably. 25 Of

course, people wil stil die of other conditions, but the tremendous pain and

costs associated with cancer would be signi cantly mitigated.

The beauty of metformin is that it impacts many diseases. Through the

power of AMPK activation, it makes more NAD and turns on sirtuins and

other defenses against aging as a whole—engaging the survival circuit upstream

of these conditions, ostensibly slowing the loss of epigenetic information and

keeping metabolism in check, so al organs stay younger and healthier.

Most of us assume that the e ects of a pil like metformin would take years to

produce any appreciable e ect on aging, but maybe not. An admittedly smal

study of healthy volunteers claimed that the DNA methylation age of blood cel s

is reversed within a week and, astoundingly, only ten hours after taking a single

850 mg pil of metformin. 26 But clearly more work is needed with greater

numbers of subjects to know for sure if metformin can delay the aging clock

over the long run.

In most countries, metformin isn’t yet prescriptible as an antiaging drug, but

for the hundreds of mil ions of people around the world who are diabetic, it’s

not a hard prescription to get. In some places, such as Thailand, metformin is

even available over the counter at every pharmacy—for just a few cents a pil . In

the rest of the world, even if you have prediabetes, it can be chal enging to

convince a doctor to prescribe you metformin. If you’ve been good to your

body, and greater than 93.5 percent of your blood’s hemoglobin isn’t irreversibly

bound to glucose—meaning it’s mostly the HbA1 type not HbA1c—you’re out

of luck, not just because the majority of physicians don’t know the data I just

shared with you, but because even if they did, aging isn’t yet considered a disease.

Among the people taking metformin—and leading the charge to evaluate its

long-term e ects on aging in humans—is Nir Barzilai, the Israeli American

physician and geneticist who, along with his col eagues at Albert Einstein

Col ege of Medicine, discovered several longevity gene variants in the insulin-like

growth hormone receptor that controls FOXO3, the cholesterol gene CETP,

and the sirtuin SIRT6, al of which seem to help ensure that some lucky people

with Ashkenazi Jewish ancestry remain healthy beyond 100.

Yes, although genes play a back-seat role to the epigenome, it does seem that

some people are genetical y primed for longevity at the digital level—enjoying

longer lives almost irrespective of how they live, thanks in part to gene variants

that stabilize their epigenomes, preventing the loss of analog information over

time. But Barzilai doesn’t see these people as winners so much as markers—they

represent the potential that most other humans have for long and healthy lives—

and he is fond of pointing out that even if we were never to extend lives past 120,

we know that 120 is possible. “So for most of us,” he has told me, “there are 40

good years stil on the table.”

Barzilai is leading the charge to make metformin the rst drug to be approved

to delay the most common age-related diseases by addressing their root cause:

aging itself. If Barzilai and his col eagues can show metformin has measurable

bene ts in the ongoing Targeting Aging with Metformin (TAME) study, the US

Food and Drug Administration has agreed to consider aging as a treatable

condition. That would be a game changer, the beginning of the end for a world

in which aging is “just the way it goes.”

Barzilai believes that day is coming. He has predicted that the traditional

Hebrew blessing “Ad me’ah ve-essrim shana,” or “May you live until 120,” may

soon need updating, for it wil be a wish not for a long life but for a very average

one.

STAC IT UP

Back in 1999, the story of the sirtuin longevity pathway we discovered in Lenny

Guarente’s lab at MIT was about to get even hotter.

We had nal y gured out a molecular cause of aging in yeast cel s, the rst

for any species. We were stil feeling the glow scientists get when they publish

new work that shows how smart they are. In a series of prominent papers that

had captured the imagination of the scienti c community, we’d reported that

the cause of yeast aging was the movement of Sir2 away from the mating-type

genes to deal with DNA breaks and a whole lot of ensuing genome instability. 27

We’d shown that extra copies of the SIR2 gene could stabilize the rDNA and

extend lifespan. We’d linked genetic instability to epigenetic instability and

found one of the world’s rst true longevity genes—and the yeast hadn’t had to

go hungry to receive its bene ts.

But splicing extra copies of a gene into a single-cel ed organism is a much

easier endeavor than putting those copies into more complex creatures. It’s also

far less ethical y complicated. That’s why a few other researchers and I entered a

scienti c race to nd ways to ramp up sirtuin activity in mammals without

inserting extra sirtuin genes.

Here is where science becomes a matter of logical guesswork and some good

old-fashioned luck. Because there are more than 100 mil ion chemicals known to

science. Where do you even start?

Thankful y, Konrad Howitz was on the case. The Cornel -educated

biochemist was then the director of molecular biology for Biomol, a

Pennsylvania company that was a supplier of molecules for life science

researchers. Howitz was looking for chemicals that would inhibit the SIRT1

enzyme, so they could be sold to the growing number of scientists who were

starting to study the enzyme. In the process of evaluating di erent contenders,

he found two chemicals that, rather than inhibiting SIRT1, stimulated or

“activated” it, making it work ten times as fast. That was a serendipitous

discovery, not only because he was expecting to nd inhibitors but because

activators are very rare in nature. They are so rare, in fact, that most drug

companies don’t even bother fol owing up when one is discovered, guring it

must be a mistake.

The rst SIRT1-activating compound, or STAC, was a polyphenol cal ed

setin, which helps gives plants such as strawberries and persimmons their color

and is now known to also kil senescent cel s. The second was a molecule cal ed

butein, which can be found in numerous owering plants as wel as a toxic plant

known as the Chinese lacquer tree. Both had a signi cant e ect on SIRT1,

though not the sort of pedal-to-the-metal reaction that might make them ripe

for further research.

THE THREE MAIN LONGEVITY PATHWAYS, mTOR, AMPK, AND SIRTUINS, EVOLVED TO

PROTECT THE BODY DURING TIMES OF ADVERSITY BY ACTIVATING SURVIVAL

MECHANISMS. When they are activated, either by low-calorie or low-amino-acid diets, or by

exercise, organisms become healthier, disease resistant, and longer lived. Molecules that tweak

these pathways, such as rapamycin, metformin, resveratrol, and NAD boosters, can mimic the

bene ts of low-calorie diets and exercise and extend the lifespan of diverse organisms.

Howitz showed his initial results to Biomol’s founder and scienti c director,

Robert Zipkin, a bril iant chemist and entrepreneur who has an encyclopedic

knowledge of chemical structures. “Fisetin and butein, huh?” Zipkin said. “You

know what those two molecules look like? They’ve got an overlapping structure:

two phenolic rings connected by a bridge. You know what else has that

structure? Resveratrol.”

In 2002, antioxidants were al the rage. They might not have been the

antiaging and health panaceas some believed them to be, but that wasn’t yet

known. One of the antioxidants, scientists from the Karol Marcinkowski

University of Medical Sciences (now Poznan University of Medical Sciences in

Poland) had learned, was resveratrol, a natural molecule that is found in red wine

and that many plants produce in times of stress. 28 A few researchers had suggested that resveratrol might explain the “French paradox,” the fact that the

French have lower rates of heart disease, even though their diet is relatively high

in foods containing saturated fat, such as butter and cheese.

Zipkin’s guess that resveratrol might have a similar e ect as setin and butein

was right on the money. When I studied it in my lab at Harvard, I saw that it

actual y far outperformed the other two molecules.

As a reminder, aging in yeast is often measured by the number of times a

mother cel divides to produce daughter cel s. In most cases, a yeast cel gets to

about twenty- ve divisions before it dies. Because the experiments required a

week of micromanipulation of cel s while looking down a microscope, and the

fewer times you put the cel s in the fridge to get some sleep, the longer the yeast

cel s live, I assembled a lab at home on my dining room table.

There, I saw something incredible: the resveratrol-fed yeast were slightly

smal er and grew slightly more slowly than untreated yeast, getting to an average

of thirty-four divisions before dying, as though they were calorie restricted. The

human equivalent would be an extra 50 years of life. We saw increases in

maximum lifespan, too—on resveratrol, they kept going past 35. We tested

resveratrol in yeast cel s with no SIR2 gene, and there was no e ect. We tested it

on calorie-restricted yeast, and saw no further increase in lifespan, suggesting

that the same pathway was being activated; this was how calorie restriction was

working.

It seemed like a joke’s punch line—not only had we found a calorie-

restriction mimetic, something that could extend longevity without hunger, but

we’d found it in a bottle of red wine.

Howitz and I were fascinated by the fact that resveratrol is produced in

greater quantities by grapes and other plants experiencing stress. We also knew

that many other health-promoting molecules, and chemical derivatives of them,

are produced in abundance by stressed plants; we get resveratrol from grapes,

aspirin from wil ow bark, metformin from lilacs, epigal ocatechin gal ate from

green tea, quercetin from fruits, and al icin from garlic. This, we believe, is

evidence of xenohormesis—the idea that stressed plants produce chemicals for

themselves that tel their cel s to hunker down and survive. Plants have survival

circuits, too, and we think we might have evolved to sense the chemicals they

produce in times of stress as an early-warning system, of sorts, to alert our bodies

to hunker down as wel . 29

What this means, if it’s true, is that when we search for new drugs from the

natural world we should be searching the stressed-out ones: in stressed plants, in

stressed fungi, and even in the stressed microbiome populations in our guts. The

theory is also relevant to the foods we eat; plants that are stressed have higher

concentrations of xenohormetic molecules that may help us engage our own

survival circuits. Look for the most highly colored ones because xenohormetic

molecules are often yel ow, red, orange, or blue. One added bene t: they tend to

taste better. The best wines in the world are produced in dry, sun-exposed soil or

from stress-sensitive varietals such as Pinot Noir; as you might guess, they also

contain the most resveratrol. 30 The most delectable strawberries are those that

have been stressed by periods of limited water supply. And as anyone who has

grown leaf vegetables can attest, the best heads of lettuce come when the plants

are exposed to a one-two combo punch of heat and cold.31 Ever wonder why

organic foods, which are often grown under more stressful conditions, might be

better for you?

Resveratrol extended the lifespan of simple yeast cel s, but would it do the

same for other organisms? When my fel ow researcher Marc Tatar of Brown

University visited me in Boston, I gave him a smal vial of white, u y resveratrol

powder—marked only with the letter R—to try on insects in his lab. He took it

back to Rhode Island, mixed it with some yeast paste, and fed it to his fruit ies.

A few months later, I got a cal from him. “David!” he said. “What is this R

stu ?”

Under lab conditions, the fruit y Drosophila melanogaster typical y lives for

an average of forty or so days. “We added a week to their lives and sometimes

more than that,” Tatar told me. “On average, they’re living for more than fty

days.”

In human terms, that’s an additional fourteen years.

In my lab, resveratrol-fed roundworms also lived longer, an e ect that

required the worm sirtuin gene to be engaged. And when we gave resveratrol to

human cel s in culture dishes, they became resistant to DNA damage.

Later, when we fed resveratrol to obese mice at one year of age, something

interesting happened: the mice stayed fat, causing postdoctoral fel ow Joseph

Baur, now a professor at the University of Pennsylvania, to conclude that I’d

wasted more than a year of his time, jeopardizing his scienti c career with a

harebrained experiment. But when he and Rafael de Cabo, our col aborator at

the NIH, opened up the mice, they were shocked. The resveratrol mice looked

identical to mice on a normal diet, with healthy hearts, livers, arteries, and

muscles. They also had more mitochondria, less in ammation, and lower blood

sugar levels. The ones they didn’t dissect wound up living about 20 percent

longer than normal.32

Other researchers went on to show in hundreds of published studies that

resveratrol protects mice against dozens of diseases, including a variety of

cancers, heart disease, stroke and heart attacks, neurodegeneration,

in ammatory diseases, and wound healing, and general y makes mice healthier

and more resilient.33 And in col aboration with de Cabo, we discovered that

when resveratrol is combined with intermittent fasting, it can greatly extend

both average and maximum lifespan even beyond what fasting alone

accomplishes. Out of fty mice, one lived more than 3 years—in human terms,

that would amount to about 115 years. 34

The rst paper on resveratrol’s e ects on aging went on to be one of the most

highly cited papers of 200635 and was widely circulated in the mainstream

media, too. We were al over TV, and I was starting to be recognized in public. I

ran o to the little German vil age cal ed Burlo, where my wife was born, and the

news had even made it there. Sales of red wine reportedly went up 30 percent. If

you like red wine but needed a good excuse to imbibe, you can thank Rob

Zipkin.36

On our kitchen wal hangs a variety of cartoons from the day. My favorite is

one by Tom Toles. In it, a wife tries to downplay the enthusiasm of her very large

husband, who covers most of a couch.

“The study said that to get the same dose as they gave the mice you’d have to

drink between 750 and 1,000 glasses of red wine every day,” the wife says.

“The news just keeps getting better and better,” the husband replies.

As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the

human gut, two attributes that most medicines need to be e ective at treating

diseases. Despite its limitations as a drug, it did serve as an important rst proof

that a molecule can give the bene ts of calorie restriction without the subject

having to go hungry, and it set o a global race to nd other molecules that

might delay aging. Final y, at least in scienti c circles, slowing aging with a drug

was no longer considered bonkers.

By studying resveratrol, we also learned that it is possible to activate sirtuins

with a chemical. This prompted a ood of research into other sirtuin-activating

compounds, cal ed STACs, that are many times more potent than resveratrol at

stimulating the survival circuit and extending healthy lifespans in animals. They

go by names such as SRT1720 and SRT2104, both of which extend the healthy

lifespan of mice when given to them late in life.37 There are, today, hundreds of

chemicals that have been demonstrated to have an e ect on sirtuins that are even

more e ective than resveratrol’s and some that have already been demonstrated

in clinical trials to lower fatty acid and cholesterol levels, and to treat psoriasis in

humans. 38

Another STAC is NAD, sometimes written as NAD+. 39 NAD has an

advantage over other STACs because it boosts the activity of al seven sirtuins.

NAD was discovered in the early twentieth century as an alcoholic

fermentation enhancer. That was fortuitous: if it hadn’t had the potential to

improve the way we make booze, scientists might not have been so enamored by

it. Instead they worked on it for decades, and in 1938 they had a breakthrough:

NAD was able to cure black tongue disease in dogs, the canine equivalent of

pel agra. It turned out that NAD is a product of the vitamin niacin, a severe lack

of which causes in amed skin, diarrhea, dementia, skin sores, and ultimately

death. And because NAD is used by over ve hundred di erent enzymes,

without any NAD, we’d be dead in thirty seconds.

By the 1960s, however, researchers had concluded that al the interesting

research on NAD had been done. For decades to come, NAD was simply a

housekeeping chemical that teenage biology students had to learn about—with

al the enthusiasm of a teenager doing housekeeping. That al changed in the

1990s, when we began to realize that NAD wasn’t just keeping things running;

it was a central regulator of many major biological processes, including aging and

disease. That’s because Shin-ichiro Imai and Lenny Guarente showed that NAD

acts as fuel for sirtuins. Without su cient NAD, the sirtuins don’t work

e ciently: they can’t remove the acetyl groups from histones, they can’t silence

genes, and they can’t extend lifespan. And we sure wouldn’t have seen the

lifespan-extending impact of the activator resveratrol. We and others also noticed

that NAD levels decrease with age throughout the body, in the brain, blood,

muscle, immune cel s, pancreas, skin, and even the endothelial cel s that coat the

inside of microscopic blood vessels.

But because it’s so central to so many fundamental cel ular processes, no

researchers in the twentieth century had any interest in testing the e ects of

boosting levels of NAD. “Bad stu wil happen if you mess with NAD,” they

thought. But not even having tried to manipulate it, they didn’t real y know

what would happen if they did.

The bene t of working with yeast, though, is that the worst-case scenario in

any experiment is a yeast massacre.

There was little risk in looking for ways to boost NAD in yeast. So that’s

what my lab members and I did. The easiest way was to identify the genes that

make NAD in yeast. We rst discovered a gene cal ed PNC1, which turns

vitamin B3 into NAD. That led us to try boosting PNC1 by introducing four

extra copies of it into the yeast cel s, giving them ve copies in total. Those yeast

cel s lived 50 percent longer than normal, but not if we removed the SIR2 gene.

The cel s were making extra NAD, and the sirtuin survival circuit was being

engaged!

Could we do this in humans? Theoretical y, yes. We already have the

technology to do it in my lab, using viruses to deliver the human equivalent of

the PNC1 gene cal ed NAMPT. But turning humans into transgenic organisms

requires more paperwork and considerably more knowledge about safety—for

the stakes are higher than a yeast massacre.

That’s why we once again began searching for safe molecules that would

achieve the same result.

Charles Brenner, who is now the head of biochemistry at the University of

Iowa, discovered in 2004 that a form of vitamin B3 cal ed nicotinamide riboside,

or NR, is a vital precursor of NAD. He later found that NR, which is found in

trace levels in milk, can extend the lifespan of yeast cel s by boosting NAD and

increasing the activity of Sir2. Once a rare chemical, NR is now sold by the ton

each month as a nutraceutical.

Meanwhile, on a paral el path, researchers, including us, were homing in on a

chemical cal ed nicotinamide mononucleotide, or NMN, a compound made by

our cel s and found in foods such as avocado, broccoli, and cabbage. In the body,

NR is converted into NMN, which is then converted into NAD. Give an animal

a drink with NR or NMN in it, 40 and the levels of NAD in its body go up about

25 percent over the next couple of hours, about the same as if it had been fasting

or exercising a great deal.

My friend from the Guarente lab Shin-ichiro Imai demonstrated in 2011 that

NMN could treat the symptoms of type 2 diabetes in old mice by restoring

NAD levels. Then researchers in my lab at Harvard showed we could make the

mitochondria in old mice function just like mitochondria in young mice after

just a week of NMN injections.

In 2016, my other lab at the University of New South Wales col aborated

with Margaret Morris to demonstrate that NMN treats a form of type 2 diabetes

in obese female mice and their diabetes-prone o spring. And back at Harvard,

we found that NMN could give old mice the endurance of young mice and then

some, leading to the Great Mouse Treadmil Failure of 2017, when we had to

reset the tracking program on our lab’s miniature exercise machines because no

one had expected that an elderly mouse, or any mouse, could run anywhere near

three kilometers.

This molecule doesn’t just turn old mice into ultramarathoners; we have used

NMN-treated mice in studies that tested their balance, coordination, speed,

strength, and memory, too. The di erence between the mice that were on the

molecule and the mice that were not was astounding. Were they human, those

rodents would long since have been eligible for senior citizen discounts.

Nicotinamide mononucleotide turned them into the equivalent of contenders

on American Ninja Warrior. Other labs have shown that NMN can protect

against kidney damage, neurodegeneration, mitochondrial diseases, and an

inherited disease cal ed Friedreich’s ataxia that lands active 20-year-olds in

wheelchairs.

As I write this, a group of mice that were put on NMN late in life are getting

very old. In fact, only seven out of the original forty mice are stil alive, but they

are al healthy and stil moving happily around the cage. The number of mice

alive that didn’t get the NMN?

Zero.

Every day I’m asked by members of the public, “Which is the superior

molecule: NR or NMN?” We nd NMN to be more stable than NR and see

some health bene ts in mouse experiments that aren’t seen when NR is used.

But it’s NR that has been proven to extend the lifespan of mice. NMN is stil

being tested. So there’s no de nitive answer, at least not yet.

Human studies with NAD boosters are ongoing. So far, there has been no

toxicity, not even a hint of it. Studies to test its e ectiveness in muscle and

neurological diseases are in progress or about to begin, fol owed by super-NAD-

boosting molecules that are a couple of years behind them in development.

But a lot of people haven’t been content to wait for these studies, which can

take years to play out. And that has given us some interesting leads about where

these molecules, or ones like them, might take us.

FERTILE GROUND

We know that NAD boosters are an e ective treatment for a wide variety of

ailments in mice and that they extend their lifespan even when given late in life.

We know that emerging research strongly suggests they could have a similar, if

not duplicative, e ect on human health.

We also know that the way it does this, in terms of the epigenetic landscape, is

by creating the right level of stress—just enough to push our longevity genes

into action to suppress epigenetic changes to maintain the youthful program. In

doing so, NMN and other vitality molecules, including metformin and

rapamycin, reduce the buildup of informational noise that causes aging, thus

restoring the program.

How do they do this? We are stil working to understand how epigenetic

noise is dampened at a molecular level, but we know in principle how it works.

When we give silencing proteins such as sirtuins a boost, they can maintain the

youthful epigenome even with DNA damage occurring, like the long-lived yeast

cel s with extra copies of the SIR2 gene. Somehow they can cope with it. Perhaps

they are just supere cient at repairing DNA breaks and head home before they

get lost, or if half the sirtuins head o , the remaining enzymes can hold down

the fort.

Either way, the increased activity of the sirtuins may prevent Waddington’s

marbles from escaping their val eys. And even if they have started to head out of

the val ey, molecules such as NMN may push them back down, like extra gravity.

In essence, this would be age reversal in some parts of the body—a smal step,

but age reversal nonetheless.

One of the rst clues this might be true in an animal larger than a mouse

came when a student who works in my lab at Harvard came into my o ce one

afternoon.

“David,” he said quietly, “do you have a moment? There is something I need

to discuss. It’s about my mother.”

Given the expression on his face and the tone of his voice, I immediately

worried that my student, who came from another country, would tel me his

mother was sick. Having been half a planet away from my mother when she was

dying, I very much knew how that felt.

“Whatever you need,” I blurted out.

The student seemed taken aback—and I realized I hadn’t yet posed the most

pertinent question. “Is your mother al right?” I asked.

“Yes,” he said. “Wel . . . I mean, yes . . . wel . . . mostly.”

He reminded me that his mother had been taking supplemental NMN, as

some of my students and their family members do. “The thing is, wel ”—his

voice lowered to a whisper—“she has started her, um . . . cycle again.”

It took me a few seconds to realize what cycle he was talking about.

As women approach and go through menopause, the menstrual cycle can

become quite irregular, which is why a year with no periods must go by before

most doctors wil con rm that menopause has occurred.

After that, such bleeding can be a cause for concern, as it could be a sign of

cancer, broid tumors, infections, or an adverse reaction to a medication.

“Has she been seen by a doctor?” I asked.

“Yes,” my student said again. “The doctors say there is nothing wrong. They

said this just looks like a normal period.”

I was intrigued. “Okay,” I said. “What we real y need is more information.

Can you give your mom a cal to ask her some more questions?”

I’ve never seen the color so quickly wash away from someone’s face.

“Oh, David,” he pleaded, “please, please, pleeease don’t make me ask my

mother any more questions about that!”

Since that conversation, which took place in the fal of 2017, I have known a

couple of other women and read the accounts of others claiming to have had

similar experiences. These cases could, perhaps, be the result of a placebo e ect.

But a trial in 2018 to test whether an NAD booster could restore the fertility of

old horses was successful, surprising the skeptical supervising veterinarian. As far

as I know, horses don’t experience the placebo e ect.

Stil , these stories and clinical results could be random chance. These matters

wil be studied in much greater detail. If, however, it turns out that mares and

women can become fertile again, it wil completely overturn our understanding

of reproductive biology.

In school, our teachers taught us that women were born with a set number of

eggs (perhaps as many as 2 mil ion). Most of the eggs die o before puberty.

Almost al the rest are either released during menstruation throughout the

course of a woman’s life or just die o along the way, until there are no more.

And then, we were told, a woman is no longer fertile. Period.

These anecdotal reports of restored menstruation and fertile horses are early

but interesting indicators that NAD boosters might restore failing or failed

ovaries. We also see that NMN is able to restore the fertility of old mice that have

had all their eggs kil ed o by chemotherapy or have gone through

“mousopause.” These results, by the way, even though they were done multiple

times and reproduced in two di erent labs by di erent people, are so

controversial that almost no one on the team voted to publish them. I was the

exception. They remain unpublished, for now.

To me it is clear that we biologists are missing something. Something big.

In 2004, Jonathan Til y—a highly controversial gure in the reproductive

biology community—claimed that human stem cel s that can give rise to new

eggs, late in life, exist in the ovaries. Controversial though this theory is, it would

explain how it is possible to restore fertility even in mice that are old or have

undergone chemotherapy. 41,42

Whether or not “egg precursor” cel s exist in the ovary, there’s no doubt in

my mind that we are moving with staggering speed toward a world in which

women wil be able to retain fertility for a much longer portion of their lives and

possibly regain it if it is lost.

Al of this, of course, is good for people who wish to have a child but haven’t

been able to for any number of social, economic, or medical reasons. But what

does it have to do with aging?

To answer that question, we need to remember what an ovary is. It’s not just,

as so many of us were taught in school, a slow-release mechanism for human

eggs. It’s an organ—just like our hearts, kidneys, or lungs—that has a day-to-day

function, both holding on to eggs that were created during embryonic

development and potential y being a repository for additional eggs derived from

precursor cel s later in life.

The ovary is also the rst major organ to break down as a result of aging, in

humans and animal models alike. What that means in mice is that, instead of

waiting for two years for a mouse to reach “old age,” we can start to see and

investigate the causes and cures for aging in about 12 months, at the age female

mice typical y lose their ability to reproduce.

We also have to remember what NMN does: it boosts NAD, and this boosts

the activity of the SIRT2 enzyme, a human form of yeast Sir2 found in the

cytoplasm. SIRT2, we’ve found, controls the process by which an immature egg

divides so that only one copy of the mother’s chromosomes remain in the nal

egg in order to make way for the father’s chromosomes. Without NMN or

additional SIRT2 in old mice, their eggs were toast. Pairs of chromosomes were

ripped apart from numerous directions, instead of exactly two. But if the old

female mice were pretreated with NMN for a few weeks, their eggs looked

pristine, identical to those of young mice.43

Al of this is why early indicators of restored ovarian function in humans,

anecdotal as they may be, are so fascinating. If true, the mechanisms that work to

prolong, rejuvenate, and reverse aging in ovaries are pathways we can use to do

the same thing in other organs.

One more thing that is important to bear in mind: NMN is hardly the only

longevity molecule showing promise in this area. Metformin is already widely

used to improve ovulation in women with infrequent or prolonged menstrual

periods as a result of polycystic ovary syndrome.44 Meanwhile, emerging

research is demonstrating that the inhibition of mammalian target of rapamycin,

or mTOR, may be able to preserve ovarian function and fertility during

chemotherapy,45 while the same gene pathway plays an important role in male

fertility, as a central player in the production and development of sperm. 46

LIFE WITH FATHER

Most of the time, rodent studies come long before formal human studies. That

was the case for NAD boosters. But the early indicators of the safety and

e ectiveness of the molecules in yeast, worms, and rodents are such that many

people have already begun their own private human experiments.

My father is among them.

Though he trained as a biochemist, my dad’s passion was computing. He was

a computer guy at a pathology company. That meant he spent a lot of his time

sitting in front of a screen and on his behind—another thing experts say is

devastatingly bad for our health. Some researchers have even suggested it could

be as bad for us as smoking.

By the time my mother died in 2014, my father’s health had also begun its

seemingly inexorable decline. He had retired at 67 and was in his mid-70s, stil

fairly active. He liked to travel and garden. But he had passed the type 2 diabetes

threshold, was losing his hearing, and his eyes were starting to go bad. He would

tire fast. He repeated himself. He was grumpy. He was hardly a picture of

exuberant life.

He started taking metformin for his borderline type 2 diabetes. The next year

he started taking NMN.

My father has always been a skeptic. But he is also insatiably curious and was

fascinated by what he heard from me about what was happening to the mice in

my lab. NMN isn’t a regulated substance; it’s available as a supplement. So he

tried it out, starting with smal doses.

He knew quite wel , though, that there are very big di erences between mice

and humans. At rst he would say to me and to anyone else who asked,

“Nothing has changed. How would I know?”

So the statement that came about six months into his NMN tryout was

tel ing.

“I don’t want to get carried away,” he said, “but something is happening.”

He was feeling less tired, he told me. Less sore. More mental y aware. “I’m

outpacing my friends,” he said. “They’re complaining about feeling old. They

can’t even come for bushwalks with me anymore. I’m no longer feeling that way.

I don’t have aches or pains. I’m beating much younger people at rowing exercises

at the gym.” His doctor, meanwhile, was struck by the fact that his liver enzymes

normalized after twenty years of being abnormal.

Upon his next visit to the United States, I noticed that something else was

di erent, something very subtle. It dawned on me: for the rst time since my

mother’s death, the smile had returned to his face.

These days, he runs around like a teenager. Hiking for six days through wind

and snow to reach the peak of the highest mountain in Tasmania. Riding three-

wheelers through the Aussie bush. Hunting remote waterfal s in the American

West. Zip-line touring through the forest in northern Germany. Whitewater

rafting in Montana. Ice cave exploring in Austria.

He’s “aging in place,” but he’s rarely at his place. 47

And because he missed working, he took on a new career at one of Australia’s

largest universities, where he sits on the ethics committee that approves human

research studies, taking ful advantage of his knowledge about scienti c rigor,

medical practice, and data security.

You might expect this sort of behavior from someone who had lived his

whole life this way, but he is de nitely not a guy who has lived his whole life this

way. Dad used to say he wasn’t looking forward to getting old. He isn’t outgoing

or optimistic by nature; he’s more like Eeyore from Winnie-the-Pooh. He

expected to have a decent ten years of retirement, then go into a nursing home.

The future was clear. He had seen what had happened to his mother. He had

watched helplessly as her health had declined in her 70s and 80s and as she had

su ered from pain and dementia in the nal decade of her life.

With al of that fresh in mind, the idea of living much past his 70s wasn’t very

interesting to him. In fact, it was pretty scary. But he’s pretty happy with how

it’s turning out and wakes up every morning with a deep-seated desire to l his

life with new, exciting experiences. To that end, he faithful y takes his metformin

and his NMN each morning and gets nervous when they start to run low. The

turnaround in his energy, enjoyment of life, and perspective on growing old has

been remarkable. It could al be unrelated to the molecules he’s taking. I suppose

his physical and mental transformation may just be how some people age. But it

sure wasn’t that way for any of my other relatives.

My father is also wondering what to think. We are a family of scientists, after

al . “I can’t be sure that the NMN is responsible,” he told me recently. He

thought about his life for a moment, then smiled and shrugged his shoulders,

“but there’s real y no other explanation.”

Recently, after touring much of the East Coast of the United States, Dad was

heading home to Australia. I sheepishly asked him if he could y back to the

United States for an event being held the fol owing month. I had been named an

O cer of the Order of Australia, an honor bestowed “for distinguished service

to medical research into the biology of ageing, to biosecurity initiatives, and as

an advocate for the study of science,” and there was going to be a ceremony at

the Australian Embassy in Washington, DC.

“Sandra says it’s not fair of me to ask for you to come back,” I told him. “It’s

only four weeks from now, and you’re almost eighty, and it’s a long journey

back, and—”

“I would love to come,” he said, “but I’m just not sure I can t it into my

schedule.”

He canceled some meetings and did t the trip into his schedule, and having

him there, along with Sandra and the kids, ensured that it was one of the best

days of my life. As I looked at Dad, standing with my family, I thought, “This is

what longer life is al about—having your parents there for life’s important

moments.”

And as he stood there, he later told me, he thought, “This is what longer life

is al about—being around for your children’s important moments.”

My father’s story of reinvigoration is, of course, completely anecdotal. I

won’t be publishing it in a scienti c journal anytime soon—a placebo can be a

powerful drug, after al . There’s simply no way to know if the combo of NMN

and metformin is the reason he’s feeling better or is simply what he started

taking at the time he decided, subconsciously, that it was time for a big change in

his approach to life.

Compel ing evidence that the clock of aging is reversible wil come when

wel -planned double-blind human clinical studies are completed. Until then, I

remain very proud of my father, an average guy who grabbed life by the horns in

his late 70s to start his life anew—a shining example of what life can be like if we

don’t accept aging as “just the way it goes.”

Stil , it’s hard for me and anyone else who has seen what has happened to my

father to not suspect that something special might be going on.

It’s also hard to know what I know, to see what I’ve seen—the results of

experiments and other clinical trials around the world years before the rest of the

world learns about them—and not believe that something profound is about to

happen to humanity.

COME WHAT MAY

By engaging our bodies’ survival mechanisms in the absence of real adversity, wil

we push our lifespans far beyond what we can today? And what wil be the best

way to do this? Could it be a souped-up AMPK activator? A TOR inhibitor? A

STAC or NAD booster? Or a combination of them with intermittent fasting

and high-intensity interval training? The potential permutations are virtual y

endless.

Maybe the research under way on any one of these molecular approaches to

battling aging wil provide half a decade of additional good health. Maybe a

combination of these compounds and an optimal lifestyle wil be the elixir that

gets us a couple of extra decades. Or maybe, as time goes by, our enthusiasm for

these molecules wil be dwarfed by what we discover next.

The discovery of the molecules I have described here can be credited to a lot

of serendipity. But imagine what the world wil discover now that we’re actively

and intentional y looking for molecules that engage our in-built defenses.

Armies of chemists are now working to create and analyze natural and synthetic

molecules that have the potential to be even better at suppressing epigenomic

noise and resetting our epigenetic landscape.

There are hundreds of compounds that have already shown potential in this

area and hundreds of thousands more that are waiting to be researched. And it’s

very possible that there is an as-yet-undiscovered chemical out there, hiding in a

microorganism such as S. hygroscopicus or in a ower such as G. officinalis, that is

just waiting to show us another way to help our bodies stay healthier longer.

And that’s just the natural chemicals—which are typical y many times less

e ective than the synthetic drugs they inspire. Indeed, the emerging analogs of

the molecules I’ve already described are demonstrating tremendous potential in

early-stage human clinical trials.

It wil take some time to sort out which of these molecules are best, when,

and for whom. But we’re getting closer every day. There wil come a time in

which signi cantly prolonged vitality is indeed only a few pil s away; there are

too many promising leads, too many talented researchers, and too much

momentum for it to be otherwise.

Wil any of these be a “cure” for aging? No. What’s likely is that researchers

wil continue to identify molecules that are better and better at promoting both

a reduction of epigenetic noise and a rejuvenation of cel ular tissue. As we do,

we’l be buying time for other advances that wil also lead to signi cantly

prolonged vitality.

But let’s say that doesn’t happen. For the sake of argument, not to mention

emphasis, let’s pretend we live in a world in which none of these molecules had

ever been discovered and no one had ever thought to address aging with a

pharmaceutical.

That would not change the inevitability of longer and healthier lives. Not at

al . For drugs that engage the ancient survival mechanisms within us are just one

of the many ways that scientists, engineers, and entrepreneurs are setting the

stage for the most signi cant shift in the evolution of our species since . . .

. . . wel , since . . .

. . . forever.

SIX

BIG STEPS AHEAD

TO THE EXTENT WE THOUGHT about it—and we seldom did—we used to think

aging would be a very complicated thing to change, if we could change it at al .

For most of human history, of course, we simply saw aging like the coming of

the seasons; indeed, the shift from spring to summer to fal to winter was a

common analogy we used to describe the movement from childhood to young

adulthood to middle age to our “golden years.” More recently, we gured that

aging was inexorable but we might be able to deal with some of the diseases that

made it a less appealing process. Later stil , we gured that we might be able to

attack each of the hal marks and perhaps we could treat a few of the symptoms

at a time. Even then, it seemed as though it would be a huge endeavor.

But here’s the thing: it’s real y not.

Once you recognize that there are universal regulators of aging in everything

from yeast to roundworms to mice to humans . . .

. . . and once you understand that those regulators can be changed with a

molecule such as NMN or a few hours of vigorous exercise or a few less meals . . .

. . . and once you realize that it’s al just one disease . . .

. . . it al becomes clear:

Aging is going to be remarkably easy to tackle.

Easier than cancer.

I know how that sounds. It sounds crazy.

But so did the idea of microorganisms before an amateur scientist named

Antonie van Leeuwenhoek rst described the world of the “smal little animals”

he saw under his homemade microscope in 1671; for hundreds of years to come,

doctors rebel ed against the idea that they needed to wash their hands before

surgery. Now infections, one of the chief reasons patients used to die after

surgery, have become the very thing hospital personnel are most fastidiously

attentive to preventing in the operating room. Just by washing up before

surgery, we have profoundly improved the rates at which patients survive. Once

we understood what the problem was, it was an easy problem to solve.

For goodness’ sake, we solved it with soap.

The idea of vaccines would also have sounded crazy to most people before the

English physician Edward Jenner successful y used uid he had gathered from a

cowpox blister to inoculate an eight-year-old boy named James Phipps in what

today would be an egregiously unethical experiment but at the time sparked a

new era in immunological medicine. Indeed, the idea of giving a patient a little

bit of a disease in order to prevent a lot of disease would have been seen as insane

—even potential y homicidal—to many people until Jenner did it in 1796. We

now know that vaccines are the single most e ective medical intervention in

human history in terms of saving and extending lifespans. So again, once we

understood what the problem was, it was an easy one to solve.

The successes of STACs, AMPK activators, and mTOR inhibitors are a

tremendously powerful indicator that we’re working in an area of our biology

that is upstream of every major aging-associated disease. The fact that these

molecules have been shown to extend the lifespan of virtual y every organism

they’ve been tested on is further evidence that we’re engaging with an ancient

and powerful program to prolong life.1

But there is another pharmaceutical target that could increase our longevity,

just a bit downstream from the processes we believe longevity molecules are

impacting but stil upstream of a lot of the symptoms of aging.

You might recal that one of the key hal marks of aging is the accumulation of

senescent cel s. These are cel s that have permanently ceased reproduction.

Young human cel s taken out of the body and grown in a petri dish divide

about forty to sixty times until their telomeres become critical y short, a point

discovered by the anatomist Leonard Hay ick that we now cal the Hay ick

limit. Although the enzyme known as telomerase can extend telomeres—the

discovery of which a orded Elizabeth Blackburn, Carol Greider, and Jack

Szostak a Nobel Prize in 2009—it is switched o to protect us from cancer,

except in stem cel s. In 1997, it was a remarkable nding that if you put

telomerase into cultured skin cel s, they don’t ever senesce.

Why short telomeres cause senescence has been mostly worked out. A very

short telomere wil lose its histone packaging, and, like a shoelace that’s lost an

aglet, the DNA at the end of the chromosome becomes exposed. The cel detects

the DNA end and thinks it’s a DNA break. It goes to work to try to repair the

DNA end, sometimes fusing two ends of di erent chromosomes together,

which leads to hypergenome instability as chromosomes are shredded during cel

division and fused again, over and over, potential y becoming a cancer.

The other, safer solution to a short telomere is to shut the cel down. This

happens, I believe, by permanently engaging the survival circuit. The exposed

telomere, seen as a DNA break, causes epigenetic factors such as the sirtuins to

leave their posts permanently in an attempt to repair the damage, but there is no

other DNA end to ligate it to. This shuts cel replication down, similar to the

way that broken DNA in old yeast distracts Sir2 from the mating genes and

shuts down fertility.

Triggering of the DNA damage response and major alterations to the

epigenome are wel known to occur in human senescent cel s—and when we

introduce epigenetic noise into the ICE cel s they go on to senesce earlier than

untreated cel s, so maybe this idea has merit. I suspect that senescence in nerve

and muscle cel s, which don’t divide much or at al , is the result of epigenetic

noise that causes cel s to lose their identity and shut down. This once-bene cial

response, which evolved to help cel s survive DNA damage, has a dark side: the

permanently panicked cel sends out signals to surrounding cel s, causing them

to panic, too.

Senescent cel s are often referred to as “zombie cel s,” because even though

they should be dead, they refuse to die. In the petri dish and in frozen, thinly

sliced tissue sections, we can stain zombie cel s blue because they make a rare

enzyme cal ed beta-galactosidase, and when we do that, they light up clearly. The

older the cel s, the more blue we see. For example, a sample of white fat looks

white when we are in our 20s, pale blue in middle age, and dark royal blue in old

age. And that’s scary, because when we have lots of these senescent cel s in our

bodies, it’s a clear sign that aging is getting a strong grip on us.

Smal numbers of senescent cel s can cause widespread havoc. Even though

they stop dividing, they continue to release tiny proteins cal ed cytokines that

cause in ammation and attract immune cel s cal ed macrophages that then

attack the tissue. Being chronical y in amed is unhealthy: just ask someone with

multiple sclerosis, in ammatory bowel disease, or psoriasis. Al these diseases are

associated with excess cytokine proteins.2 In ammation is also a driving force in

heart disease, diabetes, and dementia. It is so central to the development of age-

related diseases that scientists often refer to the process as “in ammaging.” And

cytokines don’t just cause in ammation; they also cause other cel s to become

zombies, like a biological apocalypse. When this happens, they can even

stimulate surrounding cel s to become a tumor and spread.

We already know that destroying senescent cel s in mice can give them

substantial y healthier and signi cantly longer lives. It keeps their kidneys

functioning better for longer. It makes their hearts more resistance to stress.

Their lifespans, as a result, are 20 to 30 percent longer, according to research led

by Mayo Clinic molecular biologists Darren Baker and Jan van Deursen.3 In

animal models of disease, kil ing of senescent cel s makes brotic lungs more

pliable, slows the progression of glaucoma and osteoarthritis, and reduces the

size of al sorts of tumors.

DELETING THE ZOMBIE SENESCENT CELLS IN OLD TISSUES. Thanks to the primordial

survival circuit we’ve inherited from our ancestors, our cel s eventual y lose their identities and

cease to divide, in some cases sitting in our tissues for decades. Zombie cel s secrete factors that

accelerate cancer, in ammation, and help turn other cel s into zombies. Senescent cel s are hard

to reverse aging in, so the best thing to do is to kil them o . Drugs cal ed senolytics are in development to do just that, and they could rapidly rejuvenate us.

Understanding why senescence evolved is not just an academic exercise; it

could help us design better ways to prevent or kil senescent cel s. Cel ular

senescence is a consequence of our inherited primordial survival circuits, which

evolved to stop cel division and reproduction when DNA breaks were detected.

Just as in old yeast cel s, if DNA breaks happen too frequently or they

overwhelm the circuit, human cel s wil stop dividing, then sit there in a panic,

trying to repair the damage, messing up their epigenome, and secreting

cytokines. This is the nal stage of cel ular aging—and it’s not pretty.

If zombie cel s are so bad for our health, why doesn’t our body just kil them

o ? Why are senescent cel s al owed to cause trouble for decades? Back in the

1950s, the evolutionary biologist George Wil iams was already on the case. His

work, built upon by Judith Campisi from the Buck Institute for Research on

Aging in California, proposes that we evolved senescence as a rather clever trick

to prevent cancer when we are in our 30s and 40s. Senescent cel s, after al , don’t

divide, which means that cel s with mutations aren’t able to spread and form

tumors. But if senescence evolved to prevent cancer, why would it eventual y

promote cancer in adjacent tissue, not to mention a host of other aging-related

symptoms?

This is where “antagonistic pleiotropy” comes into play: the idea that a

survival mechanism that is good for us when we are young is kept through

evolution because this far outweighs any problems it might cause when we get

older. Yes, natural selection is cal ous, but it works.

Consider the 15-mil ion-year history of hominids, the great apes. In the vast

majority of our family’s evolutionary journey, the forces of predation, starvation,

disease, maternal mortality, infection, catastrophic weather events, and

intraspecies violence meant that very few individuals saw more than a decade or

two of life. Even in the relatively recent era of the Homo genus, what we now

think of as “middle age” is an exceptional y new phenomenon.

A life expectancy of 50 and beyond was simply not a reality for most of our

evolutionary history. Therefore, it didn’t matter if a mechanism for slowing the

spread of cancer would eventual y cause more cancer and other diseases, because

it general y worked, as long as it al owed people to breed and rear some children.

The saber-toothed tigers took things from there.

These days, of course, few people have to worry about being picked o by

hungry predators. Hunger and malnutrition are stil far too common, but abject

starvation is increasingly rare. We’re getting better and better at staving o

childhood diseases and have eliminated some of them almost entirely. Childbirth

is an increasingly safe a air (although that, too, is something that can be vastly

improved upon, especial y in the developing world). Modern sanitation has

resulted in tremendous improvements in the rates at which we die of infectious

diseases. Modern technology is helping to warn us of impending catastrophes

such as hurricanes and volcanic eruptions. And although the world often seems

to be a vicious and violent place, the worldwide homicide rate and the numbers

of wars global y have been fal ing for decades.

So we live longer—and evolution hasn’t had a chance to catch up. We’re

plagued by senescent cel s, which might as wel be radioactive waste. If you put a

tiny dab of these cel s under a young mouse’s skin, it won’t be long before

in ammation spreads and the entire mouse is l ed with zombie cel s that cause

premature signs of aging.

A class of pharmaceuticals cal ed senolytics may be the zombie kil ers we need

to ght the battle against aging on this front. These smal -molecule drugs are

designed to speci cal y kil senescent cel s by inducing the death program that

should have happened in the rst place.

That’s what the Mayo Clinic’s James Kirkland has done. He needed only a

quick course of two senolytic molecules—quercetin, which is found in capers,

kale, and red onions, and a drug cal ed dasatinib, which is a standard

chemotherapy treatment for leukemia—to eliminate the senescent cel s in lab

mice and extend their lifespan by 36 percent. 4 The implications of this work cannot be overstated. If senolytics work, you could take a course of a medicine

for a week, be rejuvenated, and come back ten years later for another course.

Meanwhile, the same medicines could be injected into an osteoarthritic joint or

an eye going blind, or inhaled into lungs made brotic and in exible by

chemotherapy, to give them an age-reversal boost, too. (Rapamycin, the Easter

Island longevity molecule, is what’s known as a “senomorphic” molecule, in that

it doesn’t kil senescent cel s but does prevent them from releasing in ammatory

molecules, which may be almost as good. 5)

The rst human trials of senolytics were started in 2018 to treat osteoarthritis

and glaucoma, conditions in which senescent cel s can accumulate. It wil be a

few more years before we know enough about the e ects and safety of these

drugs to provide them to everyone, but if they work, the potential is vast.

But there is another option, just a bit further upstream, that could be even

better.

THE HITCHHIKER’S GUIDE

The sel sh genes we discussed earlier, cal ed LINE-1 retrotransposons, and their

fossil remnants, make up about half of the human genome, what is often

referred to as “junk DNA.”

It’s a lot of genetic baggage, and they are sneaky buggers. In young cel s, these

ancient “mobile DNA elements,” also known as retrotransposons, are prevented

by chromatin from jumping out of the genome, then breaking DNA to reinsert

themselves elsewhere. We and others have shown that LINE-1 genes are bundled

up and rendered silent by sirtuins. 6 But as mice age, and possibly as we do as

wel , these sirtuins become scattered al over the genome, having been recruited

away to repair DNA breaks elsewhere, and many of them never nd their way

home. This loss is exacerbated by a drop in NAD levels—the same thing we rst

saw in old yeast. Without sirtuins to spool the chromatin and silence the

transposon DNA, cel s start to transcribe these endogenous viruses.

This is bad. And it only gets worse.

Over time, as mice age, the once silent LINE-1 prisoners are turned into

RNA and the RNA is turned into DNA, which is reinserted into the genome at

a di erent place. Besides creating genome instability and epigenomic noise that

causes in ammation, LINE-1 DNA leaks from the nucleus into the cytoplasm,

where it is recognized as a foreign invader. In response, the cel s release even

more immunostimulatory cytokines that cause in ammation throughout the

body.

New work by John Sedivy at Brown University and Vera Gorbunova from

the University of Rochester raises the possibility that one of the main reasons

SIRT6 mutant mice age so rapidly is that these retroviral hel hounds have no

leash, causing numerous DNA breaks and the epigenome to degrade rapidly

instead of slowly. Convincing evidence has come from experiments showing that

antiretrovirals, the same kinds used to ght HIV, extend the lifespan of SIRT6

mutant mice about twofold. It may turn out that, as NAD levels decline with

age, sirtuins are rendered unable to silence retrotransposon DNA. Perhaps one

day, safe antiretroviral drugs or NAD boosters wil be used to keep these

jumping genes silent. 7 We would not have stopped aging completely at its

source, but we would be ghting the battle before total anarchy ensues and the

genie that is aging becomes even harder to put back in the bottle.

VAX TO THE FUTURE

In 2018, scientists at Stanford University reported that they had developed an

inoculation that signi cantly lowered the rates at which mice su ered from

breast, lung, and skin cancer. By injecting the mice with stem cel s inactivated by

radiation and later adding a booster shot like those humans use for tetanus,

hepatitis B, and whooping cough, the stem cel s primed the immune system to

attack cancers that normal y would be invisible to the immune system. 8 Other

immuno-oncological approaches are making even greater strides. Therapies such

as PD-1 and PD-L1 inhibitors, which expose cancer cel s so they can be kil ed,

and chimeric antigen receptors T-cel (CAR-T) therapies, which modify the

patient’s own immune T-cel s and reinject them to go kil cancer cel s, are saving

lives of people who, just a few years before, have been told to go home and make

funeral arrangements. Now, some of these patients are being given a new lease

on life.

If we can use the immune system to kil cancer cel s, it stands to reason that

we can do that for senescent cel s, too. And some scientists are on the case.

Judith Campisi from the Buck Institute for Research on Aging and Manuel

Serrano from Barcelona University believe that senescent cel s, like cancers,

remain invisible to the immune system by waving little protein signs that say,

“No zombie cel s here.”

If Campisi and Serrano are right, we should be able to take away those signs

and give the immune system permission to go kil senescent cel s. Perhaps a few

decades from now a typical vaccine schedule that currently protects babies

against polio, measles, mumps, and rubel a might also include a shot to prevent

senescence when they reach middle age.

When people rst hear that it may be possible to vaccinate against aging,

rather than just treat its symptoms or slow it down, it’s not uncommon for them

to immediately express worries that we are “playing God” or “interfering with

Mother Nature.” Maybe we are, but if so, that’s not unique to people involved

in the ght against aging. We ght diseases of al kinds that God or Mother

Nature gave us. We’ve been doing so for a long time, and we’re going to keep

doing so for a long time to come.

The world rightful y celebrated the eradication of smal pox in 1980. When

malaria is likewise eradicated—and I believe it wil be sometime in the coming

decades—our global community wil rejoice once again. And if I could o er the

world a vaccine for HIV, right now, there wouldn’t be many people—no decent

ones, at least—who would say that we should just “let nature run its course.”

These are ailments we’ve long considered diseases, though, and I accept that it

wil take some time to convince people that aging is no di erent.

To this end, I’ve found this thought experiment to be helpful: imagine an

Airbus A380, a double-decker “superjumbo” l ed with six hundred people on

board, on approach to Los Angeles. The plane does not have landing gear, only

parachutes. And al but one of the doors is stuck, so when the passengers

evacuate, one by one, they’l be scattered across the most densely populated area

of the country.

Oh, and one more thing: the passengers are sick. Real y sick. The disease they

carry is highly contagious; it starts with lethargy and sore joints, then develops

into hearing and vision loss, bones as brittle as century-old teacups,

excruciatingly painful heart failure, and brain signals so badly interrupted that

many victims won’t even be able to remember who they are. No one survives

this disease, and death is almost always agonizing.

After a life of faithful service to the United States, you have found yourself

behind the Resolute Desk in the Oval O ce of the White House. The phone

rings. The deputy director for infectious diseases from the Centers for Disease

Control and Prevention tel s you that if even one of the passengers is permitted

to parachute into the greater Los Angeles area, tens of thousands of people wil

catch the disease and die. Each additional parachuter wil increase the projected

death tol exponential y.

The moment you put the receiver down, the phone rings again. The

chairperson of the Joint Chiefs of Sta tel s you that six US Air Force F-22

Raptor ghters are tracking the plane as it circles over the Paci c Ocean. The

pilots have it locked in; their missiles are ready. The plane is running out of gas.

The fate of the passengers, and the entire United States, rests upon your orders.

What do you do?

This, of course, is a “trol ey problem,” an ethical thought experiment, of the

type popularized by the philosopher Philippa Foot, that pits our moral duty not

to in ict harm on others against our social responsibility to save a greater

number of lives. It’s also, however, a handy metaphor, because the highly

contagious disease the passengers are carrying is, as you doubtless have noticed,

nothing more than a faster-acting version of aging.

When presented with the idea of a disease that could infect and kil legions of

people—with horrendous symptoms, no less—very few of us would not make

the horrible but necessary cal to shoot down the plane, taking the lives of

hundreds of people to protect the lives of mil ions.

With that in mind, consider this question: If you would sacri ce hundreds of

human lives to stop a fast-acting version of aging from infecting mil ions, what

would you be wil ing to do to prevent the disease as it actual y occurs in the lives

of everyone on the planet?

Worry not: what I’m about to suggest won’t actual y come at the cost of

human lives. Not hundreds. Not dozens. Not even one. But it would require us

to confront an idea that many people would nd alarming: infecting ourselves

with a virus that would quickly move into every cel in our body, turning us into

genetical y modi ed organisms. The virus wouldn’t kil ; it would do the

opposite.

GET WITH THE REPROGRAM

Vaccines against senescent cel s, CR mimetics, and retrotransposon suppressors

are possible pathways to prolonged vitality, and work is under way already in labs

and clinics around the world. But what if we didn’t need any of that? What if we

could reset the aging clock and prevent cel s from ever losing their identity and

becoming senescent in the rst place?

Yes, the solution to aging could be cel ular reprogramming, a resetting of the

landscape—the way, for instance, that jel y sh have been shown to do by using

smal body fragments to regenerate polyps that spawn a dozen new jel ies.

The DNA blueprint to be young, after al , is always there, even when we are

old. So how can we make the cel reread the blueprint? Here it’s helpful to

return to the DVD metaphor. Over time, thanks to use and perhaps misuse, the

digital information encoded as pits in the top layer of aluminum becomes

obscured by some deep and some ne scratches, making it hard for the DVD

player to read the disk. A DVD has thirty miles of data spiraled around the disk

from the edge to the center, so if the disc is scratched, nding the start of a

particular song becomes extremely di cult.

It’s the same situation for old cel s, but far worse. The DNA in our cel s holds

about the same amount of data as a DVD, but in six feet of DNA that’s packed

into a cel a tenth the size of a speck of dust. Together, al the DNA in our body,

if laid end to end, would stretch twice the diameter of the solar system. Unlike a

simple DVD, though, the DNA in our cel s is wet and vibrating in three

dimensions. And there aren’t 50 songs, there are more than 20,000. No wonder

gene reading becomes di cult the older we get; it’s miraculous that any cel nds

the right genes in the rst place.

There are two ways to play an old, scratched DVD with delity. You could

buy a better DVD player, one with a more powerful laser that could reveal the

data under the scratches. Or you could polish the disc to expose the information

again, making the DVD as good as new. I’ve heard that a rag with toothpaste on

it works just ne.

Restoring youth in an organism is never going to be as simple as polishing a

disk with toothpaste, but the rst approach, putting a scratched DVD into a

new player, was. Oxford University professor John Gurdon rst did this in 1958,

when he removed the chromosomes from a frog’s egg and replaced them with

some chromosomes from an adult frog and obtained living tadpoles. Then, in

1996, Ian Wilmut and his col eagues at the University of Edinburgh replaced the

chromosomes of a sheep’s egg with those from an udder cel . The result was

Dol y, whose birth was met with a heated public debate about the purported

dangers of cloning. The debate overshadowed the most important point: that

old DNA retains the information needed to be young again.

WE ARE ANALOG, THEREFORE WE AGE. According to the Information Theory of Aging, we

become old and susceptible to diseases because our cel s lose youthful information. DNA stores

information digital y, a robust format, whereas the epigenome stores it in analog format, and is

therefore prone to the introduction of epigenetic “noise.” An apt metaphor is a DVD player

from the 1990s. The information is digital; the reader that moves around is analog. Aging is

similar to the accumulation of scratches on the disc so the information can no longer be read

correctly. Where’s the polish?

That debate has since died down; the world today has other concerns.

Cloning is now routinely done to produce farm animals, racehorses, and even

pets. In 2017, you could order up a dog clone for the “bargain” price of $40,000

—or two of them, as Barbra Streisand did to replace her beloved Sammie, a

curly-haired Coton de Tulear. 9 The fact that Sammie was 14 when she died and

donated cel s—that’s somewhere in the range of 75 in dog years—didn’t impact

the clones one bit.

The implications of these experiments are profound. What they show is that

aging can be reset. The scratches on the DVD can be removed, and the original

information can be recovered. Epigenomic noise is not a one-way street.

But how might we reset the body without becoming a clone?

In his 1948 publications about the preservation of information during data

transmissions, Claude Shannon provided a valuable clue.10

In an abstract sense, he proposed that information loss is simply an increase

in entropy, or the uncertainty of resolving a message, and provided bril iant

equations to back his ideas up. His work stemmed from the mathematics of

Harry Nyquist and Ralph Hartley, two other engineers at Bel Labs who, in the

1920s, revolutionized our understanding of information transmission. Their

notions of an “ideal code” were important for Shannon’s development of his

communication theory.

In the 1940s, Shannon became obsessed with communications over a noisy

channel, in which information is simply a set of possible messages that needs to

be reconstructed by the recipient of the message—the receiver.

As Shannon bril iantly showed in his “noisy-channel coding theorem,” it is

possible to communicate information nearly error free as long as you don’t

exceed the channel capacity. But if the data exceeds the channel capacity or is

subject to noise, which is often the case with analog data, the best way to ensure

it makes it to the receiver is to store a backup set of data. That way, even if some

primary data are lost, an “observer” can send this “correcting data” to a

“correcting device” to recover the original message. This is how the internet

works. If data packets are lost, they are recovered and resent moments later, al

thanks to Transmission Control Protocol/Internet Protocol (TCP/IP).

As Shannon put it, “This observer notes the errors in the recovered message

and transmits data to the receiving point over a ‘correction channel’ to enable

the receiver to correct the errors.”

Though it may sound like esoteric language from the 1940s, what dawned on

me in 2014 is that Shannon’s “A Mathematical Theory of Communication” is

relevant to the Information Theory of Aging.

In Shannon’s drawing, there are three di erent components that have analogs

in biology:

• The “source” of the information is the egg and sperm, from your parents.

• The “transmitter” is the epigenome, transmitting analog information

through space and time.

• The “receiver” is your body in the future.

When an egg is fertilized, epigenetic information—biological “radio

signals”—is sent out. It travels between dividing cel s and across time. If al goes

wel , the egg develops into a healthy baby and eventual y a healthy teenager. But

with successive cel divisions and the overreaction of the survival circuit to DNA

damage, the signal becomes increasingly noisy. Eventual y, the receiver, your

body when it is 80, has lost a lot of the original information.

We know that cloning a new tadpole or a mammal from an old one is

possible. So even if a lot of the epigenetic information is lost in old age, obscured

by epigenetic noise, there must be information that tel s the cel how to reset.

This fundamental information, laid down early in life, is able to tel the body

how to be young again—the equivalent of a backup of the original data.

CLAUDE SHANNON’S 1948 SOLUTION TO RECOVERING LOST INFORMATION DURING DATA

TRANSMISSIONS LED TO CELL PHONES AND THE INTERNET. It may also be the solution to

reversing aging.

Source: C. E. Shannon, “A Mathematical Theory of Communication,” Bell System Technical

Journal 27, no. 3 (July 1948): 379–423 and 27, no. 4 (October 1948): 623–66.

To end aging as we know it, we need to nd three more things that Shannon

knew were essential for a signal to be restored even if it is obscured by noise:

• An “observer” who records the original data

• The original “correction data”

• And a “correcting device” to restore the original signal

I believe we may have nal y found the biological correcting device.

In 2006, the Japanese stem cel researcher Shinya Yamanaka announced to the

world that after testing dozens of combinations of genes, he had discovered that

a set of four—Oct4, Klf4, Sox2, and c-Myc—could induce adult cel s to become

pluripotent stem cel s, or iPSCs, which are immature cel s that can be coaxed

into becoming any other cel type. These four genes code for powerful

transcription factors that each controls entire sets of other genes that move cel s

around on the Waddington landscape during embryonic development. These

genes are found in most multicel ular species, including chimpanzees, monkeys,

dogs, cows, mice, rats, chickens, sh, and frogs. For his discovery, essential y

showing that complete cel ular age reversal was possible in a petri dish, Yamanaka

won the Nobel Prize in Physiology or Medicine along with John Gurdon in

2012. We now cal these four genes Yamanaka factors.

At rst blush, Yamanaka’s experiments might sound like a nifty laboratory

parlor trick. But the implications for aging are profound, and not only because

he paved the way for us to grow entirely new populations of blood cel s, tissues,

and organs in the dish that can be and are being transplanted into patients.

What he identi ed, I believe, is the reset switch responsible for Gurdon’s

tadpoles—the biological correcting device.

I predict, and my students are now showing in the lab, that we can use these

and other switches not just to reset our cel s in petri dishes but to reset an entire

body’s epigenetic landscape—to get the marbles back into the val eys where they

belong—sending sirtuins back to where they came from, for instance. Cel s that

have lost their identity during aging can be led back to their true selves. This is

the DVD polish we’ve been looking for.

We are making progress every week in restoring the youthful epigenome of

mice by delivering reprogramming factors. The pace of discovery is mind

spinning. A ful night of sleep for me and my lab members is increasingly rare.

In the 1990s, there were major concerns about the safety of delivering genes

to humans. But there are a rapidly increasing number of approved gene therapy

products and hundreds of clinical trials under way. Patients with an RPE65

mutation that causes blindness, for example, can now be cured with a simple

injection of a safe virus that infects the retina and delivers, forever, the functional

RPE65 gene.

I predict that cel ular reprogramming in the body wil rst be used to treat

age-related diseases in the eye, such as glaucoma and macular degeneration (the

eye is the organ of choice to trial gene therapies because it is immunological y

isolated). But if the therapy is safe enough to deliver into the entire body—as the

long-term mouse studies in my lab suggest they might one day be—this may be

in our future:

At age 30, you would get a week’s course of three injections that introduce a

special y engineered adeno-associated virus, or AAV, which causes a very mild

immune response, less even than what is commonly caused by a u shot. The

virus, which has been known to scientists since the 1960s, has been modi ed so

it doesn’t spread or cause il ness. What this theoretical version of the virus would

carry would be a smal number of genes—some combination of Yamanaka

factors, perhaps—and a fail-safe switch that could be turned on with a wel -

tolerated molecule such as doxycycline, an antibiotic that can be taken as a

tablet, or, even better, one that’s completely inert.

Nothing, at that point, would change in the way your genes work. But when

you began to see and feel the e ects of aging, likely sometime in your mid-40s,

you would be prescribed a month’s course of doxycycline. With that, the

reprogramming genes would be switched on.

During the process, you’d likely place a drop of blood in a home biotracker or

pay a visit to the doctor to make sure the system was working as expected, but

that’s about it. Over the next month, your body would undergo a rejuvenation

process as Waddington’s marbles were sent back to where they once were when

you were young. Gray hair would disappear. Wounds would heal faster. Wrinkles

would fade. Organs would regenerate. You would think faster, hear higher-

pitched sounds, and no longer need glasses to read a menu. Your body would feel

young again.

Like Benjamin Button, you would feel 35 again. Then 30. Then 25.

But unlike Benjamin Button, that’s where you would stop. The prescription

would be discontinued. The AAV would switch o . The Yamanaka factors

would fal silent. Biological y, physical y, and mental y, you would be a couple of

decades younger, but you’d retain al your knowledge, wisdom, and memories.

You would be young again, not just looking young but actual y young, free to

spend the next few decades of your life without the aches and pains of middle

age, untroubled by the prospects of cancer and heart disease. Then, a few more

decades down the road, when those gray hairs begin showing up again, you’d

start another cycle of the prescribed trigger.

What’s more, with the pace at which biotech is advancing, and as we learn

how to manipulate the factors that reset our cel s, we may be able to move away

from using viruses and simply take a month’s course of pil s.

Does that sound like science ction? Something that is very far out in the

future? Let me be clear: it’s not.

Manuel Serrano, the leader of the Cel ular Plasticity and Disease laboratory at

the Institute for Research in Biomedicine in Barcelona, and Juan Carlos Izpisua

Belmonte, at the Salk Institute for Biological Studies in San Diego, have already

engineered mice that have al of the Yamanaka factors from birth; these can be

turned on by injecting the mice with doxycycline. In a now-famous study from

2016, when Belmonte triggered the Yamanaka factors for just two days a week

throughout the lifespan of a prematurely aging mouse breed cal ed LMNA, the

mice remained young compared to their untreated siblings and lived 40 percent

longer. 11 He’s shown that the skin and kidneys of regular old mice heal more

quickly, too.

The Yamanaka treatment, however, was highly toxic. If Belmonte overdid it

by giving the mice the antibiotic for a few more days, the mice died. Serrano had

also shown that by pushing the marbles too far up the landscape, the four-gene

combo could induce teratomas, which are particularly disgusting tumors made

up of several types of tissue, such as hair, muscle, or bone. Clearly, this tech is

not ready for prime time. At least not yet. But we’re getting closer every day to

being able to control the Waddington marbles safely, making sure they land back

precisely in their original val eys and not at the top of the mountain, where they

could cause cancer.

While al this was going on, guided by the success of the ICE mouse

experiments, my lab had been looking for ways to delay and reverse epigenetic

aging. We’d tried many di erent approaches: the Notch gene, Wnt, the four

Yamanaka factors. Some had worked a little, but most were turning into tumor

cel s.One day in 2016, after failing consistently for two years to get old cels to age

in reverse without turning into tumor cel s, a bril iant graduate student named

Yuancheng Lu came into my o ce to say he was close to quitting. As a nal

e ort, he suggested he try leaving out the c-Myc gene that was the likely cause of

the teratomas, and I encouraged him to do so.

He delivered a viral package to mice, but this time with only three of the

Yamanaka factors, then turned them on using doxycycline and waited for al the

mice to get sick or die. But none of them did. They were total y ne. And after

months of monitoring, no tumors arose, either. It was a surprise to both of us—

a great surprise.

Instead of waiting for another year to see if the mice lived longer, Yuancheng

suggested he use a mouse’s optic nerve as a way to test age reversal and

rejuvenation. I was skeptical.

“I’m not superoptimistic this wil work,” I told him. “Optic nerves just don’t

regenerate, unless you are a newborn.”

The intricate network of cel s and bers that transmit nervous signals across

our bodies is divided into two parts: the peripheral system and the central

system. We’ve known for a long time that peripheral nerves, like those in our

arms and legs, can grow back, albeit very, very slowly. The nerves of the central

system, though—optic nerves and the nerves of the spinal cord—never grow

back. Even those scientists who bucked convention, proposing novel therapies

that could regenerate some aspect of the central system, have general y been

circumspect about the potential for signi cant regrowth. Decades of work

aimed at reversing glaucoma in the eye and spinal cord injury has had almost no

positive momentum.

“You’ve picked the hardest problem in biology to solve,” I told Yuancheng.

“But,” he replied, “if we could solve that problem . . .”

There might have been a thousand ways to measure the impact of age reversal

in mice, but buoyed by his recent successes, he decided to “go big or go home.” I

liked that.

“No one changes the world by not taking risks,” I told him. “Go test it.”

The images that came to me in a text message a few months later took my

breath away—so much so that I needed to make sure that what I was seeing was

real.I caled Yuancheng immediately. “Am I seeing what I think I am seeing?”

“Maybe,” he said. “What are you seeing?”

“The future,” I said.

Yuancheng let out a tremendous sigh of relief. “David,” he said, “an hour ago

I thought I was going to fail.”

For researchers, doubt is no vice. Doubt is the very normal and very human

consequence of pushing yourself to do audacious things without knowing how

those things are going to work out.

But on that day, things sure did seem to be working out. The image

Yuancheng rst texted to me looked like an orange, glowing jel y sh; its head

was at the top, where the eye of the mouse sits, with long tentacles owing down

toward the brain. Two weeks earlier, Yuancheng and our col aborators had

squeezed the optic nerve a few mil imeters from the back of the eye with a set of

tweezers, causing almost al the nerve cel axons, the tentacles, to die back toward

the brain. They injected an orange uorescent dye into the eye that is taken up

by living neurons. So when Yuancheng took a microscope and looked below the

crush site, there were no glowing nerves, just a mass of dead cel remnants.

The next picture he sent was an example of one where the reprogramming

virus had been turned on after the crush. Instead of dead cel s, a network of

long, healthy spindly tentacles was making its way to connect up with the brain.

It was the greatest example of nerve generation in history, and Yuancheng was

only just getting started.

No one had really expected the reprogramming to work so wel . One-month-

old mice were initial y chosen for these experiments to give us the greatest chance

of success and because that’s what everyone else does. But Yuancheng and our

skil ed col aborators in Professor Zhigang He’s lab at Children’s Hospital at

Harvard Medical School have now tested our reprogramming regimen on the

damaged optic nerves of middle-aged mice aged twelve months. Their nerves also

regenerate.

As I write this, we have restored vision in regular old mice.

Vision declines dramatical y in a mouse by 12 months of age. Bruce Ksander

and Meredith Gregory-Ksander, from Massachusetts Eye and Ear at Harvard,

know this wel . There is a loss of the nerve impulses in the retina, and old mice

don’t move their heads as often when moving lines are displayed in front of

them, because they simply don’t see them.

“David, I must admit,” Bruce said, “I never expected this reprogramming

stu to work on normal aged eyes. I was only testing your virus because you were

so excited to try it.”

The result he had seen the morning before had been the most exciting day in

his research life: our OSK reprogramming virus had restored vision.

A few weeks later, Meredith showed that reprogramming also works to

reverse vision loss caused by internal eye pressure known as glaucoma.

“Do you know what we’ve discovered?” Bruce remarked. “Everyone else has

been working to slow the progression of glaucoma. This treatment restores

vision!”

If adult cel s in the body, even old nerves, can be reprogrammed to regain a

youthful epigenome, the information to be young cannot all be lost. There

must be a repository of correction data, a backup set of data or molecular

beacons, that is retained through adulthood and can be accessed by the

Yamanaka factors to reset the epigenome using the cel ular equivalent of

TCP/IP.

What those youth markers are, we’re stil not sure. They are likely to involve

methyl tags on DNA, which are used to estimate an organism’s age, the so-cal ed

Horvath clock. They likely also involve something else: a protein, an RNA, or

even a novel chemical attached to DNA that we haven’t yet discovered. But

whatever they are made of, they are important, for they would be the

fundamental correcting data that cel s retain over a lifetime that somehow direct

a reboot.

EPIGENETIC REPROGRAMMING REGROWS OPTIC NERVES AND RESTORES EYESIGHT IN OLD

MICE. The Information Theory of Aging predicts that it is a loss of epigenetic rather than

genetic information in the form of mutations. By infecting mice with reprogramming genes

cal ed Oct4, Sox2, and Klf4, the age of cel s is reversed by the TET enzymes, which remove just

the right methyl tags on DNA, reversing the clock of aging and al owing the cel s to survive and

grow like a newborn’s. How the enzymes know which tags are the youthful ones is a mystery.

Solving that mystery would be the equivalent of nding Claude Shannon’s “observer,” the

person who holds the the original data.

We also need to nd the observer, the one who records what the original

signal is when we are young. It can’t just be DNA methylation, because that

doesn’t explain how the reprogrammed cel s know to focus on some of the

youthful methyl marks and strip o the ones that accumulated during aging, the

cel equivalent of the scratches on the DVD. Perhaps it is a specialized histone, or

a transcription factor, or a protein that latches onto methylated DNA when we

are developing in utero and stays there for eighty years waiting until a signal

comes from the correcting device to restore the original information.

In Claude Shannon’s parlance, when the correcting device is switched on by

infecting cel s with OSK genes, the cel somehow knows how to contact the

observer and use the correction data to restore the original signal to that of a young cel .

Growing new nerves and restoring eyesight wasn’t enough for Yuancheng.

When the DNA of the damaged neurons was examined, they seemed to be going

through a very rapid aging program, one that was countered by the

reprogramming factors. The neurons that received the reprogramming factors

didn’t age, and they didn’t die. This is a radical idea but one that makes a lot of

sense: severe cel ular injury overwhelms the survival circuit and accelerates aging

of the cel , leading to death, unless the clock is somehow reversed.

With these discoveries, we may be on the verge of understanding what makes

biological time tick and how to wind it back. We know from our experiments

that the biological information correcting device requires enzymes cal ed ten-

eleven translocation enzymes, or TETs, which clip o methyl tags from DNA,

the same chemical tags that mark the passage of the Horvath aging clock. This is

no coincidence, and points to the DNA methylation clock as not just an

indicator of age but a control er of it. It’s the di erence between a wristwatch

and physical time.

In their role as a component of the correcting device, the TETs cannot just

strip o al the methyls from the genome, for that would turn a cel into a

primordial stem cel . We would not have old mice that can see better: we would

have blind mice with tumors. How the TETs know to remove only the more

recent methyls while preserving the original ones is a complete mystery.

It wil likely take another decade and many other labs’ work to know precisely

what the biological equivalent of the TCP/IP information recovery system is.

But whatever it is, eyesight that should not be able to be restored is being

restored and cel s that should not be able to regrow are regrowing.

Compared to the decades of research into how to slow down aging and age-

related disease by a few percent, the reprogramming work has been relatively

quick and easy. Al it took was an intrepid idea and the courage to buck

convention.

The future looks interesting, to say the least. If we can x the toughest-to- x

and regenerate the toughest-to-regenerate cel s in our body, there’s real y no

reason to suspect we cannot regrow any type of cel s our bodies need. Yes, that

could mean xing fresh spinal cord injuries, but it also means regrowing any

other kind of tissue in our body that has been damaged by age: from the liver to

the kidney, from the heart to the brain. Nothing is o the table.

So far, the three-Yamanaka-gene combination seems safe in mice even when

turned on for a year, but there is stil plenty of work to be done. There are a lot

of unanswered questions: Can we deliver the combination to al cel s? Wil it

eventual y cause cancer? Should we keep the genes on or turn them o to let the

cel s rest? Wil this work in some tissues better than others? Can it be given to

middle-aged people, before they become sick, the same way we take statins to

keep cholesterol in check to prevent heart disease?

I have little doubt that cel ular reprogramming is the next frontier in aging

research. One day it might be possible to reprogram cel s via pil s that stimulate

the activity of the OSK factors or the TETs. This may be simpler than it sounds.

Natural molecules stimulate the TET enzymes, including vitamin C and alpha-

ketoglutarate, a molecule made in mitochondria that is boosted by CR and,

when given to nematode worms, extends their lifespan, too.

For now, though, the best bet is gene therapy.

Because it could be so impactful, we should start debating the ethics of this

technology now, before it arrives on our doorstep. The rst question is who

should be al owed to use this technology. A select few? The rich? The very sick?

Should doctors let people who have terminal il nesses try it for so-cal ed

compassionate use? How about people over 100? Or 80? Or 60? When does the

reward outweigh the risk?

There is an army of people wil ing to “boldly go,” sound-minded volunteers

in their 90s and 100s whose bodies have been broken by the disease of aging. I

can assure you that there is no shortage of those who, having peered up the road

at perhaps a few more years of life that is de ned by ever-increasing frailty and

pain, are ready to take a chance at a few more good years, if not for that, then for

the chance to give their children, grandchildren, and great-grandchildren a

longer, healthier life. What do they have to lose, after al ?

The ethics of the technology become more di cult, though, if

reprogramming becomes safe enough to use in a way that is preventive. At what

age should it be given? Does a disease have to appear before an antibiotic

activator of reprogramming is prescribed? If mainstream doctors refuse to help,

wil people head overseas? If the technology could signi cantly cut health care

costs, should it be mandated?

And if we can help children live longer, healthier lives, do we have a moral

obligation to do so? If reprogramming technology can help a child repair an eye

or recover from a spinal injury, should the genes be delivered before an accident

happens so they are ready to be switched on at a moment’s notice, starting

perhaps with an antibiotic drip in the ambulance?

If smal pox were to return to our planet, after al , parents who refused to

vaccinate their children would be pariahs of the lowest order. When safe and

e ective treatments are available for a common childhood disease, parents who

refuse to save their children’s lives can have their guardianship overridden by the

doctrine of parens patriae.

Should every human have a choice to su er from aging? Or should that

choice be made, as vaccine decisions are in most cases, for the good of both

individuals and humankind? Wil those who elect to be rejuvenated stil have to

pay for those who have decided not to? Is it moral y wrong not to do so,

knowing you wil prematurely become a burden on family members?

These are theoretical questions today, but they probably won’t remain

theoretical for long.

In late 2018, a Chinese researcher, He Jiankui, reported that he had helped

create the world’s rst genetical y altered children—twin girls whose births

sparked a debate in scienti c circles about the ethics of using gene editing to

make “designer babies.”

The side e ects of inducing DNA damage in embryos and the accuracy of

gene editing are not wel understood yet, which is why the scienti c community

has had such a violent negative reaction. There is also a tacit reason: scientists are

fearful that gene-editing technologies, if abused, wil go the way of GMOs and

be outlawed for political or irrational reasons before their true potential can be

realized.

These fears may be unfounded. If news of the rst genetical y modi ed

children had broken in the 2000s, it would have sparked global debate and

dominated the news for months. Protesters would have stormed labs, and

presidents would have banned this use of the technology on embryos. But how

times have changed. With a news cycle of hours and politics dished out over the

internet, the story lasted a few days; then the world moved on to other, more

interesting topics.

He’s stated intention was to give the twins the ability to resist HIV. That may

sound admirable, but if I do the numbers, the risk wasn’t worth it. The chance

of contracting HIV in China is less than one in a thousand. If He was going to

maximize health bene ts to o set the risks of the procedure, why not edit a gene

that causes heart disease, which has an almost one-in-two chance of kil ing

them? 12 Or aging, which has a 90 percent chance of kil ing them? HIV

immunity was just the simplest edit, not the most impactful.

As these technologies become commonplace and parents ponder how to get

the biggest bang for the buck, how long wil it be before another rogue scientist

teams up with the world’s most driven helicopter parent to create a genetical y

modi ed family with the capacity to resist the e ects of aging?

It may not be long at al .

SEVEN

THE AGE OF INNOVATION

THE FOUR PRESCRIPTION MEDICINES KUHN Lawan was taking were precisely right for

the cancer with which she had been diagnosed. But the drugs weren’t working.

Not even a bit. The elderly Thai woman’s lung cancer persisted. And with it, it

seemed, the end of her life was growing ever nearer.

Her children were understandably distraught. The doctors had told them

that Lawan’s cancer was likely treatable. They seemed to have caught it early,

after al . The fear and uncertainty they’d felt when their mother was rst

diagnosed had been replaced with hope, only to give way, once again, to fear and

uncertainty.

Dr. Mark Boguski has spent a long time thinking about people such as Lawan

and about how modern medicine has long failed so many people like her,

especial y later in life.

“In the most common manner of medical thinking, Lawan was getting the

right care,” he told me one day. “Her doctors in Thailand were top notch. But

that’s the thing about how we do medicine.”

Most doctors, he said, stil rely on early-twentieth-century technology to

diagnose and treat life-threatening diseases. Take a swab and grow it in a petri

dish. Bang the knee and wait for a kick. Breathe in, breathe out. Look to the left

and cough.

When it comes to cancer, doctors note where a tumor is growing and cut out

a tissue sample. Then they send it to a lab, where it is put into wax, cut into thin

slices, stained with red and blue dyes, and looked at under the microscope. That

works—sometimes. Sometimes the correct medicine is given.

But sometimes it isn’t. That’s because, the way I see it, looking at a tumor in

this way is the equivalent of a mechanic trying to diagnose a car’s faulty engine

without plugging into the vehicle’s computer. It’s an educated guess. Most of us

accept this sort of approach when it comes to potential y life-and-death

decisions. Yet in the United States alone, with one of the better health care

systems in the world, about 5 percent of cancer patients, or 86,500 people, are

misdiagnosed every year. 1

From the time he began studying computational biology in the early 1980s,

Boguski has been driven by the idea of making medical care more exacting. He is

a luminary in the eld of genomics—and one of the rst scientists engaged in

the Human Genome Project.

“What we cal ‘good medicine’ is doing what works for most of the people

most of the time,” Boguski told me. “But not everyone is most people.”

And so there was a chance, and not a smal one, that Kuhn Lawan was getting

the wrong care. And that might have actual y been making her worse.

But Boguski believes there is hope in a new way of doing medicine. A better

way. A way that uses new technologies, many that are already here but simply

not being utilized to their ful est potential, to refocus our medical system on

individuals—upending centuries of deeply entrenched medical culture and

philosophy. He coined the term precision medicine to describe the promise of

next-generation health monitoring, genome sequencing, and analytics for

treating patients based on personal data, not diagnostic manuals.

Thanks to the plummeting prices of DNA sequencing, wearable devices,

massive computing power, and arti cial intel igence, we’re moving into a world

in which treatment decisions no longer have to be based on what is best for most

people most of the time. These technologies are available to some patients now

and wil be available to most people on the planet in the next couple of decades.

That’s going to save mil ions of lives—and it’s going to extend average healthy

lifespans irrespective of whether we extend maximum lifespans.

But for mil ions of people like Lawan, these advances cannot come soon

enough. When her family sought a second opinion in the form of precision

DNA sequencing of her lung tumor biopsy, the totality of the danger she was in

became crystal clear. Lawan did have an aggressive cancer but not the kind of

cancer for which she was being treated. She didn’t have lung cancer; she had a

solid form of leukemia growing in her lung.

In the vast majority of cases in which cancer is found where it was found in

Lawan’s body, it is indeed lung cancer. But now that we can detect the genetic

signature of speci c forms of cancer, using the place where you nd the cancer as

the only guide for what treatment to use is as ridiculous as categorizing an

animal species based on where you’ve located it. It is like saying a whale is a sh

because they both live in water.

Once we have a better idea of what kind of cancer we’re dealing with, we can

better apply emerging techniques for dealing with it. We can even design a

therapy tailored to a patient’s speci c tumor—kil ing it before it has a chance to

grow or spread to another place in the body.

That’s the idea behind one of the cancer- ghting innovations we discussed

earlier, CAR T-cel therapy, in which doctors remove immune system cel s from

a patient’s blood and add a gene that al ows the cel s to bind to proteins on the

patient’s tumor. Grown en masse in a lab and then reinfused into the patient’s

body, the CAR T-cel s go to work, hunting down cancer cel s and kil ing them

by using the body’s own defenses.

Another immuno-oncology approach we discussed earlier, checkpoint

blockade therapy, quashes the ability of cancerous cel s to evade detection by our

immune systems. Much of the early work on this technique was completed by

Arlene Sharpe, whose lab is located on the oor above mine at Harvard Medical

School. In this approach, drugs are used to block the ability of cancer cel s to

present themselves as regular cel s, essential y con scating their fake passports

and thus making it easier for T-cel s to discriminate between friend and foe. This

is the approach that was used, along with radiation therapy, by former president

Jimmy Carter’s doctors to help his immune system ght o the melanoma in his

brain and liver. Prior to this innovation, a diagnosis like his was, without

exception, fatal.

CAR-T therapy and checkpoint inhibition are less than a decade old. And

there are hundreds of other immuno-oncology clinical trials under way. The

results thus far are promising, with remission rates of greater than 80 percent in

some studies. Doctors who have spent their entire careers ghting cancer say this

is the revolution they’ve been waiting for.

DNA-sequencing technology has also o ered us an opportunity to

understand the evolution of a speci c patient’s cancer. We can take single cel s

from a slice of a tumor, read every letter of the DNA in those cel s, and look at

the cel s’ three-dimensional chromatin architecture. In doing so, we can see the

ages of di erent parts of the tumor. We can see how it has grown, how it has

continued to mutate, and how it has lost its identity over time. That’s

important, because if you look at only one part of a tumor—an older part, for

instance—you could be missing the most aggressive part. Accordingly, you

might treat it with a less e ective therapy.

Through sequencing, we can even see what kinds of bacteria have managed to

make their way into a tumor. Bacteria, it turns out, can protect tumors from

anticancer drugs. Using genomics, we can identify which bacteria are present

and predict which antibiotics wil work against those single-cel ed tumor

protectors.

We can do al of this. Right now. Yet in many hospitals around the world the

if-it-is-here-it-must-be-this and if-the-symptoms-are-this-it-must-be-that modes

of diagnosis are stil practiced. And so, procedural y speaking, the doctors who

treated Lawan had done nothing wrong. They had simply done what doctors al

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over the world do, fol owing an empirical process of diagnosis and intervention

that leads to positive outcomes in most people most of the time.

If you accept that this is simply the way we care for people—and that it

usual y produces the right results—you could cal this an understandable

medical approach. But if you picture your own mother accidental y receiving a

cancer treatment she doesn’t need while the medicine that wil save her life sits

on a shelf nearby, you’l probably come to a di erent conclusion about what is,

in fact, “understandable.”

The hardworking, ethical doctors, nurses, and medical professionals who go

to war with death every day, while navigating the overarching standard-of-care

stipulations of governmental programs and insurance companies, should never

be expected to be perfect. But we can prevent a lot of unnecessary deaths by

giving medical sta more information, just as Lawan’s doctors were able to get

her onto a new treatment regimen once they better understood what they were

dealing with.

Indeed, it wasn’t long after Lawan’s DNA-based diagnosis that she was on a

new treatment regimen—one that was speci c to the actual cancer in her body.

Months later she was doing much better. Hope had returned.

There is hope for al of us. We know that humans, both male and female, are

capable of living past the age of 115. It has been done, and it can be done again.

Even for those who reach only their 100th year, their 80s and 90s could be

among their best.

Helping more people reach that potential is a matter of bringing costs down

and using emerging treatments, therapies, and technologies in a way that truly

puts individuals at the center of their own care. And that’s not just about

diagnosing people right when something does go wrong—it’s also about

knowing what to do for us, as individuals, even before a diagnosis has been

made.

KNOWING THYSELF

Since the new mil ennium, we’ve been told that “knowing our genes” wil help

us understand what diseases we are most susceptible to later in life and give us

the information we need to take preventive actions to live longer. That is true,

but it is only a smal part of the DNA-sequencing revolution that is under way.

There are 3.234 bil ion base pairs, or letters, in the human genome. In 1990,

when the Human Genome Project was launched, it cost about $10 to read just

one letter in the genome, an A, G, C, or T. The entire project took ten years,

thousands of scientists, and cost a few bil ion dol ars. And that was for one

genome.

Today, I can read an entire human genome of 25,000 genes in a few days for

less than a hundred dol ars on a candy bar–sized DNA sequencer cal ed a

MinION that I plug into my laptop. And that’s for a fairly complete readout of

a human genome, plus the DNA methyl marks that tel you your biological age. 2

Targeted sequencing aimed at answering a speci c question—such as “What

kind of cancer is this?” or “What infection do I have?”—can now be done in less

than twenty-four hours. Within ten years, it wil be done in a few minutes, and

the most expensive part wil be the lancet that pricks your nger. 3

But those aren’t the only questions that our DNA can answer. Increasingly, it

can also tel you what foods to eat, what microbiomes to cultivate in your gut

and on your skin, and what therapies wil work best to ensure that you reach

your maximum potential lifespan. And it can give you guidance for how to treat

your body as the unique machine it is.

It’s common knowledge that we don’t al respond to drugs in the same way.

Sometimes these aren’t smal di erences in smal numbers of people. G6PD

genetic de ciency, for instance, a ects 300 mil ion people of primarily Asian and

African descent. It’s the most common genetic disease of humanity. After

ingesting recommended doses of medicines for headaches and malaria and

certain antibiotics, G6PD carriers can be caught unawares by hemolysis—what

amounts to red blood cel mass suicide.4

Some mutations sensitize people to particular foods. If you’re a G6PD

carrier, for example, fava beans can kil you. And while gluten is usual y a

harmless protein that comes in foods rich in the ber, vitamins, and minerals we

need, for those with celiac disease, it’s a poison.

The same is true of medical interventions: our genes can tel us which are

better for us and which could do more harm than good. That’s changing the

game for many breast cancer patients. Those who score in a certain range on a

genetic test cal ed Oncotype DX, it has been discovered, respond every bit as wel

to hormone treatments as they do to chemotherapy, the latter of which has far

more side e ects. 5 The tragedy of this discovery is that it didn’t come until 2015.

The Oncotype DX test has been in use since 2004, but it wasn’t until a team of

researchers decided to take another look at possible treatment options and

outcomes that it became clear that the medical community had been subjecting

tens of thousands of women to treatments that were more harmful and no more

e ective.

What Lawan’s case and this study demonstrate is that we can’t simply rest on

“this is how we do it” as a strategy for treating patients. We need to be constantly

chal enging the assumptions upon which medical manuals are based.

One of these assumptions is that males and females are essential y the same.

We’re al too slowly coming around to the shameful recognition that, for most

of medical history, our treatments and therapies have been based on what was

best for males,6 thus hindering healthy clinical outcomes for females. Males

don’t just di er from females at a few sites in the genome; they have a whole

other chromosome.

The bias begins early in the drug development process. Until recently, it was

perfectly ne to study male mice only. Scientists general y aren’t rodent sexists,

but they are always trying to reduce statistical noise and save precious grant

money. Ever since female mice have been regularly included in lifespan

experiments, thanks largely to NIH stipulations, large gender di erences in the

e ects of longevity genes and molecules have been seen. 7 Treatments that work

through insulin or mTOR signaling typical y favor females, whereas chemical

therapies typical y favor males, and no one real y knows why.8

If females and males are in the same environment, in general, females wil live

longer. It’s a common theme throughout the animal kingdom. Scientists have

tested whether it is the X chromosome or the ovary that is important. Using a

genetic trick, they created mice with one or two Xs, with either ovaries or testes.9

Those with a double dose of the X lived longer, even if they had testes and

especial y if they didn’t, thus proving once and for al that female is the stronger

sex.Besides the X, there are dozens of other genetic factors at play. One of the

most promising uses of genomics is predicting how drugs wil be metabolized.

That’s why an increasing number of drugs now have pharmacogenetic labels—

information about how the medication is known to act di erently among

people of di erent genotypes. 10 Examples include the blood-thinning drugs

Coumadin and Plavix, the chemotherapy drugs Erbitux and Vecitibix, and the

depression drug Celexa. In the future, a patient’s epigenetic age wil also be

determined and used to predict drug responses, a new eld cal ed

pharmacoepigenetics. It’s a rapidly advancing technology but some

pharmacogenetic tests can’t come soon enough.

For more than two hundred years, the drug digoxin from the digitalis family

of plants has been used in smal doses by doctors to treat failing hearts (and in

larger doses by murderers). 11 Even under a doctor’s supervision, your chance of

death if you are on digoxin increases by 29 percent, according to one study.12

To help reduce uid buildup owing to her weakening heart, my mother was

prescribed digoxin. I had no idea of the risk and I suspect neither did my mother,

who was sensitive to the drug. She steadily declined from living a reasonably

normal life to being barely able to walk. Fortunately, my father, a biochemist and

a pretty smart guy, diagnosed the problem: the amount of the drug prescribed

was superlow, but it had been accumulating in my mom’s heart. He told the

doctor to test for drug levels, which she reluctantly agreed to do, and the test

came back positive for an overdose.

The drug was immediately discontinued, and my mom recovered to her

original self in a matter of weeks. Yes, the doctor should have done regular blood

tests for drug levels, but if a test for sensitivity to digoxin prior to prescription

existed, the doctor could have been on high alert. How close are we to a test?

Not close enough. A few studies have identi ed genetic variants that predict

digoxin blood levels and risk of death, but they haven’t been repeated.13

Hopeful y, there wil be a pharmacogenetic test for this drug soon, as wel as for

many more. They are badly needed. We cannot keep prescribing medicines as

though we al respond to them the same way, because we don’t.

Drug developers have gured this out. They are using genomic information

to nd new and revive failed drugs that work for people with speci c genetic

variations. One of these drugs is Bayer’s Vitrakvi, known generical y as

larotrectinib, which is the rst of many drugs to be designed from the beginning

to treat cancers with a speci c genetic mutation, not where in the body the

cancer came from. A similar story is being written about the failed blood

pressure drug Gencaro. It worked wel on a subset of the population and, if

revived by the FDA, would become the rst heart drug to require a genetic test.

This is the future. Eventual y, every drug wil be included in a huge and ever-

expanding database of pharmacogenetic e ects. It won’t be long before

prescribing a drug without rst knowing a patient’s genome wil seem medieval.

And vital y, with genomic information aiding in our doctors’ decisions, we

won’t have to wait to become sick to know what treatments wil work best to

prevent those diseases from developing in the rst place.

As Julie Johnson, the director of the University of Florida’s Personalized

Medicine Program, has pointed out, we are about to enter a world in which our

genomes wil be sequenced, stored, and already red-lighted for treatments that

have been demonstrated to have adverse e ects on people with similar gene types

and combinations as we have.14 Likewise, we’l be green-lighted for treatments

that are known to work for people with similar genes, even if those treatments

don’t work for most other people most of the time. This wil be particularly

important in developing countries, where the local genetics and gut ora are

wildly di erent from the population the drug was tested on.15 These di erences

are rarely talked about in medical circles, but they can have a marked e ect on

drug e cacy and patient survival, including the e cacy of what are thought of

as wel -understood cancer chemotherapies.16

We are also learning to read the entire human proteome—al of the proteins

that can be expressed by every type of cel . Researchers in my lab and others have

discovered hundreds of new proteins in human blood, and each protein can tel

a story about the kind of cel from which it came, a story we can use to

understand what diseases are in our bodies long before they are detectable any

other way. That wil o er a faster, better view of the problems we’re facing,

giving doctors the ability to target those problems with far greater precision.

Right now, when people fal il , especial y older people, they often wait to see

if things just “work themselves out” before making an appointment to see a

doctor. Only when symptoms persist do they make the cal . Then they have to

wait—nearly a month, according to one 2017 study—before they are able to see

a physician. That wait time has been growing in recent years, owing to the

combination of a doctor shortage and an increase in baby boomer patients. And

in some places, it’s much worse. In the city in which I live, Boston—home to

twenty-four of the best hospitals in the world—the wait is fty-two days.17

That’s atrocious.

Long wait times aren’t just in the United States, which has a largely private

medical system; Canada’s socialized system has notoriously long wait times, too.

The problem isn’t how we pay for care; the problem is that we’ve set up doctors

as the only conduits to diagnosis and often, in the case of primary care

physicians, as the only people who can refer a patient to a specialist.

The backlog could clear soon, thanks to technologies that give doctors the

ability to conduct video home visits. Within a decade, using a device the size of a

package of gum and possibly even disposable, it wil be technical y feasible to

col ect the samples your doctor needs at home, plug the device into your

computer, and look together at a readout of your metabolites and your genes.

There are more than a hundred companies just in the United States pursuing

lightning-fast, superfocused DNA testing that can o er us early and accurate

diagnoses of a vast range of ailments and even estimate our rate of biological

aging. 18 A few are aimed at detecting the genetic signature of cancer and other

il nesses years before they can normal y be detected. Soon, we wil no longer have

to wait for tumors to grow so big and so heterogeneously mutated that their

spread is no longer control able. With a simple blood test, doctors wil be able to

scan for circulating cel -free DNA, or cfDNA, and diagnose cancers that would

be impossible to spot without the aid of computer algorithms optimized by

machine learning processes trained on thousands of cancer patient samples.

These circulating genetic clues wil tel you not just if you have cancer but what

kind of cancer you have and how to kil it. They wil even tel you where in your

body an otherwise undetectable tumor is growing, since the genetic (and

epigenetic) signatures of tumors in one part of the body can be vastly di erent

from those from other parts.19

Al of this means we’re on the way to a fundamental shift in the way we

search for, diagnose, and treat disease. Our awed, symptom- rst approach to

medicine is about to change. We’re going to get ahead of symptoms. Way ahead.

We’re even going to get ahead of “feeling bad.” Many diseases, after al , are

genetical y detectable long before they are symptomatic. In the very near future,

proactive personal DNA scanning is going to be as routine as brushing our

teeth. Doctors wil nd themselves saying the words “I just wish we’d caught this

earlier” less and less—and eventual y not at al .

But the coming age of genomics is just the start.

THE RIGHT TRACK

The dashboard on a car equipped with intel igent vehicle technologies is a

marvelous thing. It can tel you how fast you’re going, of course, and how many

miles the vehicle has remaining before it needs a re l —adjusted second by

second based on the conditions of the road and the way in which you are

driving. It can tel you the temperature outside, inside, and under the hood. It

can tel you what cars, bicycles, and pedestrians are around you and warn you if

they’re getting a little close for comfort. When something is wrong—a tire with

too little air or a transmission that isn’t shifting perfectly—it can let you know

that, too. And if you get a bit distracted and begin to veer over the line, it wil

take control of the wheel and pul you back on course or drive autonomously

down the highway, with no more than a bit of resistance from a hand on the

steering wheel to tel it there’s a human there, just in case.

Back in the 1980s, there were very few sensors in cars. But by 2017, there

were nearly 100 sensors in each new vehicle—a number that had doubled in the

prior couple of years. 20 Car buyers increasingly expect features such as tire sensors, passenger sensors, climate sensors, nighttime pedestrian warning

sensors, steering angle guides, proximity alerts, ambient light sensors, washer

uid sensors, automatic high-beam, rain sensors, blind spot detection sensors,

automatic suspension lift, voice recognition, automatic reverse parking, active

cruise control, auto emergency braking, and autopilot.

Perhaps there are people out there who’d be happy to drive without any

dashboard at al , relying solely on their intuition and experience to tel them how

fast they are going, when their car needs fuel or recharging, and what to x when

something goes wrong. The vast majority of us, however, would never drive a car

that wasn’t giving us at least some quantitative feedback, and, through our

purchasing decisions, we have made it clear to car companies that we want more

and more intel igent cars.

Of course we do. We want them to protect us, and we want them to last.

Surprisingly, we’ve never demanded the same for our own bodies. Indeed, we

know more about the health of our cars than we know about our own health.

That’s farcical. And it’s about to change.

We’ve already taken some pretty big steps into the age of personal biosensors.

Our watches monitor our heart rate, measure our sleep cycles, and can even

provide suggestions for food intake and activity. Athletes and health conscious

individuals are increasingly wearing sensors twenty-four hours a day that

monitor the ways in which their vital signs and major chemicals are rising and

fal ing in response to diet, stress, training, and competition.

As just about anyone with diabetes or HIV can attest, blood sugar and blood

cel monitoring are exceptional y easy and increasingly painless a airs these days,

with noninvasive and minimal y invasive monitoring technologies ever more

available, a ordable, and accurate.

In 2017, the US Food and Drug Administration approved a glucose sensor,

rst launched in Europe in 2014, that you stick on your skin to provide a

constant readout of blood sugar levels on your phone or watch. In thirty

countries, a nger prick for diabetics is becoming a distant memory.

Rhonda Patrick, a longevity scientist turned health and tness expert, has

been using a continual blood glucose–sensing device to see what foods give her

body a major sugar spike, something many of us believe is to be avoided if we are

to give ourselves the greatest chance of a long life. She’s seen that, at least for her,

white rice is bad and potatoes aren’t so bad. When I asked her what food had

been the most surprising, she didn’t hesitate.

“Grapes!” she exclaimed. “Avoid grapes.”

Researchers at MIT are working on scanners, straight out of Star Trek, that

can give readouts of thousands of biomarkers. Meanwhile, researchers at the

University of Cincinnati have been working with the US military to develop

sensors that can identify diseases, diet changes, injuries, and stress through

sweat. 21 A few companies are developing handheld breath analyzers that can

diagnose cancer, infectious diseases, and in ammatory diseases. Their mission:

to save 100,000 lives and $1.5 bil ion in health care costs.22 Numerous other companies are working on designing clothing with sensors that can track

biomarkers, and automotive engineers are exploring putting biosensors in car

seats that would send an alert to your dashboard or doctor if there’s something

amiss in your heart rate or breathing pattern.

As I write this, I am wearing a regular-sized ring that is monitoring my heart

rate, body temperature, and movements. It tel s me each morning if I slept wel ,

how much I dreamed, and how alert I wil be during the day. Technology like

this has been around for some time, I suppose, for people such as Bruce Wayne

and James Bond. Now it costs a few hundred dol ars and can be ordered by

anyone online. 23

Recently, my wife and eldest child came home with matching ear piercings,

which got me thinking: there’s real y no reason that an even smal er piece of

body jewelry—particularly one that pierces the skin—couldn’t be used to track

thousands of biomarkers. Every member of the family could be measured:

grandparents, parents, and children. Even infants and four-legged family

members wil have monitors on them, because they are the ones who are least

able to tel us what they are feeling.

Eventual y, I suspect, very few people wil want to live without tech like this.

We won’t leave home without it, the same way we feel about our smartphones.

The next iteration wil be innocuous skin patches, eventual y giving way to

under-skin implants. Future generations of sensors wil measure and track not

only a person’s glucose but his or her basic vital signs, the level of oxygen in the

blood, vitamin balance, and thousands of chemicals and hormones.

Combined with technologies that coalesce data from your day-to-day

movements and even the tone of your voice,24 your biometric vitals wil be the

bel wether for your body. If you are a man who has been spending more time in

the bathroom than usual, your AI guardian wil check for prostate-speci c

antigens and prostate DNA in your blood, then book you an appointment for a

prostate exam. Changes in how you move your hands while speaking, and even

the manner in which your strike the keys on your computer,25 wil be used to

diagnose neurodegenerative diseases years before symptoms would be noticed by

you or your doctor.

One biotechnological advancement at a time, this world is coming, and fast.

Real-time monitoring of our bodies, the likes of which we could hardly have

imagined a generation ago, wil be as inherent to the experience of living as

dashboards are to the experience of driving. And for the rst time in history, that

wil permit us to make data-driven day-to-day health decisions.26

The most critical daily decisions that a ect how long we live are centered

around the foods we eat. If your blood sugar is high at breakfast, you’l know to

avoid sugar in your morning co ee. If your body is low on iron at lunch, you’l

know it and can order a spinach salad to compensate. When you get home from

work, if you’ve failed to go outside for your daily dose of vitamin D from the

sun, you’l know that, too, and you’l be able to mix up a smoothie that wil

address the de ciency. If you’re on the road and you need X vitamin or Y

mineral, you’l know not only what you need but where to get it. Your personal

virtual assistant—the same AI-driven being who answers your internet search

queries and reminds you about your next meeting—wil point you to the nearest

restaurant that has what you need or o er to have it delivered by a drone to

wherever you are. It could, quite literal y, be dropped into your hands from the

sky.Biometrics and analytics already tel us when and how much to exercise, but

increasingly they wil also help us monitor the e ects of our exercise—or lack

thereof. And our levels of stress. And even how the uids we drink and the air

we’re breathing are impacting our body’s chemistry and functionality.

Increasingly, our devices wil o er recommendations on what to do to mitigate

suboptimal blood biomarkers: to take a walk, meditate, drink a green tea, or

change the lter on the air conditioner. This wil help us make better decisions

about our bodies and our lifestyles.

Al of this is coming soon. There are companies that are crunching data from

hundreds of thousands of blood tests, comparing them to customers’ genomes

and providing feedback to them on what to eat and how to truly optimize their

particular bodies, and looking to rol out new generations of these technologies

every year.

I am fortunate to have been one of the rst people to get an early look at what

this sort of technology can o er us. I am a scienti c adviser to a local company,

spun out of MIT, cal ed InsideTracker. 27 By signing up for regular tests, I have

been able to fol ow a few dozen blood biomarkers over the past seven years,

including vitamins D and B12, hemoglobin, zinc, glucose, testosterone,

in ammatory markers, liver function, muscle health markers, cholesterol, and

triglycerides. My tests are taken every few months instead of every few seconds—

as they wil soon be in our future—but the reports, adjusted to my speci c age,

sex, race, and DNA, have been instrumental in helping me choose what to order

when I sit down at a restaurant and what to pick up when I stop at the market

on my way home. I can even have daily text messages, based on my most recent

results, that remind me what my body needs.

Along the way, I am creating data speci c to my body. And over time, that

data is helping me identify negative and positive trends that may be subtly

di erent for me than for other people. We know, of course, that our genetic

heritage can have a signi cant impact on the sorts of food our bodies need,

tolerate, or reject, but everyone’s genetic heritage is di erent. What you need,

what your partner needs, and what your children need can likely be found in the

meals you put on your table, but the particulars may be quite di erent.

Biotracking wil also help us stop acute and traumatic preventable deaths—

by the mil ions. In 2018, a peer-reviewed study published by the team at

InsideTracker and me, showed that biotracking and computer-generated food

recommendations reduce blood sugar levels as e ciently as the leading diabetes

drug, while optimizing other health biomarkers, too.

The signs of an increasingly blocked carotid artery might be hard to notice in

our day-to-day lives, or even in periodic visits to the doctor, but they wil be

almost impossible to miss when our bodies are being measured and monitored

al the time. Same, too, for heartbeat irregularities, minor strokes, venous

blockages during air medical transport, and many other medical problems that

currently are almost always treated in critical care conditions—when it is too

late. Before, if you suspected your heart was malfunctioning, and even if you

didn’t, it would take a visit to a couple of doctors to get an electrocardiogram.

Now mil ions of people can conduct their own accurate ECG in 30 seconds,

wherever they are, just by pressing their nger to the dial on their watch.

TECHNOLOGIES TO EXTEND OUR LIVES. In the near future, families wil be monitored by

biosensing wearables, smal devices at home, and implants that wil optimize our health and save

lives by suggesting meals and detecting fal s, infections, and diseases. When an anomaly is found,

an AI-assisted, videoconferenced doctor wil send an ambulance, a nurse, or medicines to your

door.

Of course, I use the term watch loosely, given that today’s wrist devices don’t

just tel you the time and date. They are also calendars, audiobooks, tness

trackers, email and text programs, newsstands, timers, alarms, weather stations,

heart rate and body temperature monitors, voice recorders, photo albums, music

players, personal assistants, and phones. If these devices can do al of that, there’s

no reason we should not expect them to help us avoid traumatic health

incidents, too.

In the future, if you are experiencing a heart attack—even if it’s perceptible

only as a slight pain in your arm—or a ministroke, which so often goes

undiagnosed until it’s identi ed on a brain scan years later, you’l be alerted, and

so wil those around you who need to know. In an emergency, a trusted

neighbor, a best friend, or whatever doctor happens to be closest to you can also

be alerted. An ambulance wil be dispatched to your door. This time, the doctors

at the nearest hospital wil know exactly why you are coming in before you even

arrive.

Do you know an emergency room doctor? Ask her about the value of a single

minute of additional treatment time. Or a single blood test’s worth of additional

information. Or a recent electrocardiogram. Or a patient who is stil conscious,

not in pain, and not su ering from a loss of blood to their brain when they

arrive—a person who is able to help in the process of making appropriate

emergency health care choices. It may not be long before medics routinely ask

for a download of your most recent biotracking data to aid them in making what

could be life-and-death decisions.

Biotracking is already helping us identify diseases faster than ever before.

That is what happened in the summer of 2017 to a woman named Suzanne.

After a time of subtle shifts in her menstrual cycle, changes her doctor very

reasonably attributed to a shift into menopause, the 52-year-old woman

downloaded an app that helped her track her periods. Three months later, the

app sent her an email alerting her to the possibility that her data might be

“outside the norm” for women of her age. Armed with that data, Suzanne

returned to her doctor. She was immediately sent for blood tests and an

ultrasound that revealed mixed Mül erian tumors, a malignant form of cancer

found predominantly in postmenopausal women over the age of 65. It took a

radical hysterectomy to remove the cancer before it could spread further, but

Suzanne’s life was spared. 28

The app she used was relatively simple compared to those that are on the way.

It required proactive data entry and tracked only a few metrics. Yet it saved her

life. Imagine, then, what “hands-o ” trackers that col ect mil ions of daily data

points can o er us. Now imagine coupling that data with what we learn from

routine DNA sequencing.

And don’t stop imagining there. Because biotracking won’t just tel you

when your heart rate is up, your vitamin levels are low, or your cortisol level is

spiking, it wil also tel us when our bodies are under attack—and that could save

everyone on this planet.

READY FOR THE WORST

In 1918—long before our modern, superfast, hyperconnected global

transportation network took shape—a worldwide in uenza pandemic that some

historians believe originated in the United States kil ed more people in absolute

numbers than any other disease outbreak in history.29 It was a violent death, with hemorrhage from mucous membranes, especial y from the nose, stomach,

eyes, ears, skin, and intestines. 30 At a time in which the era of human ight was

in its infancy and most people had never ridden in a car, the H1N1 virus found

its way to some of the furthest reaches of our globe. It kil ed people on remote

islands and in arctic vil ages. It kil ed without regard to race or national

boundaries. It kil ed like a new Black Death. Average life expectancy in the

United States plummeted from 55 to 40 years. It recovered, but not until more

than 100 mil ion people of al ages global y had had their lives cut short.

This could happen again. And given how much more humans and animals

are in contact and how much more interconnected our planet is now than it was

a century ago, it could happen quite easily.

The gains in life expectancy we’ve witnessed over the past 120 years, and

those to come, could be wiped out for a generation unless we address the greatest

threat to our lives: other life-forms that seek to prey on us. It doesn’t matter if we

live decades upon decades longer if a pandemic quickly snu s out hundreds of

mil ions of lives—negating and even rol ing back the gains in average lifespan we

wil have achieved. Global warming is a long-term, critical issue to deal with, but

one could also argue that, at least within our lifetimes, infections are our greatest

threat.

Ensuring the next big outbreak never happens could be the greatest gift of

the biotracking revolution. Individual y, of course, real-time monitoring of vitals

and body chemicals o ers incredible bene ts for optimizing health and

preventing emergencies. Col ectively, though, it could help us get ahead of a

global pandemic.

CHANGE IN LIFE EXPECTANCY DURING THE 1918 FLU EPIDEMIC.

Source: S. L. Knobler, A. Mack, A. Mahmoud, and S. M. Lemon, eds., The Threat of Pandemic

In uenza: Are We Ready? Workshop Summary, Institute of Medicine (Washington, DC:

National Academies Press, 2005), https://doi.org/10.17226/11150, PMID: 20669448.

Thanks to wearables, we already have the technology in place to monitor the

body temperature, pulse, and other biometric reactions of more than a hundred

mil ion people in real time. The only things separating us from doing so are a

recognized need and a cultural response.

The need is already here. It has been for quite some time. It took about

twenty years for the deadly mosquito-transmitted Zika virus to spread from

Central Africa, where it was rst documented, to South Asia and about forty-

ve more years to reach French Polynesia in the Central Paci c in 2013. In the

span of those sixty- ve years, it a ected just a smal part of the world. In the next

four years, though—four years, that’s al —the virus spread like wild re across

South America, through Central America, into North America, and back across

the Atlantic Ocean to Europe.

Zika, at least, is somewhat limited in the way it can be spread—mostly

through mosquito bites but also from mother to child and from sexual partner

to sexual partner. It cannot, as far as we know, be transmitted by doorknobs, via

food, or in the air-recirculating climate control systems on airplanes.

But in uenza can, as can other, potential y deadlier viruses.

On March 23, 2014, the World Health Organization reported cases of Ebola

virus disease in the forested rural region of southeastern Guinea, and from there

it spread rapidly to three neighboring countries, causing widespread panic. Even

the richest country in the world, where eleven people were treated for Ebola, was

caught without a uni ed plan.

That October, people in hazmat suits boarded American Airlines ight 45

when it landed in New Jersey to shine infrared heat detectors on people’s

foreheads in an attempt to detect a fever. Kaci Hickox, who worked for Doctors

Without Borders, later won a lawsuit that led to a “quarantine bil of rights,”

after she was placed in Governor Chris Christie’s “private prison.” On that

occasion, and a few since then, the deadly virus has been contained, but

humanity may not always be so lucky.

“Whether it occurs by a quirk of nature or at the hand of a terrorist,

epidemiologists say a fast-moving airborne pathogen could kil more than 30

mil ion people in less than a year,” Bil Gates told a crowd at the Munich

Security Conference in 2017, “and they say there is a reasonable probability the

world wil experience such an outbreak in the next 10–15 years. ”31

If that happens, 30 mil ion could be a very conservative estimate.

As our transportation networks continue to expand in reach and speed, as

more people travel to more corners of our world faster than our ancestors could

possibly have imagined, pathogens of al sorts are traveling faster than ever, too.

But with the right data in the right hands, we can move faster, especial y if we

combine mass “biocloud” data with superfast DNA sequencing to detect

pathogens as they spread through cities and along transportation corridors. In

doing so, we can get ahead of a kil er pathogen with emergency travel restrictions

and medical resources. In this ght, every minute wil matter. And every minute

that passes without action wil be measured in human lives.

Not everyone is ready for the biotracking world. That makes sense. To many,

clearly, it wil feel like a step too far. Maybe several steps too far.

In order to get to a world in which hundreds of mil ions of humans—al

being tracked in real time for hormone levels, chemicals, body temperature, and

heart rate—are standing as sentinels to warn us of public health crises as they

happen, someone is going to have to have the data. Who wil that be? One

government? A coalition of governments? Any and every government?

Maybe a computer company. Or maybe a pharmaceutical manufacturer. Or

an internet shopping company. Or an insurer. Or a pharmacy. Or a supplement

company. Or a hospital network.

Most likely, it wil be a combination of these companies, al under one roof.

Consolidation has already started and wil continue as these companies set their

sights on the largest and fastest-growing sector of the global economy, health

care, which now exceeds 10 percent of global GNP and is increasing at an annual

rate of 4.1 percent.

Whom do you trust to know your every move? To listen to your every

heartbeat? To see you when you’re sleeping and know when you’re awake, like a

certain benevolent mythical being of wintertime lore? To be able to identify,

through the data, when you are feeling sad, driving too fast, having sex, or had

too much to drink?

There’s no sense in trying to convince people that there is nothing to worry

about. Of course there are things to worry about. Think having your credit card

data stolen is bad? That’s nothing. You can always cal the bank and get a new

credit card, but your medical records are permanent—and far more personal.

More than 110 mil ion medical records were breached in the United States

between 2010 and 2018.32 Jean-Frédéric Karcher, the head of security at

Maintel, a UK communications provider, predicts that attacks wil become far

more common.

“Medical information can be worth ten times more than credit card numbers

on the deep web. Fraudsters can use this data to create fake IDs to buy medical

equipment or drugs,” he has warned. 33

We already trade a tremendous amount of privacy for technological services.

We do it al the time. We do it every time we start a bank account or sign up for a

credit card. We do it often when we point our internet browsers to a new web

page. We do it when we sign up for school. We do it when we get onto an

airplane. And we do it—a lot—when we use our mobile phones. Have these

been good trade-o s for everyone? That’s a matter of personal opinion, of

course. But when most people imagine not being able to use a credit card, surf

the web, sign up for school, travel by air, or use their phones and smart watches,

they quickly conclude that the trade is tolerable.

Wil people trade a little more privacy to stop a global disease pandemic?

Sadly, probably not. The tragedy of the commons is that humans are not very

good at taking personal action to solve col ective problems. The trick to

revolutionary change is nding ways to make self-interest align with the

common good. For people to accept widespread biometric tracking in a way that

could help us get ahead of fast-moving deadly viruses, they’l need to be o ered

something they have a hard time seeing themselves without.

How to get ready for this world is a conversation that needs to be had. And

soon.

I’m there already. Before I began having my biomarkers checked on a regular

basis, I did worry about what the ever-changing chemical signals in my body

could disclose about me to someone with access to my data. Al the data are held

on health care– or HIPAA-compliant servers, and the data are encrypted. But

there’s always the fear that the data wil be hacked. There’s always a way.

But after I began, the information I received was worth far more than the

concerns I carry. It’s a personal choice, no question. Now, having seen the

changes on my dashboard, I cannot imagine living without it. Just as I now

wonder how I ever managed to drive without a GPS, I wonder how I ever made

decisions about what I should be eating and how much I should be exercising

before I received regular updates from my biosensor ring and blood biomarker

reports. Indeed, I am eager for the day in which the data about my health are

processed in real time. And if that can help protect others, al the better.

MOVING FASTER

While I was doing my PhD, I had a night job. For about eight dol ars an hour, I

tested body uids—urine, feces, spinal uid, blood, and genital swabs horribly

twisted in hair—for the presence of deadly bacteria, parasites, and fungi. It was

glamorous work.

At my disposal, I had al the trappings of nineteenth-century technology:

microscopes, petri dishes, sterile water. A lab technician transported from 1895

to that 1980s microbiology lab would have felt right at home. Today, this is stil

how many microbiology labs operate.

Making life-and-death cal s this way was frustrating. In every other branch of

medicine, we’ve made enormous strides technological y with robotics,

nanotechnology, scanners, and spectrometers.

These days, though, I’m no longer frustrated. I’m furious.

Antibiotic-resistant strains of bacteria continue to spread, and new studies

implicate bacteria as causal agents in cancer, heart disease, and Alzheimer’s

disease. 34

But I wasn’t working to solve this problem, until recently. A brush with

Lyme disease has a way of intensifying a person’s feelings about these sorts of

things.

Our daughter Natalie was 11 years old when it happened. In New England,

where we live, there is an epidemic of ticks that carry the bacterial spirochete

Borrelia burgdorferi, which causes Lyme disease. Recent estimates suggest that

approximately 300,000 people in the United States may contract the disease each

year. Left untreated, Borrelia hides out in skin cel s and lymph nodes, causing

facial paralysis, heart problems, nerve pain, memory loss, and arthritis. It hides in

a protective bio lm, making it extremely di cult to kil .

Natalie never had a red ring of skin around a tick bite—a sure sign you’ve

contracted the parasite. She had been complaining about a headache and sore

back, typical signs of u. But quickly it became clear that this wasn’t u—it was

something much worse.

She was unable to turn her head. She was losing her eyesight. She was

terri ed. My wife and I were, too—we’d never felt so helpless in our lives. We

began searching online for answers. Potential diseases included leukemia and a

viral infection of the brain.

Doctors at Boston’s Children’s Hospital began poring over her. The rst test

lit up Lyme disease proteins, but the insurance company needed con rmation

because the rst test occasional y gives a false positive. The second test failed,

putting the course of treatment into limbo pending more lab results.

I asked for a microliter sample of Natalie’s spinal uid to test. My lab was

across the street, and I could sequence the DNA of the pathogen. The hospital

refused.

Given the state of her symptoms at that point, I’ve since learned, she had a 50

percent chance of survival. Her life came down to a coin ip. At a time when

every second counted, doctors were waiting on lab results.

It took three days to con rm that it was a Lyme disease infection, and nal y

the doctors gave Natalie intravenous antibiotics directly into the large vein next

to her heart. She received that treatment every day for nearly a month.

She is okay now, but it was clear to everyone involved, especial y Natalie, that

we desperately need to be applying twenty- rst-century technologies to

diagnosing infectious diseases. In Cambridge, Massachusetts, and Menlo Park,

California, I’ve helped gather a group of very smart folks—infectious disease

doctors, microbiologists, geneticists, mathematicians, and software engineers—

to develop tests that can rapidly and unambiguously tel physicians what an

infection is and how best to kil it, using “high-throughput sequencing.”

The rst step in this process is the extraction of nucleic acids from blood

samples, saliva, feces, or spinal uid. Because it adds cost and reduces sensitivity,

the patient’s DNA is removed using innovative methods honed by the same

scientists who extract ancient DNA from mummies—one of countless cases of

one eld of science bene ting another. Next, the samples are processed through

agnostic DNA-sequencing technologies, meaning that the system is not looking

for any one speci c infectious agent but rather reading the genomes in the entire

sample. That list is then scanned against a database of al known human

pathogens at the strain level. The computer spits out a highly detailed report

about what invaders are present and how best to kil them. The tests are as

accurate as the standard ones, but they provide strain-level information and are

pathogen agnostic. In other words, soon doctors won’t have to guess what to

look for when ordering a test or what treatment wil work best. They wil know.

Just a few years ago, this wouldn’t just have been a slow process, it wouldn’t

even have been possible. Now it can be done in days. Soon it wil be able to be

done in hours and eventual y minutes.

But there’s another way to deal with such diseases: we could prevent them

altogether.

THE NEW AGE OF INOCULATION

There is no rational debate over the immensely positive impact of vaccines on

life expectancy and healthy lifespans over the past century. Childhood mortality

around the world has plummeted, in no smal part because we’ve wiped out

diseases such as smal pox. The number of healthy children in the world has risen

because we’ve destroyed polio. The number of healthy adults has, too. Within

fty years, postpolio syndrome, which causes fatigue, muscle weakness,

abnormal spinal curvature, and speech defects in adults, wil be extinct.

And, of course, the more diseases we can vaccinate for, especial y those that

claim elderly people’s lives, such as u and pneumonia, the more life expectancy

wil rise in the coming years.

When we inoculate the herd, it doesn’t just protect us individual y, it protects

the weakest among us: the young and the old. Chickenpox once claimed

thousands of lives each year around the world—mostly among the very young

and the very old—and accounted for hundreds of thousands of hospitalizations

and mil ions of days of missed work. Those days are over.

A shining example of the power of vaccines to extend lifespan came in the

years after the introduction of vaccines for Streptococcus pneumoniae, a major

source of il ness in older persons and the most common cause of death by

respiratory infection. After the Prevnar vaccine for infants was launched in

2000, hospitalization and deaths from pneumonia fel across the board,

according to a study published in the New England Journal of Medicine.

“The protective e ect we saw in older adults, who do not receive the vaccine

but bene t from vaccination of infants, is quite remarkable,” the study’s rst

author, Marie Gri n, explained. “It is one of the most dramatic examples of

indirect protection, or herd immunity, we have seen in recent years. ”35

In the rst three years alone, deaths from pneumonia were halved, averting

more than 30,000 cases and 3,000 deaths in the United States alone, according

to another study. 36

We can snu out a lot of kil ers with vaccines like this.

Yet for several decades, the promise of vaccines to improve the lives of bil ions

of people around the world has been slowed, not only by a distrust of vaccines

promulgated by debunked science, but by plain old market forces. The golden

era of vaccine research was in the mid–twentieth century, a time that saw the

quick development of a succession of exceptional y e ective inoculations against

whooping cough, polio, mumps, measles, rubel a, and meningitis.

But by the latter part of the century, the business model that long sustained

vaccine research and development was badly broken. The cost of testing new

vaccines had risen exponential y, thanks in large part to increasing public

concerns about safety and risk-averse regulatory bodies. The “low-hanging fruit”

of the inoculation world had already been picked. Now a simple vaccine can take

more than a decade to produce and cost more than half a bil ion dol ars, and

there is stil the chance it won’t be approved for sale. Even some vaccines that

have worked wel and been critical for the prevention of epidemics, such as

GlaxoSmithKline’s Lyme disease vaccine, have been taken o the market because

the unfounded backlash against vaccines made continuation of the product “just

not worth it.” 37

Governments don’t make vaccines; companies do. So when the market forces

are not conducive, we don’t get the medicines we so badly need. Funding gaps

are sometimes made up by charitable organizations, but not nearly enough. And

economic downturns such as the global recession of the late 2000s and early

2010s left foundations—many of which base their giving on market-tied

endowment earnings—unable or unwil ing to invest as much in these lifesaving

interventions.38

The good news is that we are experiencing a minirenaissance in vaccine

research and development, which has tripled between 2005 and 2015, now

accounting for about a quarter of al biotechnology products being developed. 39

The big one is malaria, infecting 219 mil ion people and claiming 435,000

people in 2017. 40 Thanks to Bil and Melinda Gates, GlaxoSmithKline, and

Program for Appropriate Technology in Health (PATH), a partial y e ective

vaccine against malaria known as Mosquirix was deployed for the rst time in

2017, giving hope that the malaria parasite wil one day be pushed to

extinction. 41

We are also learning how to quickly grow vaccines in human cel s, mosquito

cel s, and bacteria, avoiding the time and expense of infecting the mil ions of

fertilized chicken eggs we currently use, a remarkably antiquated process. One

Boston-based research consortium was able to get a vaccine for Lassa fever, a

disease similar to Ebola, al the way to the animal-testing stage in just four

months and for about $1 mil ion, cutting many years and many mil ions of

dol ars from the usual process. 42 That’s nothing short of astounding.

At this moment, researchers are starting the nal sprint toward the end of a

very long race to develop vaccines that wil inoculate us against diseases that are

so ubiquitous that we simply accept them as part of life. Many thought leaders

predict, though with some trepidation, that it won’t be long before we’re no

longer throwing Hail Mary passes such as the annual in uenza vaccine, which in

some years protects less than a third of its recipients, which is stil far better than

nothing. (If you don’t get u vaccines or vaccinate your kids, please do. We are

privileged to live in an age in which we can protect ourselves and our children

from potential y deadly diseases.)

The ability to quickly detect, diagnose, treat, and even prevent diseases that

aren’t related to aging but that claim many mil ions of lives each year wil al ow

us to continue to push our average life expectancy higher and higher, closing the

gap between the mean and the maximum.

Even then, organs wil fail and body parts wil wear out. What wil we do

when al other technologies fail? There’s a revolution happening there, too.

THE ORGAN GRIND

The Great Ocean Road, which runs along the Australian coast west of

Melbourne, is among the most beautiful stretches of highway in the world. But

whenever I’m on it, I can’t help but remember one of the most frightening days

of my life—the day I got a cal tel ing me that my brother, Nick, had been in a

motorcycle accident.

He was 23 years old at the time and touring the country by motorbike. He

was an expert rider, but he hit an oil patch, ew from his bike, and slid under a

metal barrier that crushed his ribs and ruptured his spleen.

Fortunately, he pul ed through, but to save his life, the emergency room

doctors had to remove his spleen, which is involved in the production of blood

cel s and is an important part of the immune system. For the rest of his life, he

has to be careful not to get a major infection, and he certainly seems to get sicker

more often and take longer to get better. People without a spleen are also at

higher risk of dying of pneumonia later in life.

It doesn’t take age or disease to do a number on our organs. Sometimes life

does that to us in other ways, and we’re lucky if it’s just our spleen that we lose.

Hearts, livers, kidneys, and lungs are a lot harder to live without.

The same kind of cel ular reprogramming we can use to restore optic nerves

and eyesight may one day o er us the ability to restore function in damaged

organs. But what can we do for organs that have completely failed or need to be

removed because of a tumor?

Right now, there’s only one way to e ectively replace damaged and diseased

organs. It’s a morbid truth, but it’s a truth nonetheless: when people pray for an

organ to become available for a loved one who needs one, part of what they’re

praying for is a deadly car accident.

There’s a lot of irony, or some would say logic, in the fact that the

Department of Motor Vehicles is the organization that asks people whether they

want to be organ donors: each year in the United States alone, more than 35,000

people are kil ed in motor vehicle accidents, making this mode of death one of

the most reliable sources of tissues and organs. If you haven’t signed up to be an

organ donor, I hope you consider it. Between 1988 and 2006, the number of

people waiting for a new organ grew sixfold. As I write this sentence, there are

114,271 people on the US online registry waiting for organ transplants, and

every ten minutes, someone new is added to the transplant waitlist.43

It’s even worse for patients in Japan, where the ability to get an organ

transplant remains far below those of Western countries. The reasons are both

cultural and legal. In 1968, the Buddhist belief that the body should not be

divided after death fueled an emotion-laden restorm in the media about

whether the rst Japanese heart donor had truly been “brain dead” when the

heart was removed by Dr. Juro Wada. A strict law was immediately enacted that

banned the removal of organs from a cadaver until the heart had stopped

beating. The law was relaxed thirty years later, but the Japanese remain divided

on the issue and good organs remain hard to come by.

My brother also su ers from an eye disease cal ed keratoconus, which caused

the corneas covering his lenses to wrinkle like a nger pushed into plastic wrap.

To treat this, he had two separate corneal transplant surgeries, one in his

twenties, the other in his thirties, that swapped two other people’s corneas for

his. Both times, he su ered through six months of corneal stitches that felt like

“branches” in his eyes, but his vision was saved. The fact that Nick now literal y

sees the world through others’ eyes is an amusing topic for dinner conversation

that belies the true depth of our family’s gratefulness to his deceased donors.

Now, as we rapidly approach the era of self-driving cars—a technological and

social paradigm shift that almost every expert expects wil rapidly reduce car

crashes—we need to confront an important question: Where wil the organs

come from?

The geneticist Luhan Yang and her former mentor Professor George Church

in my department at Harvard Medical School had just discovered how to gene

edit mammalian cel s when they began working to edit out genes in pigs. To

what end? They envisioned a world in which pig farmers raise animals

speci cal y designed to produce organs for the mil ions of people who are on

transplant waiting lists. Though scientists have had dreams of widespread

“xenotransplantation” for many decades, Yang took one of the biggest steps

toward that goal when she and her col eagues demonstrated that they could use

gene editing to eliminate dozens of retroviral genes from pigs that currently

prevent them from donating organs. That’s not the only obstacle to

xenotransplantation, but it’s a big one—and one that Yang gured out how to

overcome before her 32nd birthday.

That’s not the only way we’l be getting organs in the future. Ever since

researchers discovered in the early 2000s that they could modify inkjet printers

to lay down 3D layers of living cel s, scientists around the world have been

working toward the goal of printing living tissue. Today scientists have

implanted printed ovaries into mice and spliced printed arteries into monkeys.

Others are working on printing skeletal tissue to x broken bones. And printed

skin is likely to start being used for grafts in the next few years, with livers and

kidneys coming soon after that and hearts—which are a bit more complicated—

a few years behind.

Soon it won’t matter if the morbid pipeline for human organ transplantation

ends. That pipeline never met the demand anyway. In the future, when we need

body parts, we might very wel print them, perhaps by using our own stem cel s,

which wil be harvested and stored for just such an occasion, or even using

reprogrammed cel s taken from blood or a mouth swab. And because there

won’t be competition for these organs, we won’t have to wait for things to go

catastrophical y wrong for someone else to get one—we’l only have to wait for

the printer to do its job.

JUST IMAGINE

Is al this hard to imagine? That’s understandable. We’ve spent a long time

building up our expectations of what medical care should look like—and indeed

what human life should look like. For a lot of people, it’s simply easier to say, “I

just don’t believe that wil happen,” and leave things at that.

But we’re actual y quite a bit better at changing our minds about what we

expect out of life, and what age actual y means, than many of us think we are.

Consider Tom Cruise. As the Top Gun actor entered his late 50s, with

bulging muscles and a straight line of dark hair sprouting from a minimal y

wrinkled forehead, he was stil at work. Not just acting, but doing the sort of

acting that has long been the purview of much younger actors. He was stil

doing many of his own dangerous stunts, too: riding motorcycles at high speed

through al eys, being strapped to the outside of a plane as it takes o , hanging o

the top of the world’s tal est building, skydiving from the upper reaches of the

atmosphere.

How easily do the words “Fifty is the new thirty” slide from our lips these

days? We forget what we used to expect life past 50 to look like, not hundreds of

years in the past but just a few decades ago.

It didn’t look like Tom Cruise jumping out of airplanes. It looked like

Wilford Brimley. In the 1980s, Brimley was one of Cruise’s costars in the movie

The Firm. Cruise was 39 and Brimley 58, already a gray-haired old man with a

walrus mustache.

A few years earlier, Brimley had starred in Cocoon, a movie about a group of

senior citizens who stumble upon an alien “fountain of youth” that gives them

the energy—although not the looks—of their youth. The image of old folks

running around like teenagers was played to great comedic e ect.

It was audacious to think of someone that age acting so youthful. At the time

the movie was released, though, Brimley was ve or six years younger than

Cruise is now. According to Ian Crouch of the New Yorker, Cruise has easily

blasted through what he cal s “the Brimley Barrier.” 44

Barriers fal . And they wil fal again. In another generation, we’l be wel

accustomed to seeing movie stars in their 60s and 70s riding motorcycles at high

speeds, jumping from great heights, and delivering kung fu kicks high into the

air. Because 60 wil be the new 40. Then 70 wil be the new 40. And on it wil

go.When wil this happen? It’s already happening. It is not fanciful to say that if

you are reading these words, you are likely to bene t from this revolution; you

wil look younger, act younger, and be younger—both physical y and mental y.

You wil live longer, and those extra years wil be better.

Yes, it is true that any one technology might lead to a dead end. But there is

simply no way that al of them wil fail. Taken separately, any of these

innovations in pharmaceuticals, precision medicine, emergency care, and public

health would save lives, providing extra years that would otherwise have been

lost. When we take them together, though, we are staring up the road at decades

of longer, healthier life.

Each new discovery creates new potential. Each minute saved in the quest for

faster and more accurate gene sequencing can help save lives. Even if it doesn’t

move the needle much on the maximum number of years we live, this age of

innovation wil ensure that we stay much healthier much longer.

Not many of us much of the time, but al of us.

PART III

WHERE WE’RE GOING

(THE FUTURE)

EIGHT

THE SHAPE OF THINGS TO COME

LET’S DO A LITTLE MATH.

And let’s make it conservative math. Let’s assume that each of these vastly

di erent technologies emerging over the next fty years independently

contributes to a longer, healthier lifespan.

DNA monitoring wil soon be alerting doctors to diseases long before they

become acute. We wil identify and begin to ght cancer years earlier. If you have

an infection, it wil be diagnosed within minutes. If your heartbeat is irregular,

your car seat wil let you know. A breath analyzer wil detect an immune disease

beginning to develop. Keystrokes on the keyboard wil signal early Parkinson’s

disease or multiple sclerosis. Doctors wil have far more information about their

patients—and they wil have access to it long before patients arrive at a clinic or

hospital. Medical errors and misdiagnoses wil be slashed. The result of any one

of these innovations could be decades of prolonged healthy life.

Let’s say, though, that al of these developments together wil give us a decade.

Once people begin to accept that aging is not an inevitable part of life, wil

they take better care of themselves? I certainly have. So, too, it seems, have most

of my friends and family members. Even as we have al stepped forward to be

early adopters of biomedical and technological interventions that reduce the

noise in our epigenomes and keep watch over the biochemical systems that keep

us alive and healthy, I’ve noticed a de nite tendency to eat fewer calories, reduce

animal-based aminos, engage in more exercise, and stoke the development of

brown fat by embracing a life outside the thermoneutral zone.

These are remedies available to most people regardless of socioeconomic

status, and the impact on vitality has been exceptional y wel studied. Ten

additional healthy years is not an unreasonable expectation for people who eat

wel and stay active. But let’s cut that by half. Let’s cal it ve.

That’s fteen years.

Molecules that bolster our survival circuit, putting our longevity genes to

work, have o ered between 10 and 40 percent more healthy years in animal

studies. But let’s go with 10 percent, which gives us another eight years.

That’s twenty-three years total.

How long wil it be before we are able to reset our epigenome, either with

molecules we ingest or by genetical y modifying our bodies, as my student now

does in mice? How long until we can destroy senescent cel s, either by drugs or

outright vaccination? How long until we can replace parts of organs, grow entire

ones in genetical y altered farm animals, or create them in a 3D printer? A

couple of decades, perhaps. Maybe three. One or al of those innovations is

coming wel within the ever-increasing lifespans of most of us, though. And

when that happens, how many more years wil we get? The maximum potential

could be centuries, but let’s say it’s only ten years.

That’s thirty-three years.

At the moment, life expectancy in the developed world is a tad over 80 years.

Add 33 to that.

That’s 113 years, a conservative estimate of life expectancy in the future, as

long as most people come along for the ride. And recal that this number means

that over half the population wil exceed that number. It’s true that not al of

these advances wil be additive, and not everyone wil eat wel and exercise. But

also consider that the longer we live, the greater chance we have of bene ting

from radical medical advances that we cannot foresee. And the advances we’ve

already made are not going away.

That’s why, as we move faster and faster toward a Star Trek world, for every

month you manage to stay alive, you gain another week of life. Forty years from

now, it could be another two weeks. Eighty years from now, another three.

Things could get real y interesting around the end of the century if, for every

month you are alive, you live another four weeks.

This is why I say that Jeanne Calment, who may have had the longest lifespan

of any person on our planet, wil eventual y fal o the list of the top ten oldest

humans in history. And it won’t be more than a few decades after that that she

wil leave the top 100. After that she wil leave the top mil ion. Imagine if people

who have lived beyond 110 had had access to al these technologies. Could they

have made it to 120 or 130? Perhaps.

Fel ow scientists often warn me not to be so publicly optimistic. “It’s not a

good look,” one wel -meaning col eague recently told me.

“Why?” I asked.

“Because the public isn’t ready for these numbers.”

I disagree.

Ten years ago, I was a pariah to many of my col eagues for even talking about

making medicines to help patients. One scientist told me that our job as

researchers is to “just show a molecule extends lifespan in mice, and the public

wil take it from there.” Sadly, I wish that were true.

Today, many of my col eagues are just as optimistic as I am, even if they don’t

admit it publicly. I’d wager that about a third of them take metformin or an

NAD booster. A few of them even take low doses of rapamycin intermittently.

International conferences speci cal y about longevity interventions are now held

every few weeks, the participants not charlatans but renowned scientists from

the world’s most prestigious universities and research centers. In these gatherings

it is no longer unusual to hear chatter about how raising the average human

lifespan by a decade, if not more, wil change our world. Mind you, the debate is

not about whether this wil happen; it is about what we should do when it

happens.

The same is increasingly true among the political, business, and religious

leaders with whom I spend more and more of my time these days, talking not

just about new technologies but about their implications. Slowly but surely,

these individuals—legislators, heads of state, CEOs, and thought leaders—are

coming to recognize the world-changing potential of the work being done in the

eld of aging, and they want to be ready.

Al these people might be wrong. I might be wrong. But I expect to be

around long enough to know one way or the other.

If I am wrong, it might be that I was too conservative in my predictions.

Though there are many examples of false predictions—who can forget nuclear-

powered vacuum cleaners and ying cars?—it is far more common for people

not to see something coming. Al of us are guilty of it. We extrapolate linearly.

More people, more horses, more horse manure. More cars, more air pol ution,

always more climate change. But that’s not how it works.

When technologies go exponential, even experts can be blindsided. The

American physicist Albert Michelson, who won a Nobel Prize for measuring the

speed of light, gave a speech at the University of Chicago in 1894, declaring that

there was probably little else to discover in physics besides additional decimal

places.1 He died in 1931, as quantum mechanics was in ful swing. And in his

1995 book, The Road Ahead, Bil Gates made no mention of the internet,

though he substantial y revised it about a year later, humbly admitting that he

had “vastly underestimated how important and how quickly” the internet

would come to prominence. 2

Kevin Kel y, the founding editor of Wired magazine, who has a better track

record than most at predicting the future, has a golden rule: “Embrace things

rather than try and ght them. Work with things rather than try and run from

them or prohibit them. ”3

We often fail to acknowledge that knowledge is multiplicative and

technologies are synergistic. Humankind is far more innovative than we give it

credit for. Over the past two centuries, generation after generation has witnessed

the sudden appearance of new and strange technologies: steam engines, metal

ships, horseless carriages, skyscrapers, planes, personal computers, the internet,

at-screen TVs, mobile devices, and gene-edited babies. At rst we are shocked;

then we barely notice. When the human brain was evolving, the only things to

change in a lifetime were the seasons. It should come as no surprise that we nd

it hard to predict what wil happen when mil ions of people work on complex

technologies that suddenly merge.

No matter if I’m right or wrong about the pace of change, barring a war or an

epidemic, our lifespan wil continue to rise. And the more thought leaders I

speak to around the globe, the more I realize how vast the implications are. And

yes, some of those people have al owed me to think and plan for events wel

beyond the initial scope of my research. But the people who push me to think

even harder are the younger people I teach at Harvard and other universities, and

the often even younger people I hear from via email and social media nearly

every day. They push me to think about how my work wil impact the future

workforce, global health care, and the very fabric of our moral universe—and to

better understand the changes that must take place if we are to meet a world of

signi cantly prolonged human healthspans and lifespans with equity, equality,

and human decency.

If the medical revolution happens and we continue on the linear path we’re

already on, some estimates suggest half of al children born in Japan today wil

live past 107. 4 In the United States the age is 104. Many researchers believe that

those estimates are overly generous, but I don’t. They might be conservative. I

have long said that if even a few of the therapies and treatments that are most

promising come to fruition, it is not an unreasonable expectation for anyone

who is alive and healthy today to reach 100 in good health—active and engaged

at levels we’d expect of healthy 50-year-olds today. One hundred twenty is our

known potential, but there is no reason to think that it needs to be for the

outliers. And I am on record as saying, in part to make a statement and in part

because I have a front-row seat on what’s around the corner, that we could be

living with the world’s rst sesquicentenarian. If cel ular reprogramming reaches

its potential, by century’s end 150 may not be out of reach.

At the moment I write this, there is no one on our planet—no one whose age

can be veri ed, at least—who is over the age of 120. So it wil be several decades,

at least, before we know if I’m right about this, and it could take 150 years before

someone steps over that threshold.

But as for the next century? And the next? It is not at al extravagant to expect

that someday living to 150 wil be standard. And if the Information Theory of

Aging is sound, there may be no upward limit; we could potential y reset the

epigenome in perpetuity.

This is terrifying to a lot of people—and understandably so. We’re on the

cusp of upending nearly every idea we’ve ever had about what it means to be

human. And that has a lot of people saying not just that it can’t be done but that

it shouldn’t be done—for it wil surely lead to our doom.

The critics of my life’s work aren’t nameless, faceless social media trol s.

Sometimes they are my col eagues. Sometimes they are close personal friends.

And sometimes they are my own esh and blood.

Our oldest child, Alex, who at 16 hopes for a career in politics and social

justice, has often struggled to see the future with the same optimism I do.

Especial y when you’re young, it is hard to see much of an arc to the moral

universe, let alone one that bends toward justice.5

Alex grew up, after al , in a world that is quickly and disastrously warming; in

a nation that has been at war for the better part of two decades; and in a city that

su ered a terrorist attack on the people participating in one of its most cherished

traditions, the Boston Marathon. And like so many other young people, Alex

lives in a hyperconnected universe where news of one humanitarian crisis after

the next, from Syria to South Sudan, is never far from the screen of a

smartphone.

So I understand. Or I try to, at least. But it was disappointing to learn, one

recent night, that Alex didn’t share the optimism I’ve always had about the

future. Of course I’m proud that our kid has such a strong moral compass, but it

was saddening to realize this more pessimistic view of the world casts a

signi cant shadow over the way Alex sees my life’s work.

“Your generation, just like al the ones that came before, didn’t do anything

about the destruction that is being done to this planet,” Alex told me that

evening. “And now you want to help people live longer? So they can do even

more damage to the world?”

I went to bed that night troubled. Not by our rstborn’s denouncement of

me; of that, I admit, I was a little proud. We’l never destroy the global patriarchy

if our children don’t rst practice on their fathers. No, what I was troubled by—

what kept me up that night and has done so many since—were the questions

that I simply could not answer.

Most people, upon coming to the realization that longer human lives are

imminent, also quickly recognize that such a transition cannot possibly occur

without signi cant social, political, and economic change. And they are right;

there can be no evolution without disruption. So what if the way I see the future

isn’t at al what we’re headed toward? What if giving bil ions of people longer

and healthier lives enables our species to do greater harm to this planet and to

one another? Greater longevity is inevitable; I’m sure of it. What if it inevitably

leads to our self-destruction?

What if what I do makes the world worse?

There are plenty of people out there—some of them very smart and very

informed—who think that’s the case. But I’m stil optimistic about our shared

future. I don’t agree with the naysayers. But that doesn’t mean I do not listen to

them. I do. And we al should. That’s why, in this chapter, I’m going to explain

some of their concerns—indeed, concerns I share in many cases—but I’l also

present a di erent way of thinking about our future.

You can take it from there.

THE HUNDRED YEARS’ WARNING

The number of Homo sapiens grew slowly over the rst few hundred thousand

years of our history, and at least on one occasion, we almost went extinct. While

there are many young skeletons from the Late Archaic and Paleolithic periods,

there is only a handful of skeletons of individuals over the age of 40. It was rare

for individuals to make it to the point we now have the luxury of cal ing middle

age. 6 Recal , this was a time when teenage girls were mothers and teenage boys

were warriors. Generations turned over quickly. Only the fastest, smartest,

strongest, and most resilient tended to survive. We rapidly evolved superior

bipedal and analytical skil s but at the expense of mil ions of brutal lives and

early deaths.

Our ancestors bred as fast as biology al owed, which was only slightly faster

than the death rate. But that was enough. Humanity endured and scattered to al

ends of the planet. It wasn’t until right around the time Christopher Columbus

rediscovered the New World that we reached the 500-mil ion-individuals mark,

but it took just three hundred more years for that population to double. And

today, with each new human life, our planet becomes more crowded, hurtling us

toward, or perhaps further beyond, what it can sustain.

How many is too many? One report, which examined sixty- ve di erent

scienti c projections, concluded that the most common estimated “carrying

capacity” of our planet is 8 bil ion.7 That’s just about where we’re at right now.

And barring a nuclear holocaust or a global pandemic of historical y deadly

proportions—nothing anyone in his or her right mind would ever wish for—

that’s not where our population is going to peak.

When the Pew Research Center pol ed members of the largest association of

scientists in the world, 82 percent said that there isn’t enough food and other

resources on this planet for its fast-growing human population.8 Among those

who held that opinion was Frank Fenner, an eminent Australian scientist who

helped bring an end to one of the world’s deadliest diseases as the chairman of

the Global Commission for the Certi cation of Smal pox Eradication. It was

Fenner, in fact, who had the distinct honor of announcing the eradication of the

disease to the World Health Organization’s governing body in 1980. Having

helped mil ions of people avoid a virus that kil ed nearly a third of those who

contracted the disease it caused, Fenner would have been justi ed in indulging in

a little exuberant optimism about the ways in which people can come together

to save themselves.

He had planned a quiet retirement. 9 But his mind wouldn’t stop working.

He couldn’t stop trying to identify and solve big problems. He spent the next

twenty years of his life writing about other threats to humankind, many of

which had been virtual y ignored by the same world health leaders who had

banded together to stop smal pox.

His nal act of forewarning came just a few months before his death in 2010,

when he told the Australian newspaper that the human population explosion

and “unbridled consumption” had already sealed our species’ fate. Humanity

would be gone in the next hundred years, he said. “There are too many people

here already.” 10

We’ve heard this song before, of course. At the turn of the nineteenth

century, as the global human population was screaming past the 1 bil ion mark,

the English scholar Thomas Malthus warned that advances in food production

inevitably led to population growth, placing increasing numbers of poor people

at greater risk of starvation and disease. Viewed from the developed world, it

often looks as though a Malthusian catastrophe has largely been avoided;

agricultural advances have kept us one step ahead of disaster. Viewed global y,

though, Malthus’s warnings were little short of prophetic. About the same

number of people who lived on the planet in Malthus’s time go hungry in our

time. 11

In 1968, as the global population approached 3.5 bil ion, Stanford University

professor Paul Ehrlich and his wife, associate director of Stanford’s Center for

Conservation Biology Anne Ehrlich, sounded the Malthusian alarm once again

in a best-sel ing book cal ed The Population Bomb. When I was young, that book

had a rather prominent place on my father’s bookshelf—right at eye level for a

young boy. The cover was disturbing: a plump, smiling baby sitting inside a

bomb with a lit fuse. I had nightmares about that.

What was inside the cover was worse, though. In the book, Ehrlich described

his “awakening” to the horrors to come, a revelation he had during a cab ride in

New Delhi. “The streets seemed alive with people,” he wrote. “People eating,

people washing, people sleeping. People visiting, arguing, and screaming. People

thrusting their hands through the taxi window, begging. People defecating and

urinating. People clinging to buses. People herding animals. People, people,

people, people. ”12

With every new year, the Ehrlichs wrote, global food production “fal s a bit

further behind burgeoning population growth, and people go to bed a little

hungrier. While there are temporary or local reversals of this trend, it now seems

inevitable that it wil continue to its logical conclusion: mass starvation.” 13 It’s

horrifyingly clear, of course, that mil ions of people have indeed died of

starvation in the decades that have passed since The Population Bomb was rst

published, but not nearly at the levels the Ehrlichs predicted and not typical y

because of a lack of food production but rather as a result of political crises and

military con icts. When a child starves, though, it doesn’t much matter to them

or their family how it came to happen.

Though the direst of their predictions did not come to pass, in focusing so

intently on the food production–population relationship Malthus and the

Ehrlichs may actual y have underestimated the greater and longer-term risk—

not mass starvation that might claim hundreds of mil ions of lives but a

planetary rebel ion that wil kil us al .

In November 2016, the late physicist Stephen Hawking predicted that

humanity had less than 1,000 years left on “our fragile planet.” A few months of

contemplation later, he revised his estimate downward by 90 percent. Echoing

Fenner’s warnings, Hawking believed that humanity would have 100 years to

nd a new place to live. “We are running out of space on Earth,” he said. A lot of

good that wil do; the Earth-like planet that is nearest to our solar system is 4.2

light-years away. Barring major advances in warp speed or wormhole-transit

technology, it would take us ten thousand years to get there.

The problem is not just population, it’s consumption. And it’s not just

consumption, it’s waste. In comes the food; out goes the e uent. In come the

fossil fuels; out go the carbon emissions. In come the petrochemicals; out goes

the plastic. On average, Americans consume more than three times the amount

of food they need to survive and about 250 times as much water.14 In return,

they produce 4.4 pounds of trash each day, recycling or composting only about

of a third of it.15 Thanks to things such as cars, planes, big homes, and power-

hungry clothes dryers,16 the annual carbon dioxide emissions of an average

American are ve times as high as the global average. Even the “ oor”—below

which even monks living in American monasteries typical y do not go—is twice

the global average. 17

It isn’t just that Americans consume and waste so much, it’s that hundreds of

mil ions of other people consume and waste as much and in some cases more,18

and bil ions of other people are moving in that same direction. If everyone in the

world consumed as Americans do for one year, the nonpro t Global Footprint

Network estimates it would take the Earth four years to regenerate what has

been used and absorb what has been wasted. 19 This is textbook unsustainability;

we use and use and use, and return little of value to our natural world.

The increasing number of scientists making hundred-year warnings has

formed around a terrifying environmental reality: even with “very stringent and

unrealistical y ambitious abatement strategies,” 20 we likely wil not be able to prevent global temperature changes that wil be greater than 2°C, a “tipping

point” that many scientists believe wil be catastrophic for humanity.21 Indeed, as Fenner said, it might truly be “too late.”

We are not yet at that two-degree tipping point, and nonetheless the

consequences are already quite staggering. Human-caused climate change is

destroying food webs around the globe, and by some estimates, one in six species

is now at risk of extinction. Warming temperatures have “cooked the life out of

the corals” of our oceans, 22 including the Great Barrier Reef, which is roughly

the size of California and the most diverse ecosystem on our planet. More than

90 percent of that Australian natural wonder has su ered from bleaching,

meaning it is being starved of the algae it needs to survive. In 2018, the

Australian government released a report acknowledging what scientists had been

saying for many years: that the reef is headed toward “col apse.” 23 And in the

same year, Australian researchers said that global warming had claimed its rst

mammalian victim, a long-tailed marsupial mouse cal ed the Bramble Cay

melomys, which was sent into extinction when its island ecosystem was

destroyed by surging seawater.

There can also be no debate, at this point, that the melting of the Antarctic

and Greenland ice caps is driving a rise in sea levels, which the National Oceanic

and Atmospheric Association and others have warned wil worsen coastal

ooding in the coming years, threatening cities such as New York, Miami,

Philadelphia, Houston, Fort Lauderdale, Galveston, Boston, Rio de Janeiro,

Amsterdam, Mumbai, Osaka, Guangzhou, and Shanghai. A bil ion people or

more live in areas likely to be a ected by rising sea levels.24 Meanwhile, we’re facing more—and more severe—hurricanes, oods, and droughts; the World

Health Organization estimates that 150,000 people are already dying each year

as a direct result of climate change, and that number is likely to at least double in

coming years. 25

Al of these dire warnings are predicated upon a world in which humans live

for an average of about 75 or 80 years. Thus even the most pessimistic of

assertions about the future of our environment are actual y underestimating the

extent of the problem. There is simply no model in which more years of life does

not equate to more people and in which that does not lead to more crowding,

more environmental degradation, more consumption, and more waste. As we

live longer, these environmental crises wil be exacerbated.

And that could be only part of our woes.

THE HUNDRED-YEAR POLITICIAN

If there has been a consistent driving force that has made our world a kinder,

more tolerant, more inclusive, and more just place, it is that humans don’t last

long. Social, legal, and scienti c revolutions, after al , are waged, as the

economist Paul Samuelson often noted, “one funeral at a time.”

The quantum physicist Max Planck also knew this to be true.

“A new scienti c truth does not triumph by convincing its opponents and

making them see the light,” Planck wrote shortly before his death in 1947, “but

rather because its opponents eventual y die, and a new generation grows up that

is familiar with it.” 26

Having witnessed a few di erent sorts of revolutions during my life—from

the fal of the Berlin Wal in Europe to the rise of LGBTQ rights in the United

States to the strengthening of national gun laws in Australia and New Zealand

—I can vouch for these insights. People can change their minds about things.

Compassion and common sense can move nations. And yes, the market of ideas

has certainly had an impact on the way we vote when it comes to issues such as

civil rights, animal rights, the ways we treat the sick and people with special

needs, and death with dignity. But it is the mortal attrition of those who

steadfastly hold on to old views that most permits new values to ourish in a

democratic world.

Death by death, the world sheds ideas that need to be shed. Ipso facto, birth

by birth, the world is o ered an opportunity to do things better. Alas, we don’t

always get it right. And it’s often a slow and uneven sort of progress. With a

generation time of twenty minutes, bacteria evolve rapidly to survive a new

chal enge. With a generation time of twenty years, human culture and ideas can

take decades to evolve. Sometimes they devolve.

In recent years, nationalism has moved from being the purview of angry

fringe groups to being the force behind powerful political movements around

the world. There is no one single factor that can explain al of these movements,

but the economist Harun Onder is among those who have made a demographic

observation: nationalist arguments tend to resonate with older people.27

Therefore, it is likely that the antiglobalist wave wil be with us for some time to

come. “Virtual y every country in the world,” the United Nations reported in

2015, “is experiencing growth in the number and proportion of older persons in

their population.” Europe and North America already have the largest per capita

share of older persons; by 2030, according to the report, those over the age of 60

wil account for more than a quarter of the population on both of these

continents, and that proportion wil continue to grow for decades to come.

Once again, these are estimates based on ridiculously low projections for

lengthened lifespans. 28

Older constituencies support older politicians. As it is now, politicians seem

steadfastly opposed to stepping down in their 70s and 80s. More than half of the

US senators running for reelection in 2018 were 65 or older. Democratic leader

Nancy Pelosi was 78 that year. Dianne Feinstein and Chuck Grassley, two

powerful senators, were 85. On average, members of the US Congress are 20

years older than their constituents.

At the time of his death in 2003, Strom Thurmond was 100 years old and

had served 48 years as a US senator. That Thurmond was a centenarian in

Congress is no vice—we want our leaders to have experience and wisdom, as

long as they aren’t stuck in the past. The travesty was that Thurmond somehow

managed to keep his seat in spite of a long record of supporting segregation and

opposing civil rights, including basic voting rights. At the age of 99, he voted to

use military force in Iraq, opposed legislation to make pharmaceuticals more

a ordable, and helped kil a bil that would have added sexual orientation,

gender, and disability to a list of categories covered by hate crimes legislation.29

After his death, the “family values” politician was revealed to have had a

daughter with his family’s teenage African American housekeeper when he was

22, which was almost certainly an act of statutory rape under South Carolina

law. Though he knew about the child, he never publicly acknowledged her.30

Thurmond lived in retirement only six months; those who were too young to

vote then wil have to live with the consequences of his votes for the rest of their

lives.We tend to tolerate a bit of bigotry among older people as a condition of the

“age in which they grew up,” but perhaps also because we know we won’t have

to live with it for long. Consider, though, a world in which people in their 60s

wil be voting not for another twenty or thirty years but for another sixty or

seventy. Imagine a man like Thurmond serving in Congress not for half a

century but for an entire century. Or, if it makes it easier to envision from your

place on the political spectrum, picture the politician you despise more than any

other holding power longer than any other leader in history. Now consider how

long despots in far less democratic nations wil cling to power—and what they

wil do with that power.

What wil this mean for our world political y? If a steadfast driving force for

kindness, tolerance, inclusivity, and justice suddenly ceases to exist, what wil our

world look like?

And the potential problems don’t stop there.

SOCIAL INSECURITY

Few people were spared the trauma in icted by the worldwide Great Depression

during the 1930s. But the impact was particularly felt by those in the last decades

of their lives. Stock market crashes and bank failures claimed the life savings of

mil ions of older Americans. With so many people out of work, the few

employers who were o ering jobs were reluctant to hire older workers.

Destitution was rampant. About half of the elderly were poor. 31

Those people had been deacons in churches, pil ars of communities, teachers

and farmers and factory workers. They were grandmothers and grandfathers,

and their desperation shook the nation to its core, prompting the United States

in 1935 to join about twenty other countries that had already instituted a social

insurance program.

Social Security made moral sense. It made mathematical sense, too. At that

time, just over half of men who reached their 21st birthday would also reach

their 65th, the year at which most could begin to col ect a supplemental income.

Those who reached age 65 could count on about thirteen more years of life.32

And there were a lot of younger workers paying into the system to support that

short retirement; at that time only about 7 percent of Americans were over the

age of 65. As the economy began to boom again in the wake of World War II,

there were forty-one workers paying into the system for every bene ciary. Those

are the numbers that supported the system when its rst bene ciary, a legal

secretary from Vermont named Ida May Ful er, began col ecting her checks.

Ful er had worked for three years under Social Security and paid $24.75 into the

system. She lived to the age of 100 and by the time of her death in 1975 had

col ected $22,888.92. At that point, the poverty rate among seniors had fal en to

15 percent, and it has continued to fal ever since, owing largely to social

insurance.33

Now about three-quarters of Americans who reach the age of 21 also see 65.

And changes to the laws that govern the US social insurance safety net have

prompted many to retire—and begin col ecting—earlier than that. New bene ts

have been added over the years. Of course, people are living longer, too;

individuals who make it to the age of 65 can count on about twenty more years

of life. 34 And as just about every social insurance doomsdayer can tel you, the

ratio of workers to bene ciaries is an unsustainable three to one.

That is not to say that Social Security is necessarily doomed. There are

reasonable adjustments that can be made to keep it solvent for decades to come.

But al of the most commonly recommended adjustments, as you might by now

suspect, are predicated on the assumption that we wil enjoy only modest gains

in lifespan in coming years. There are very few policy makers in the United States

—let alone the 170 other countries that now have some form of social insurance

program—who have so much as considered a world in which, at the age of 65,

many people wil be reaching the midpoint of their lives.

Even upon considering this, it can be assured that many politicians, if not the

overwhelming majority of them, wil choose to bury their heads in the sand.

Lyndon Johnson’s landslide victory over Barry Goldwater in the 1964 US

presidential race can largely be attributed to Goldwater’s perceived hostility to

social insurance. But by the 1980s, politicians on both sides of the political aisle

had taken to cal ing Social Security the “third rail” of American politics: “Touch

it, you’re dead. ”35 At that time 15 percent of Americans were col ecting Social

Security. Today about 20 percent are.36 Today, people over the age of 65 make

up 20 percent of the voting population and wil grow by 60 percent by 2060,37

in addition to which they are about twice as likely as 18- to 29-year-olds to go to

the pol s. 38

There is a very rational argument for the resistance of the AARP (formerly

the American Association of Retired Persons) to any change to social insurance.

A few more years of waiting for retirement might not seem so bad to people who

work in occupations with low physical impact or in a job they love, but what of

those who have spent 45 years doing heavy manual labor, working on an

assembly line, or toiling in a meatpacking plant? Is it fair to expect them to work

even longer? Longevity drugs and healthspan therapies are very likely to help

those people feel better and stay healthier for longer, but that wouldn’t justify

forcing people who have worked arduously for most of their lives back to the

mines.

There are no easy answers, but if past is prologue—and it so often is with

human behavior—politicians wil watch this slow-moving disaster until it

becomes a fast-moving disaster; then they wil sit and watch some more. In many

nations, and particularly those of western Europe, social insurance programs are

relatively generous to bene ciaries and have been embraced by the political Left

and Right alike. These programs have become strained in recent years under the

weight of government de cits and the inability to meet long-held promises to

aging workers,39 prompting ghts over which entitlements are most sacred,

pitting education against health care and health care against pensions and

pensions against disability compensation. These ghts wil only increase as the

systems become further strained. And that strain is inevitable without

revolutionary reforms that account for the fact that the ranks of retirees wil

soon be brimming with those who, when the systems were designed in the mid-

1900s, were aged outliers.

At least every couple of months, I get a cal from a politician for an update on

the latest developments in biology, medicine, or defense. Almost always we end

up discussing what wil happen to the economy as people live longer and longer.

I tel him or her that there is simply no economic model for a world in which

people live forty years or more past the time of traditional retirement. We

literal y have no data whatsoever on the work patterns, retirement arrangements,

spending habits, health care needs, savings, and investments of large groups of

people who live, quite healthily, wel into their 100s.

Working with the world-renowned economists Andrew Scott at the

University of London and Martin El ison at Oxford University, we are

developing a model to predict what the future looks like. There are quite a few

variables, not al of them positive. Wil people continue to work? What jobs wil

they be able to get in a world in which the labor market wil already be being

upended by automation? Wil they spend a half century or more in retirement?

Some economists believe that economic growth is slowed when a country ages,

in part because people spend less in retirement. What wil happen if people

spend half of their very long lives out of work, spending only enough to get by?

Wil they save more? Invest more? Get bored soon after retirement and start a

new career? Take long sabbaticals from work, only to return decades later when

their money runs out? Spend less on health care because they are so much

healthier? Spend more on health care because they are living so much longer?

Invest more years and money into their educations early on?

Anyone who claims to know the answer to any of these questions is a

charlatan. Anyone who says these questions aren’t important is a fool. We have

absolutely no idea what’s going to happen. We are ying blind into one of the

most economical y destabilizing events in the history of the world.

Yet that is not the worst of it.

WHAT DIVIDES US GROWS GREATER

If you were a member of the American upper middle class in the 1970s, you

weren’t just enjoying a more a uent life, you had a longer one, too. Those in the

top half of the economy were living an average of 1.2 more years than those in

the bottom half.

By the early 2000s, the di erence had increased dramatical y. Those in the

upper half of the income spectrum could expect nearly six additional years of

life, and by 2018, the divide had widened, with the richest 10 percent of

Americans living thirteen more years of life than the poorest 10 percent. 40

The impact of this disparity cannot be overstated. Just by living longer, the

rich are getting richer. And of course, by getting richer, they are living longer.

Extra years o er more time to preside over family businesses, and more time for

family investments to multiply exponential y.

Riches are not just invested into companies; they provide rich people with

access to the world’s leading doctors (there are about ve in the United States

that they al seem to use), nutritionists, personal trainers, yoga instructors, and

the latest medical therapies—stem cel injections, hormones, longevity drugs—

which mean they stay healthier and live longer, which al ows them to

accumulate even more wealth during their lifetimes. The accumulation of

wealth has been a virtuous cycle for families lucky enough to get onto it.

And the rich don’t invest only in their health; they also invest in politics,

which is no smal part of the reason why a series of revisions to the US tax code

has resulted in a dramatic reduction in taxes on the wealthy.

Most countries tax people when they die as a way to limit wealth

accumulation over generations, but it’s a little-known fact that, in the United

States, estate taxes weren’t initial y designed to limit multigenerational wealth;

they were imposed to nance wars.41 In 1797, a federal tax was imposed to build

a navy to fend o a possible French invasion; in 1862, an inheritance tax was

instituted to nance the Civil War. The 1916 estate tax, which was similar to

present-day estate taxes, helped pay for World War I.

In recent times, the burden of paying for wars has shifted to the rest of the

population. Thanks to tax loopholes, the percentage of rich American families

who pay what were cleverly branded as “death taxes” decreased vefold,

providing the lowest cost for “dying rich” in modern times. 42

Al this means that the children of the wealthy are faring extremely wel .

Unless there is an upward revision to the tax code, they wil continue to do

better, both in how much money they inherit and in how much longer they wil

live than others do.

Remember, too, that aging is not yet considered a disease by any nation.

Insurance companies don’t cover pharmaceuticals to treat diseases that aren’t

recognized by government regulators, even if it would bene t humanity and the

nation’s bottom line. Without such a designation, unless you are already

su ering from a speci c disease, such as diabetes in the case of metformin,

longevity drugs wil have to be paid for out of pocket, for they wil be elective

luxuries. Unless aging is designated a medical condition, initial y only the

wealthy wil be able to a ord many of these advances. The same wil be true for

the most advanced biotracking, DNA sequencing, and epigenome analyses to

permit truly personalized health care. Eventual y prices wil come down, but

unless governments act soon, there wil be a period of major disparity between

the very rich and the rest of the world.

Imagine a world of haves and have-nots unlike anything we have experienced

since the dark ages: a world in which those born into a certain station in life can,

by virtue of nothing more than exceptional fortune, live thirty years longer than

those who were born without the means to literal y buy into therapies that

provide longer healthspans and enable more productive working years and

greater investment returns.

We have already taken the rst tenuous steps into a world that was predicted

by the 1997 lm Gattaca, a society in which technologies original y intended to

assist in human reproduction are used to eliminate “prejudicial conditions,” but

only for those who can a ord them. In the coming decades, barring a safety issue

or a global backlash against the unknown, we’l likely see the increased ability

and acceptance of gene editing global y, providing would-be parents with the

option to limit disease susceptibility, choose physical traits, and even select

intel ectual and athletic abilities. Those of means who wish to give their children

“the best possible start,” as a doctor tel s two prospective parents in Gattaca, wil

be able to do so, and with longevity genes identi ed, they could be given the best

possible nish, too. Whatever advantages genetical y enhanced people wil

already have, they could be multiplied by virtue of economic access to longevity

drugs, organ replacements, and therapies we haven’t even yet dreamed of.

Indeed, unless we act to ensure equality, we stand at the precipice of a world

in which the über-rich could ensure that their children, and even their

companion animals, live far longer than some poor people’s children do.

That would be a world in which the rich and poor wil be separated not

simply by di ering economic experiences but by the very ways in which human

life is de ned—a world in which the rich wil be permitted to evolve and the

poor are left behind.

Yet . . .

Notwithstanding the potential that extending human longevity has to

exacerbate some of the direst problems of our world—and indeed to give us new

troubles in the decades to come—I remain optimistic about the potential of this

revolution to change the world for the better.

We’ve been here before, after al .

TO WEND OUR WAY

To understand the future, it is often helpful to travel into the past. So if we want

to better understand the desperate world we are about to enter, a good place to

go is to another desperate time.

In a city brimming with iconic landmarks, from the Tower of London to

Trafalgar Square, from Buckingham Palace to Big Ben, it is perfectly reasonable

that many people, and indeed even many Londoners, have never dedicated so

much as a thought to the Cannon Street Railway Bridge.

There are no songs about it; not to my knowledge, at least. I know of no

authors who have set their stories upon its rusted rails. When it appears in

cityscape paintings, it is almost always an incidental character.

Granted, it is a rather unsightly thing, an uninvolving and utterly utilitarian

structure of green-painted steel and concrete. And if you were to look easterly

upon the River Thames from the far more charming, lamp-lined sidewalks of

Southwark Bridge, you could indeed be forgiven for missing it altogether,

although it is right before you, for just beyond on the right is architect Renzo

Piano’s famous Shard building, and just beyond that, spanning the river, is the

even more famous London Bridge, among other grand sights downstream.

In 1866, the year the Cannon Street Railway bridge was opened, there were

nearly 3 mil ion people in London. More arrived in the years to come, often

arriving from abroad by boat to Cannon Street Station, London’s equivalent of

El is Island, and dispersing from there by rail, across the humble bridge, to the

other parts of the city as it grew more and more crowded by the day. I can

scarcely imagine what someone looking upon the throngs of out-of-town

arrivals must have thought in the years in which London seemed so clearly

unable to sustain any more people, let alone the masses coming from other parts

of the world and the many more being born into the already overcrowded city.

Even the exodus to colonies in the Americas and Australia did nothing to

stem the population explosion. By 1800, approximately a mil ion people were

living in London, and by the 1860s that number had tripled, unleashing dire

consequences on the capital of the British Empire.

Central London was a particularly hel ish place. The mud and horse manure

were often ankle deep in streets further littered by newspapers, broken glass,

cigar ends, and rotting food. Dockworkers, factory workers, laundresses, and

their families were packed into tiny hovels with dirt oors. The air was thick

with soot in the summer and soot-drenched fog in the winter. With every

breath, Londoners l ed their lungs with mutagenic, acid-coated particles of

sulfur, wood, metals, soil, and dust.

A sewer system intended to take human waste away from the richer

neighborhoods of central London did just that—sending it into the River

Thames, where it owed east past the Isle of Dogs toward the poorer quarters,

where people drew the water to wash and drink. 43, 44

In those squalid conditions, it should come as little surprise that cholera

could spread with devastating speed. And it had, with three large outbreaks so

far that century, in 1831, 1848, and 1853, claiming more than 30,000 lives, with

thousands more lost to smal er outbreaks during the intermediate years.

The Final Catastrophe, as it came to be known, was focused almost

exclusively on the inhabitants of Soho in the West End, where a contaminated

wel provided water to more than a thousand people. Today, the Broad Street

pump is preserved on what is now Broadwick Street, surrounded by pubs,

restaurants, and high-end clothing stores. The pump’s granite base is often used

as a seat by unsuspecting tourists. Save for the keystone plaque on the building

nearby, there are no clues about the misery this site wrought.

Twenty people died in the rst week of the cholera outbreak, July 7 to 14 of

1866, fal ing to diarrhea, nausea, vomiting, and dehydration. Doctors had only

just realized that they were dealing with another outbreak when the second wave

began. More than three hundred additional people had died by July 21. From

there it only got worse. On no day between July 21 and August 6 did fewer than

a hundred people perish, and the death tol continued to mount through

November.

That was the hel scape in which a former domestic servant named Sarah Neal

gave birth to her fourth child on September 21, 1866, just six miles south of the

epicenter of the outbreak. She cal ed her son “Bertie.” So did her husband,

Joseph Wel s. But the boy would ultimately choose to go by the initials of his

given name, Herbert George.

In the center of despair and squalor, in a city breaking under the weight of a

population boom, in the heart of hopelessness, was born the father of utopian

futurism, H. G. Wel s.

Wel s is most famous today for his dystopian ction The Time Machine, but

in stories such as The Shape of Things to Come, he audaciously predicted a

“future history” that included genetic engineering, lasers, airplanes, audiobooks,

and television. 45 He also predicted that scientists and engineers would lead us

away from ghting war after war toward a world devoid of violence, poverty,

hunger, and disease. 46 It was, in many ways, a blueprint for Star Trek creator Gene Roddenberry’s vision of a future Earth that would be a utopian base for

exploration of the “ nal frontier.” 47

How did we go from a world of such misery to one in which such dreams

were even possible?

Wel , as it turned out, the disease was the cure.

The Cannon Street Bridge, completed the same year that cursed London

with the Final Catastrophe and blessed the world with the genius of H. G. Wel s,

stands as a testament to the ways in which the London of yesterday came to be

the London of today, of how population and progress are intrinsical y

connected, and, indeed, of utopian dreams realized. For London’s nineteenth-

century population boom forced the city to confront its most horri c

chal enges. There was simply no other option. The choice was clear: adapt or

perish. 48

And so it was that the late nineteenth century brought to London some of

the world’s rst public housing projects, replacing dirt- oored shanties with

plumbed tenements that would, upon the passage of the Housing of the

Working Classes Act of 1900, also have access to electric power. The same time

period saw a tremendous rise in the number and quality of public institutions of

education, including mandated schooling for children between the ages of 5 and

12, imperfectly but increasingly drawing legions of children away from the

dangerous and exploitative conditions of life on London’s streets.

Perhaps the most important of the reforms, however, was in the eld of

public health, beginning in 1854 with the physician John Snow’s rebel ion

against the entrenched medical view that cholera was caused by miasma, or “bad

air.” By talking to residents and triangulating the problem, Snow had the Broad

Street pump’s handle removed. The epidemic soon ended. Government o cials

were quick to replace the pump handle, in part because the fecal-oral route of

infection was too horri c to contemplate. Final y, in the eventful year of 1866,

Snow’s chief opponent, Wil iam Farr, was investigating another cholera

outbreak and came to the realization that Snow was right. The resolution of that

public health skirmish led to improved water delivery and sewage systems in the

capital of the world’s largest empire.

Those innovations were soon copied around the globe—one of the greatest

global health achievements in human history. Far more than any other lifestyle

change or medical intervention, clean water and working sanitation systems have

led to longer and healthier lives the world over. And London, where this al

began, is Exhibit A. Lifespans in the United Kingdom have more than doubled

in the past 150 years, in no smal part because of innovations that were made in

direct response to the overcrowding in it that the early-nineteenth-century

parliamentarian Wil iam Cobbett derisively cal ed the Great Wen, a nickname

that compared the city to a swel ing, pus- l ed, sebaceous cyst.

The movement from miasmatic theory to germ theory, meanwhile,

fundamental y shifted ideas about how to combat al sorts of other diseases,

setting the stage for Louis Pasteur’s breakthroughs in fermentation,

pasteurization, and vaccination. The ripples are manifold and can be measured,

without the slightest hint of hyperbole, in hundreds of mil ions of human lives.

If it hadn’t been for the advances that came out of that period of our history,

bil ions upon bil ions of people would not be alive today. You might be here. I

might be here. But the chances that we would both be here would be very slim.

It turned out that the population of London wasn’t the problem after al .

The problem wasn’t how many people lived in the city but how they lived in

the city.

At 9 mil ion residents and stil growing, London today has three times as

many people as it did in 1866 but far less death, disease, and despair.

Indeed, if you were to describe the London of today to Londoners of the

1860s, I submit that you would be hard-pressed to nd a single soul who would

not agree that their city, in the twenty- rst century, would have far surpassed

their most sanguine utopian dreams.

Do not get me wrong: the limitless and legitimate concerns people express

about a world in which humans live twice as long as they do now—or longer—

cannot be dismissed with a story about old London. The city is by no means

perfect. Anyone who has ever priced a one-bedroom at in the city knows this to

be true.

But today, we can plainly see that the city is ourishing not in spite of its

population but because of it, such that today the capital of and most populous

city in the United Kingdom is home to a myriad of museums, restaurants, clubs,

and culture. It is home to several Premier League footbal clubs, the world’s

most prestigious tennis tournament, and two of the best cricket teams on the

globe. It is home to one of the world’s largest stock exchanges, a booming tech

sector, and many of the world’s biggest and most powerful law rms. It is home

to dozens of institutions of higher education and hundreds of thousands of

university students.

And it is home to what is arguably the most prestigious national scienti c

association in the world, the Royal Society.

Founded in the 1600s during the Age of Enlightenment and formerly headed

by Australia’s catalyst, the botanist Sir Joseph Banks, as wel as such legendary

minds as Sir Isaac Newton and Thomas Henry Huxley, the society’s cheeky

motto is a pretty good one to live by: “Nullius in Verba,” it says underneath the

society’s coat of arms. That’s Latin for “Take nobody’s word for it.”

So far in this chapter I have presented a case—one agreed upon by many great

scientists—that even at current and very conservative population growth

projections, based on lives that are extended only slightly in the coming decades,

our planet is already past its carrying capacity and we, as a species, are only

exacerbating that problem with the ways in which we are increasingly choosing

to live. And yes, advances in healthspans and lifespans could greatly exacerbate

some of the problems we already face as a society.

But there is another way of seeing our future—one in which prolonged

vitality and increasing populations are every bit as inevitable but not damning to

our world. In this future, the coming changes are our salvation.

But, please: don’t just take my word for it.

A SPECIES WITH NO LIMITS

When he is remembered at al , the Dutch amateur scientist Antonie van

Leeuwenhoek is almost always thought of as the father of microbiology. But

Leeuwenhoek dabbled in great questions of al sorts, including one that may

impact the world every bit as grandly. In 1679, by way of trying to convey to the

Royal Society just how multitudinous the unseen microscopic world was, he

embarked upon an e ort to calculate—“but very roughly,” he hastened to add—

the number of human beings who could survive on the Earth. 49 Using the

population of Hol and at the time, which was roughly 1 mil ion people, and

some very round estimates for the globe’s size and total land surface, he came to

the conclusion that the planet could carry about 13.4 bil ion people.

That wasn’t a bad guess for someone using what we might today cal “back-

of-the-napkin” math. Albeit high, it’s in the bal park of the estimates of many

more contemporary scientists who have explored the same question with far

more data to work with.

A United Nations Environment Programme report detailing sixty- ve

scienti c estimates of global carrying capacity found that the majority—thirty-

three—had pegged the maximum sustainable human population at 8 bil ion or

fewer people. And yes, by these estimates, we have either already met or wil soon

meet the maximum number of human beings our planet can sustain.50

But an almost equal number of estimates—thirty-two of them—concluded

that the number is somewhere above 8 bil ion. Eighteen of those estimates

suggested that the carrying capacity is at least 16 bil ion. And a few estimates

suggested that our planet has the potential to sustain more than 100 bil ion

people.

Clearly, someone’s numbers must be way o .

As you might imagine, these varying estimates are largely dependent on

di erences in the ways in which the constraining limits of population are

de ned. Some researchers consider only the most basic factors; not unlike

Leeuwenhoek, they speculate as to a maximum population per square mile,

multiply that by the roughly 25 mil ion square miles of habitable land on Earth,

and that’s that.

More robust estimates have included basic constraining factors such as food

and water. After al , it does not matter if we can t tens of thousands of people

into a square mile—as is the case in exceptional y dense cities such as Manil a,

Mumbai, and Montrouge—if those people starve or die of thirst.

Detailed estimates of the entire globe’s carrying capacity include the

interaction of constraining factors and the impact of human exploitation of the

global environment. Having enough land and water doesn’t matter, either, if

continued population growth aggravates the already dire consequences of

climate change, further destroying the forests and biological diversity that

sustain our existence.

But whatever the method and whatever the resulting number, the very act of

engaging in the process of trying to derive a carrying capacity acknowledges that

there is, in fact, a de nitive uppermost limit. Indeed, my col eague at Harvard,

the Pulitzer Prize–winning biologist Edward O. Wilson, wrote in The Future of

Life, “it should be obvious to anyone not in a euphoric delirium that whatever

humanity does or does not do, Earth’s capacity to support our species is

approaching the limit. ”51 That was in 2002, when the Earth’s population was a

paltry 6.3 bil ion. In the next fteen years, another 1.5 bil ion people were added.

Scientists general y pride themselves on rejecting the notion that anything

“should be obvious.” Evidence, not obviousness, drives our work. So at the very

least, the overwhelming certainty that a limit exists deserves to be debated, as any

scienti c idea does.

It needs to be pointed out that very few of the global carrying capacity

models account for human ingenuity. As we have discussed, it is easier not to see

things coming than to see them, so we tend to extrapolate into the future

directly from the way things are now. That’s unfortunate and, in my view,

scienti cal y wrong, for it eliminates an important factor from the equation.

Positive views about the future aren’t as popular as negative ones. In rejecting

wel -meaning but imperfect estimates and arguing that there is no scienti cal y

foreseeable limit to the number of people the planet can sustain, the

environmental scientist Erle C. El is at the University of Maryland has taken a

lot of heat. That, of course, is what happens when scientists chal enge

entrenched ideas. But El is has stood rm, even penning an op-ed for the New

York Times in which he cal ed the very notion that we might be able to identify a

global carrying capacity “nonsense. ”52

“The idea that humans must live within the natural environmental limits of

our planet denies the realities of our entire history, and most likely the future,”

he wrote. “. . . Our planet’s human-carrying capacity emerges from the

capabilities of our social systems and our technologies more than from any

environmental limits. ”53

If there were anything like a “natural” limit, El is has argued, the human

population probably exceeded it tens of thousands of years ago, when our

hunter-gatherer ancestors began to rely upon increasingly sophisticated water

control systems and agricultural technologies to sustain and grow their numbers.

From that point on, our species has grown only by the combined grace of the

natural world and our ability to adapt to it technological y.

“Humans are niche creators,” El is stated. “We transform ecosystems to

sustain ourselves. This is what we do and have always done.”

In this way of thinking, few of the adaptations that sustain our lives are

“natural.” Water delivery systems are not natural. Agriculture is not natural.

Electricity is not natural. Schools and hospitals and roads and clothes are not

natural. We have long since crossed al of those gurative and literal bridges.

On a plane from Boston to Tokyo recently, I introduced myself to a man

sitting next to me and we chatted about our work. When I told him that I was

endeavoring to extend human lives, he curled his upper lip.

“I don’t know about that,” he said. “It sounds unnatural.”

I gestured for him to look around. “We are in reclinable chairs, ying at six

hundred miles an hour seven miles above the North Pole, at night, breathing

pressurized air, drinking gin and tonics, texting our partners, and watching on-

demand movies,” I said. “What about any of this is natural?”

You don’t have to be in an airplane to be removed from the natural world.

Look around. What about your current situation is “natural”?

We long ago left a world in which the vast majority of humans could expect a

life of “no arts; no letters; no society,” as Thomas Hobbes wrote in 1651, “and

which is worst of al , continual fear, and danger of violent death.”

If that is indeed what is natural, I have no interest in living a natural life, and I

would wager that you do not wish for that, either.

So what is natural? Certainly we can agree that the impulses that compel us

to live better lives—to strive for existences with less fear, danger, and violence—

are natural. And it is true that most of the adaptations that enable survival on

this planet, including our wonderful survival circuit and the longevity genes it

has created, are the products of natural selection, weeding out over bil ions of

years those who failed to hunker down when times were tough, but a great many

are skil s we’ve accumulated over the past 500,000. When chimps use sticks to

probe termite nests, birds drop rocks on mol usks to break their shel s, or

monkeys bathe in warm volcanic pools in Japan, it’s al natural.

Humans just happen to be a species that excels at acquiring and passing on

learned skil s. In the past two hundred years, we have invented and utilized a

process cal ed the scienti c method, which has accelerated the advancement of

learning. In this way of thinking, then, culture and technology are both

“natural.” Innovations that permit us to feed more people, to reduce disease,

and, yes, to extend our healthy lives are natural. Cars and planes. Laptop

computers and mobile phones. The dogs and cats who share our homes. The

beds on which we sleep. The hospitals in which we care for one another in times

of sickness. Al of this is natural for creatures who long ago exceeded the

numbers that could be sustained in conditions Hobbes famously described as

“solitary, poor, nasty, brutish, and short.”

To me, the only thing that seems unnatural—in that it has never happened in

the history of our species—is to accept limitations on what we can and cannot

do to improve our lives. We have always pushed against perceived boundaries; in

fact, biology compels us to.

Prolonging vitality is a mere extension of this process. And yes, it comes with

consequences, chal enges, and risks, one of which is increased population. But

possibility is not inevitability, for as a species we are naturally compel ed to

innovate in response. The question, then, is not whether the natural and

unnatural bounties of our Earth can sustain 8 bil ion, 16 bil ion, or 20 bil ion

people. That’s a moot point. The question is whether humans can continue to

develop the technologies that wil permit us to stay ahead of the curve in the face

of population growth, and indeed make the planet a better place for al creatures.

So can we?

Absolutely. And the past century is proof.

PEOPLE, PEOPLE, GLORIOUS PEOPLE

After our species was almost driven to extinction 74,000 years ago, up until

1900, the human population grew at a rate amounting to a fraction of a percent

each year as we expanded to al habitable regions on the planet, breeding with at

least two other human species or subspecies. By 1930, thanks to sanitation and

decreases in child-mother mortality, our species was increasing its numbers at 1

percent each year. And by 1970, due to immunization and improvements in

food production global y, the rate was 2 percent each year.

Two percent might not seem like a lot, but it added up fast. It took more than

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