Aging Is a Scratched Disc. David Sinclair Thinks the Body Kept a Backup

Lex Fridman opens with a feeling he cannot shake: the person sitting in the chair is the same one who was twelve, even as the body and mind keep aging. David Sinclair, a professor of genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for the Biology of Aging, recognizes the tension immediately. He still feels like a kid. That, he says, is not a defect in a scientific career. Scientists need wonder about the world, and wonder is what you have at six or seven, not what you keep after you decide to grow up.

The other half of the day is performance. He runs a lab of twenty people, writes, does science, and manages companies, so on most days he has to pretend to be a grown-up. Mentally he remains the boy who can look at something as if for the first time and then explain it the way he would to a six-year-old—because, he says, he is one. Fridman reads the A. A. Milne poem that opens Sinclair's book *Lifespan*: after the years of barely being, "now I am six, I am as clever as clever, so I think I'll be six now forever and ever."

Sinclair gets misty. His grandmother, who partly raised him, read that poem almost every day. She hated small talk, preferred human beings and culture, and had seen the worst of the twentieth century: hiding Jewish friends in a Budapest apartment during the war, living under the Russians afterward, joining the 1956 revolution, then escaping the country. Her instruction, expressed through the poem, was to stay young and innocent, keep wonder, and make humanity as good as it can be. That, Sinclair says, is why he gets up in the morning: to leave the world better, and to show whoever is watching—aliens or a future historian—that we can do better than we did in the last century.

Fridman has a private project: animating Einstein, Alan Turing, Isaac Newton, and Richard Feynman so later generations can see the quirks, not just the theorems. The first layer is visual. The second, further out, is compressing text, video, and audio into something that can talk. He cites Replika, born when its founder trained a language model on messages with a friend who had been killed by a car. The chat was obviously a machine. It still gave her solace.

Sinclair has seen the *Black Mirror* episode in which a widow buys her partner back, first as a voice and then as a body. Capturing Feynman's sense of humor would be the hard part, he says, but it would be wonderful. The dark side is real too: if the person died young, a replica might stop the living from moving on. His own historical hunger runs the other direction. He would rather pull Benjamin Franklin into the future than build a time machine, just to watch the look on Franklin's face when he sees a thinking machine in a pocket.

They agree to keep Franklin on science and off Congress, and definitely off Twitter. The sharper point is about data density. Feynman left video, interviews, and other people's stories, so you can assemble a whole person. Turing left almost nothing; Fridman has never found the radio recording that is supposed to exist. Official biographies, Sinclair and Fridman both suggest, are a thin compression. The embarrassing, distracted, joking fragments are the actual shape. The upside of the digital age is a kind of accidental immortality, with the option to highlight the best and throw away the rest.

Sinclair is a biologist who finds animals and humans interesting as machines, which is why he did not become an engineer or a surgeon. The first merger of machine and human, in his view, is the wearable. In *Lifespan* he pictured continuous monitoring so a heart attack would not be a surprise, so a doctor would know whether you needed an antibiotic, and so a device smarter than both of you would suggest what to eat and take. He also pictured video visits and medicines arriving by courier, then drone, then a kitchen synthesizer. The book was barely two years old when he sat down with Fridman. Covid had shoved that future into the present.

The kit he already uses is not science fiction. A blood test can flag cancer a decade or two before a tumor. A genome costs less than a hundred dollars. He wears an Oura ring with years of data, a watch, and, as of the night before the taping, a BioButton on his chest: an inch long, a few millimeters thick, FDA-cleared, meant for patients sent home after a heart attack or surgery. It samples a thousand times a second—speech vibration, orientation, sleep side and place, sneezes, coughs, temperature, heart rate, other cardiac signals. Hospitals already save at least two thousand dollars by discharging a cardiac patient a week early with one of these.

For twelve years he has also used InsideTracker, a consumer blood service he consults for, tracking thirty-four markers including testosterone, glucose, and inflammation. At fifty-one those numbers look like someone in their early forties; if he works at it, the biochemistry can look like the early-to-mid thirties, dessert notwithstanding. You go to a lab, or upload existing results, and an algorithm plots you against people your age, then recommends food and supplements drawn from thousands of papers and hundreds of thousands of human data points. Sinclair co-authored a paper claiming those recommendations beat the leading type 2 diabetes drug. Upload a genome and the same stack will soon know you better than you know yourself. A yearly checkup, he says, will look like a joke.

Fridman asks the large question: from an engineering view of the biological machine, is aging a feature or a bug? Both, Sinclair says. Evolution only keeps you alive long enough to replace yourself efficiently. A mouse gets two or three years because it will probably starve, get eaten, or freeze, so it spends on rapid reproduction and not on the body. A bowhead whale, at the top of the food chain, can live hundreds of years, so it breeds slowly and builds something that lasts. Humans sit in between, only recently off a savanna where a cat could pick us off. Even the strongest person in a cage with a chimpanzee, he says, would have their head knocked off. We are pathetic. We have to engineer what evolution withheld.

Ask the field and you will hear eight or nine hallmarks: telomeres worn to nubs, senescent cells leaking inflammatory molecules, mitochondria winding down, stem-cell loss, proteostasis failure. Sinclair does not deny them. He wants the equation upstream. Most biologists say you cannot boil it down. He says you can: preservation of information, lost to entropy, which is noise. The line starts in the 1990s at MIT, in baker's yeast, *Saccharomyces cerevisiae*. In four years his lab found genes that control how yeast get old. One was SIR2, Silent Information Regulator 2. Extra copies made the cells live 30 percent longer and suppressed the informational chaos. Humans have seven cousins, SIRT1 through SIRT7. More SIRT1 in a mouse slowed aging in the brain.

A cell holds two main kinds of information. The genome, four letters, billions of them, does degrade—but in old animals and people it is mostly still there. A friend in Los Angeles cloned his dog three times. The other kind is the epigenome: how DNA is wrapped or looped so a cell can read particular passages. Sinclair's analogy is a compact disc. The pits are the genome. The epigenome is the reader, playing different music in a skin cell than in a brain cell, a score laid down in the womb so a skin cell does not become a neuron tomorrow. Over time the reader slips. Brain cells start to look like skin cells; kidney cells start to look like liver cells. His lab calls it ex-differentiation. The metaphor for that is scratches on the disc.

The scratches are wear, not a calendar. There is no program for aging, and no evolutionary selection for it; after you have reproduced you are at the whim of the second law. What is good when you are young can hurt you later—antagonistic pleiotropy. The main noise his group has pinned down is a broken chromosome. The cell panics, because the outcomes are cancer or death, and it plays ping-pong with the proteins that keep its identity: they leave their posts, repair the break, and come home. In youth they make it back. With age some never do. The body sees close to a trillion DNA breaks a day; eighty years of that scramble the reader. The lab built a mouse whose breaks can be turned up like a rheostat. Sinclair, who drove a Tesla to the studio and loves *This Is Spinal Tap*, can send it to 11 and age the animal in months. At about 4, it is old in ten months: gray hair, old skin, the diseases, an epigenetic clock 50 percent ahead of its birthday. Cell stress and chemicals such as smoke add more scratches. The question becomes whether you can send the balls back.

Anyone who has dubbed a cassette or photocopied a photocopy knows that lost information usually stays lost. Sinclair spent about five years hunting for a backup, inspired by Claude Shannon's observer in the 1940s mathematical theory of communication—the copy that fills gaps, the thing we now talk about as TCP/IP. In December 2020 his group reported a reset switch in *Nature*. Three embryonic genes, from the set of four Shinya Yamanaka used to win the 2016 Nobel Prize, can be put into an adult animal and take tissue age backward. Yamanaka's full quartet, at high levels, makes stem cells. The disaster in an eye would be a pocket of those. The finding is that you can take age back to a point and stop, safely, without a tumor and without a stem cell.

Delivery is viral, so they control where and when the genes turn on. A mouse that had gone blind from aging, its neurons no longer talking well to the brain, could see again in four to eight weeks. They are now using the same trick on the animals they aged with extra DNA breaks; those mice are getting the ability to learn back. Overdo it and you might cause tumors. In the eye they find it very safe. High levels put into the veins throughout the body did not produce cancer for more than a year. Sinclair was optimistic enough, in June 2021, to say human studies were less than two years away.

Fridman wants to know where AI helps. If you are not using it in biology, Sinclair says, you are getting left behind. His lab uses it to read the scratches as biological clocks, to predict protein folds so they can aim molecules, to assemble genomes, to forecast a mouse's remaining life from hearing, eyesight, and frailty. After his daughter Natalie was nearly blinded by Lyme disease and a hospital would not hand him spinal-fluid DNA for a same-day answer, he started a company that identifies microorganisms from a sample—work already used on transplant patients. Biologists now generate terabytes a week, soon per day. He cannot hire enough bioinformaticians. DeepMind's AlphaFold is, in that light, not a curiosity. It is the new default instrument.

Fridman notes that hospitals and patients share driving data more readily than biology. Sinclair thinks the next health revolution is nevertheless the gathering of body data, the same arc as social media: resisted, then mandatory. He bets on a court case in two or three years. Someone will ask how their father died of a heart attack when a twenty-dollar biosensor existed and was not used. After that, every hospital has to hand you one. If you run a hospital and can save two thousand dollars per cardiac patient, you use it, or the hospital down the road will. The United States already spends about 17 percent of GDP on healthcare. A few-cent, rechargeable sticker that predicts sickness, spares needless antibiotics, and stops heart attacks is, in that arithmetic, billions to trillions.

He has a decade of InsideTracker graphs his doctor might have been expected to roll his eyes at. At the first video checkup in a year the physician was flying blind, asking the usual questions about sleep and food. Sinclair offered the new tests; the doctor was delighted, because he cannot order them at will. Then Sinclair asked for an HbA1c. No family history, no diabetes symptoms, so the doctor could not order it. Sinclair almost wanted to reach through the screen. He paid for the test himself and brought it back. Consumer health, he says, is already the place you get better data than your physician can legally fetch.

Fridman thinks doctors will have to take the expert hat off when a patient arrives with orders of magnitude more data than clinic intuition. Sinclair is not against the profession—many of his friends are doctors, and he works at Harvard—but he thinks they need a dashboard as much as anyone else. We would not drive a car without one. The last generation of physicians, he says bluntly, are no-hopers; the students he teaches at Harvard Medical School are excited that aging is something they can do something about. CFOs and insurers will finish the argument. Privacy is the remaining fight. He would not give insurers automatic access, though a voluntary slice for a discount is already being designed. A chest button can probably tell if you had sex last night. Stolen credit cards are one kind of leak. Health records are permanent. InsideTracker treated security as first. Fridman adds a consumer rule: if you can demand deletion, you will share more, and you can award data to companies that deserve it.

Fridman had just done a seventy-two-hour fast. Time slowed. He felt like a machine that turns food into thoughts and then, briefly, stops, and he started asking how to run that machine so it produces gratitude instead of jealousy. Sinclair is impressed, then practical. Abstinence is one of the oldest health interventions, known in some form for five thousand years. What is new is the optimum and the mechanism. In the early 2000s his lab was first to show, in any species, how calorie restriction extends lifespan in yeast: it turns on the longevity genes they work on. Hunger, heat, cold, or a hard run all look to the body like adversity. Whales live in that defensive state. Mice do not. Hunger is the most reliable way to switch it on.

You do not even have to feel hungry once you are used to it. His own practice drifted from skipping breakfast most of his life to skipping lunch as well. He has his twenty-year-old physique back, feels sharper, is no longer tired in the afternoon, and sleeps well. He is a poor candidate for saintliness: he tried two days, maybe made the third, and gave up, and he hates exercise. If he can do one meal a day, he says, anybody can. Do not jump from snacking and three meals. Spend two or three weeks. Tea, coffee with milk, even the diet sodas he is criticized for, can fill the stomach while you break the habit of always chewing. After that window, the habit is gone.

Fridman still eats one meal, but since moving to Austin he has gained about fifteen pounds of barbecue, partly because Texas meat comes with camaraderie. He contrasts himself with Joe Rogan, who knows he feels best on keto or carnivore, then eats pasta anyway and pays it back with kettlebells and hills. Fridman cannot take pleasure in food he knows will make him feel bad, so he overeats the good stuff instead of cheating with cake. Sinclair's gut has been remodeled in the other direction. A fried chicken dinner sat in him for two days, wrecked his sleep, and would not go down. He is now at a point where bingeing on steak and fried food is physically unavailable.

People obsess over the contents of the plate. Animal data, Sinclair says, say timing matters more. Rafael de Cabo at the NIH put 10,000 mice on different mixes of carbs, protein, and fat, hunting for the perfect ratio. The only animals that lived longer were the ones that ate once a day. Humans are not mice, but they are close enough that he takes the result seriously. The best bargain is still to do both: eat less often and eat the right things. He is not a zealot. He will steal a dessert, because a long life that is not enjoyable is not the point. The data he tries to follow say plant-heavy beats meat-heavy. Mediterranean and Okinawan long-livers eat mostly plants, a little meat, not much red meat.

There is a mechanism. mTOR senses amino acids that are more abundant in meat; when it responds, lifespan shortens, and starving those amino acids lengthens it. Rapamycin does the same trick, and some people are already experimenting, though he is careful to say the human results are not in. Meat, like testosterone or growth hormone, can make you feel great now—more muscle, more energy—at a price he suspects is paid in long-term health. He reaches for the disposable soma theory, associated with Kirkwood in the 1970s: resources go to growth and reproduction, like a mouse, or to preservation, like a whale. Meat probably puts you in the mouse column. If you want to be a whale, restrict it. He aims for leafy greens, especially spinach for the iron, and he is militant about sugar: almost never added, fruit juice avoided, cheesecake maybe once or twice a year, stevia if he needs a hit.

Then there are the molecules with the ugly name he coined with Konrad Howitz: xenohormetic. Cross-species hormesis—what does not kill you makes you healthier, borrowed from another species. Plants under adversity make colorful compounds that turn on their own sirtuin defenses. Drive nails into an orange tree before harvest and the fruit is better; dry the vines or let fungus on the grapes and the wine is better. Humans, in his theory, evolved to read that signal as a coming famine and hunker down. Practically, if it is full of color, or a caterpillar has chewed it, and it was grown on a local farm, he eats it. Watery, pale, California-greenhouse lettuce he skips. Fridman supplies the joke: you want the David Goggins of vegetables. The textbook molecule is resveratrol, which grapevines pour out when they are dried, over-lit, or fungal, and which Sinclair takes as a supplement because it activates the sirtuin enzyme that extended yeast life and slowed aging in the mouse brain.

Exercise is not a debate. Cyclists who ride more than eighty miles a week show about a 40 percent reduction in a cluster of diseases, especially heart disease. The curve is asymptotic: you do not need much to get most of the benefit, and overdoing it, especially on joints, can give some back. Ten minutes on a treadmill a few times a week, hard enough to lose your breath, looks very good for long-term health. That is the aerobic Sinclair actually likes. He also lifts, partly for hormones, mostly because he sits all day and because after a certain age you lose about a percent of muscle a year. He does not want to be the person who falls and breaks a hip, an event that happens every twenty seconds in the United States.

Fridman prefers long slow runs for the philosophy, often with brown noise in his ears—white noise, but deeper, like ocean. Five years earlier, brown noise at work had snapped his attention into a narrow channel and stripped the room of distraction. He treats that as a hint that more such switches are lying around. LASIK gave him the same delayed anger: why didn't I do this sooner. Sinclair's sleep case is harder-edged. Deprive a rat of sleep for two weeks and it develops type 2 diabetes. Proteins that time the sleep-wake cycle in most of our cells, when disrupted, cause premature aging; aging then flattens the amplitude, which is why sleep gets worse with age and the worse sleep accelerates aging. Shift workers are more susceptible to age-related disease. Sinclair's ring exists so yesterday's fried chicken can be retired as a bad idea.

Fridman optimizes for a stupid smile, not a blog's eight-hour target. Sometimes eight hours, sometimes four plus a nap; all-nighters still happen when the work is love, not Diablo, and he experiences 7 a.m. without sleep as a celebration of the human spirit. Sinclair agrees that quality beats quantity. Alcohol before bed wrecks the deep sleep that actually predicts his next day; four hours of that depth beat eight hours of none, especially if cortisol is not flooding the system. Then he puts the brain at the center of longevity. Mental stress shows up in heart rate and hormones. He keeps fish, and the picked-on one looks like crap. As a child he was a shy perfectionist who cried over anything short of an A-plus. In his twenties and thirties he trained himself to almost never get stressed. He has never lost his temper in a twenty-person lab that is often a kindergarten, even when millions or billions are at stake. At Washington University, Shin-ichiro Imai up-regulated SIRT1 only in neurons and the animals lived longer. Change inflammation in the hypothalamus and they live longer too. Get the brain in order first.

Fridman asks what a person born in fifty or a hundred years should aim for. Sinclair keeps revising the number up. Start in your twenties with the diets he described and skipped meals—in animals that is an extra 20 to 30 percent, and even 5 percent in humans would matter at planetary scale. Anyone, he thinks, should aim for a century. He was born a bit too early to take full advantage; people in their twenties should not see 100 as exotic. The arithmetic is homely. Someone who looks after themselves but does not really pay attention averages about eighty; Japanese men a bit more. Eat well, do not overeat, do not become obese, move a little, sleep, and do not live in chronic stress, and you get on average fourteen extra years, to ninety-four. Focus on those things and a hundred is not a big deal. Medicines on top—rapamycin, and metformin, the diabetes drug he takes—should push past it.

The record is 122. He does not believe in a biological ceiling. Why can a whale live 300 years and we cannot, when the structure is basically the same? Anyone who says you max out at some number is, in his words, full of it. Nothing he has seen says organisms must die. Trees live thousands of years with biochemistry close to ours. Fridman presses the identity question: if you live two hundred or a thousand years, or keep replacing the parts that break, is it the same person? Short answer, yes, we already replace parts. What makes us human is the brain. Swapping neurons is brutally hard because the network is so tight that a perturbation changes everything. The more interesting finding in his lab is that when you reverse the age of nerve cells, memories appear to come back. They were not lost; the cells had forgotten how to read them. He would rather rejuvenate the brain in place than replace it cell by cell.

Neuralink-style interfaces, in our lifetime, he sees as repair: retina, visual cortex, maybe a nudge to the hypothalamus. Preserving a whole mind by recording it will, he suspects, require death, then extremely detailed scans, even atomic microscopy, and a rebuild. Structure is not half the problem. Which genes are on and off—the epigenome of this conversation, written into neurons—does not show up easily under a microscope. Down the hall, George Church's lab invented a way to read that pattern in situ, cell by cell in the brain. Scanning connections without that layer will not recreate you. It is easier, Sinclair says, to reset the hardware you already have. Information will still leak. Genes degrade by mutation, so strict immortality is not on that road. Resetting the body hundreds of times and living thousands of years is, he thinks, on it.

Fridman turns to Ernest Becker's *The Denial of Death* and to Heidegger: most people live inside an illusion that they will not die, because taking non-existence seriously is a terror that would stop ordinary life. Sinclair does not treat that as a theory. He watches it every day. Talk near the subject and discomfort rises. We have to live that way. If we really thought about it daily we would be brought to tears, not only for ourselves but for family and friends. Every living form is built, biochemically and genetically, not to want to die. The yeast cells he studied at MIT were fighting for their lives without a thought. Consciousness is the human curse and gift: we know. A tribe that obsessed over dying every day, he suspects, would have cried in the hut instead of inventing anything. Natural denial of aging is part of being human, and it is the wall he hits in public. People do not want to think about their age. The book and the tests, he hopes, make it less shocking. Avoid the subject and you reach eighty and regret it.

Fridman puts Becker next to Viktor Frankl and the philosopher Bernard Williams: even uncontemplated, the knowledge of death is a source of meaning; scarcity makes the moment sweeter. Sinclair's reply is personal and flat. In his case that is completely wrong. He does not get joy from each day because he is going to die. He gets joy because the day is joyous and he makes it that way, and he would enjoy this moment just as much if he thought he would live forever. Fridman admits he is afraid that immortality would dull the appetite, and that the fear may be how he consoles himself about dying. Enjoying life, mortal or not, takes work. You can stare at ugliness, of which there is plenty, or notice that you have a roof in a Boston rain, or run into the warm rain on purpose. You can curse JetBlue when the wifi dies, or notice that you are flying through the sky and that the movies are coming off a satellite.

Sinclair's own conversion is from nothing-works to every-day-is-great, and he thinks the same stance survives a hypothetical forever. Everything is relative, so he refuses the neighbor's money and the missing wifi as the comparison class. He is still six. A six-year-old tells his fingers to make a fist and is delighted when they do. On the table is a metal cube, an inch on a side. About once a day he looks at some inanimate object and reminds himself: I am alive, I can think, I can move, I can eat, I am full of energy, and that leaf or that cube will never be. Relative to the lump of metal, we are wondrous things in the universe, probably the most wondrous, for as long as we last—even if that were forever. Fridman reads the Milne poem again. Staying six is a thing worth aspiring to. Sinclair's grandmother, who had seen humanity at its worst, already knew.