The key ideas

Lifespan: Why We Age—and Why We Don’t Have To

David Sinclair, Matthew LaPlante, 2019

The author’s grandmother described her fading old age by saying, “That’s just how it is.” Harvard geneticist David Sinclair devoted his life to challenging that. In his theory, aging is a loss of information in cells; aging has a cause and can therefore be slowed. The book explains what activates longevity genes today and what still works only in mice.

Who it is for

For anyone who wants to understand aging at the cellular level and distinguish what we can do now from bold promises for the future.

There is no law of biology that says we must age.

The grandmother who conducted symphonies

David Sinclair’s grandmother was named Vera. During World War II, she hid Jews; later, she lived in New Guinea, and once she was escorted off Sydney’s Bondi Beach for wearing a bikini. In her sixties and seventies, she remained young at heart: drinking wine with friends, telling stories, helping the poor and sick, and laughing as she pretended to conduct a symphony.

By her mid-eighties, little of that woman remained. Music no longer delighted her, and she hardly left her chair. “That’s just how it is,” she told her grandson. Vera died at ninety-two, but the Vera Sinclair knew had gone much earlier.

Her grandson grew up, became a geneticist and Harvard Medical School professor, and devoted his life to challenging her words. The book appeared in 2019, coauthored with journalist Matthew LaPlante. The author’s idea is bold: aging is not a law of nature but a process with an understandable cause, which can be slowed and perhaps even reversed. This is his position, and many scientists dispute it. But it rests on years of experiments in yeast and mice.

Ahead are an ancient microbe that learned to survive, a pianist forgetting the tune, mice unwilling to leave a treadmill, and a son’s question the author had to answer. Let us begin with where aging came from in the first place, because in Sinclair’s view, hope lies in that answer.

The ancient survivor that learned to wait

To explain where aging comes from, Sinclair proposes a thought experiment. Imagine one of Earth’s first living organisms, around four billion years ago. The author names it Magna superstes, Latin for “great survivor.” It is an invented organism, an explanatory image rather than a discovered fossil.

It has two genes. Gene A tells the cell not to reproduce when conditions are bad. Gene B produces a protein that silences gene A in good times, allowing the cell to divide peacefully. Then something decisive happens: gene B’s protein gains a second job, repairing DNA. When DNA breaks, the protein leaves gene A to make repairs. Gene A switches on, and reproduction pauses until the damage is fixed.

This is the survival circuit: postponing reproduction during difficulty to focus on repairs. Such an organism survives disasters that kill its neighbors and passes its circuit to descendants. Sinclair believes we inherited it too.

In humans, gene B’s descendants are sirtuins. These enzymes determine which genes work in a cell and which remain silent. Mammals have seven of them, produced by almost every cell in the body. They need a molecule called NAD to function; the author writes that its levels decline with age.

Sinclair found his first clue in yeast while working in Leonard Guarente’s laboratory. Old yeast cells stopped mating. It turned out that Sir2, the protein keeping mating genes switched off, increasingly left to repair DNA breaks and did not always return. Repair won out over reproduction, and the cell became infertile.

Imagine a fire brigade that maintains order in the city on quiet days. While fires are rare, everything works. But with constant callouts, nobody remains to keep order. In the author’s view, this is how cells age.

Read in Livria

About the author

David Sinclair is an Australian-American geneticist and professor at Harvard Medical School who has spent many years studying aging and sirtuins. Matthew LaPlante is an American journalist and journalism instructor, and the book’s coauthor.

All books by this author: David Sinclair, Matthew LaPlante

Terms from the book

  • Planck
  • Hormesis
  • AMPK
  • capillaries
  • Yamanaka
  • Nature
  • Senolytics
  • Vera: The author’s grandmother, born in Hungary, who moved to Australia. Her old age opens the book.
  • Bondi: A famous beach in Sydney, Australia.
  • LaPlante: Matthew LaPlante, an American journalist and coauthor of the book.
  • Magna superstes: Latin for “great survivor.” An ancient microorganism invented by the author to explain the survival circuit. An image from the book, not a real species.
  • Sirtuins: A family of enzymes that control genes switching on and off and participate in DNA repair. Sinclair considers them the main longevity genes.
  • NAD: Nicotinamide adenine dinucleotide, a molecule present in every cell and necessary for sirtuins to work. Its level declines with age.
  • Guarente: Leonard Guarente, an American biologist and aging researcher in whose laboratory Sinclair worked after graduate school.
  • Sir2: The yeast gene that gave all sirtuins their name. Its protein keeps mating genes switched off and helps repair DNA.
  • Epigenome: The system of chemical tags and DNA packaging that determines which genes in a cell work and which remain silent.
  • ICE: A line of mice from Sinclair’s laboratory with an activatable gene that cuts DNA at specific sites. The name abbreviates “inducible changes to the epigenome.”
  • Slime mold: A simple organism living on decaying wood and fallen leaves. It belongs to a separate group, neither fungi nor plants.
  • Olshansky: Jay Olshansky, an American demographer at the University of Illinois who studies life expectancy.
  • mTOR: A protein that monitors how many amino acids a cell has for building proteins and controls cell growth. Sinclair includes it among longevity mechanisms.
  • Postdoc: A researcher who has completed a doctorate and holds a temporary research position in someone else’s laboratory.
  • Bonkowski: Michael Bonkowski, a researcher in Sinclair’s laboratory who conducted treadmill experiments with old mice.
  • Resveratrol: A substance plants such as grapes produce in response to stress. Sinclair believes it boosts sirtuin activity. Its effect in humans has not been proven.
  • Xenohormesis: An idea proposed by Sinclair and colleagues: stressed plants produce substances that, when consumed in food, activate protective mechanisms in our cells too. A hypothesis, not a proven fact.
  • Rapamycin: A drug that inhibits mTOR. It is used medically, including after organ transplantation.
  • Metformin: A long-established, widely used drug for type 2 diabetes. It is being studied as a possible treatment for aging.
  • NMN: Nicotinamide mononucleotide, a substance cells use to make NAD. Sold as a dietary supplement, its effects in humans are being studied.
  • Stem cell: A cell that has not yet chosen a specialization and can become a cell of any tissue.
  • Glaucoma: An eye disease in which the optic nerve gradually dies and vision deteriorates.
  • Hanauer: Nick Hanauer, an American entrepreneur and venture capitalist who writes about the harm of growing inequality.

All terms

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