How to Stop Aging (Can Humans Become Immortal?) with Dr. David Sinclair

High-Level Overview

Harvard geneticist David Sinclair returns to The School of Greatness for a second, wider-ranging conversation with Lewis Howes. It starts with the biggest question, whether humans could ever be immortal, and works back toward the practical: what happens in the body during a fast, why pulsing stress and rest seems to work better than constant pressure, how much fruit and sugar make sense, and why age is the dominant risk factor for COVID-19. Sinclair also describes the result he is most excited about, a gene therapy that reset the age of cells in the eyes of old mice and restored their vision, and explains why it has made him more optimistic than he was even a year or two earlier.

The tone is relaxed and curious, with Howes asking open, sometimes speculative questions and Sinclair answering carefully, often stressing what has only been shown in animals and what he does and does not endorse. The conversation swings between frontier science, everyday eating habits and big-picture musings on artificial intelligence, cryonics and alien life.

The Discussion Explores:

• Why Sinclair doubts immortality but thinks lifespans of hundreds of years are conceivable
• The goal of living longer in a youthful state and dying quickly, not slowly
• What fasting switches on: mTOR, AMPK, sirtuins and autophagy
• Why he favors pulsing fasting and other stresses instead of doing them constantly
• Vaccines, technology in the body, and whether machines could think like humans
• Aging, inflammation and NAD as factors in how people respond to COVID-19
• Fruit, sugar, plant-heavy diets and what long-lived populations do
• Resetting the cellular clock, biological age tests, vaping, and alien life

Deep Dive into Main Ideas

Immortality and the loss of information

Asked whether humans will ever be immortal, Sinclair's honest answer is no, though he allows that never is a strong word. With the best technology he can imagine, and a thousand years to develop it, he thinks people could live for many hundreds of years. Immortality itself means fighting entropy and the second law of thermodynamics. In his lab's view, aging comes down to a loss of information, in the way a compact disc or DVD gets scratched. Some plants live thousands of years and a few mammals, such as the bowhead whale, live for hundreds, but keeping an adult organism intact forever is another matter.

Howes suggests storing the information in the cloud. Sinclair grants the point: "Maybe if we are able to upload ourselves somehow or rebuild ourselves from scratch, that's immortality." But he says that is beyond anything he sees now, and that people who talk about downloading the brain underestimate it. Each nerve cell is extremely complex, there are a great many of them, and mapping a brain without damaging it, let alone rebuilding it, is very hard.

Longer in youth, and a quicker end

On the ideal lifespan, Sinclair points to Jeanne Calment, the French woman whose recorded age is the longest known, and notes that someone who lives that long was necessarily healthy and active past 100. His key idea is that "you don't live longer in old age, you live longer in a youthful state". In mice, interventions that extend life by 20 percent add that time in midlife, without disease. He describes the classic experiment that has been repeated for about 80 years: feed one group of mice less, or every other day, and compare them with mice that eat all they want. The restricted mice have shiny coats, little evidence of cancer and plenty of energy; the others become decrepit. He says the same has been done in monkeys and in Labrador dogs.

He is careful to say that food is not the cause of death and that he is not talking about malnutrition or eating disorders. The point is that constant eating, three large meals a day, switches off the body's protective mechanisms. Personally, he says, "I wouldn't mind living for 200 years", and he has not met a happy, healthy person who wants to die. For society, he argues the gain is economic as well as personal: he says the US spends at least 17 percent of GDP caring for the sick, most of it in the last years of life, and that people who live longest tend to cost less because they decline quickly. He acknowledges that he and Howes are privileged to work from an armchair and that not everyone would want more years of a hard life, but hopes longer lives would allow three, four or five careers. He adds that "a good life actually leads to a longer life".

What fasting does

Howes describes his own experiment, a four-day fast with water, black coffee and a little juice, after which he says he felt lighter, more flexible and less inflamed a week or two later. He cautions listeners to talk to a doctor before trying anything similar. Sinclair says the field is only now moving from animal studies to human ones, but lays out what is known. A one-day fast turns on three main protective pathways: mTOR, which senses amino acids; AMPK, which registers how much energy the cell has and is switched off by sugar; and the sirtuins, the seven proteins his lab studies.

Fasting also turns on autophagy, literally self-eating, in which cells break down and recycle damaged proteins that otherwise clump together, as happens in Alzheimer's disease. From his reading, about three days of fasting triggers a deeper form called chaperone-mediated autophagy, discovered by his friend Ana Maria Cuervo, who has shown it matters for the health and lifespan of mice. He says he is helping her a little with a company trying to bring this to humans.

He does not think these defenses should be on all the time. In one of his studies, mice on calorie restriction lived longest when given resveratrol every second day instead of daily. His conclusion: "I think pulsing it is the right way to go", with a hunker-down phase followed by a repair phase. There is no formula yet for calories or schedules, in part because longevity experiments take about three years in rodents and funding is scarce. He warns against losing too much weight, especially for young people, says the body needs nutrition and some fat, and admits that the longest he has fasted himself is a day; his habit is to skip breakfast and eat a late lunch or go straight to dinner. Both men say hunger fades with practice and focus improves.

Vaccines, cyborgs and thinking machines

Howes asks what separates natural humans from altered ones. Sinclair says we are already there: he wears a computer on his wrist, a phone gives access to the world's information, and vaccines are themselves artificial. He sees future integration of technology into the body as an extension of what humans have always done, and does not think it will cost us our humanity.

Howes mentions getting angry mail after an earlier guest defended childhood vaccination, and asks what the science says. Sinclair answers that his knowledge here comes from reading the literature: papers that claimed vaccines cause autism were retracted after other scientists could not support them, and he estimates that if you asked 1,000 scientists, about 998 would say the same. He asks listeners not to attack him for reporting what is published. Howes notes that science keeps revising itself and encourages people to do their own research.

On artificial intelligence, Sinclair thinks computers may one day develop something close enough to be called human thought. He describes researchers who model actual nerve cells, which he calls analog devices with chemical waves, instead of the simpler connections in typical neural networks.

Back from the dead?

Asked whether people could be brought back from death, Sinclair says we already do it after a few minutes. Reviving frozen bodies is much harder because freezing damages cells, but he will not call it impossible: some frogs and fish freeze solid all winter, with no breathing or heartbeat, and thaw out alive thanks to special antifreeze proteins. He does not think we can yet safely freeze and thaw a brain.

COVID-19, inflammation and NAD

On why the coronavirus affects people so differently, Sinclair says genetics plays a part, including variations in the ACE2 receptor, but that from his reading age matters far more than anything else, with diabetes and heart disease further down the list: "Aging is your biggest risk." Older immune systems have fewer types of immune cells and multiply them less readily, and older bodies carry more inflammation, governed by a protein complex called the inflammasome, so the body can overreact to the virus. For those able to do so, he says losing excess weight and moving more are the most reliable ways to improve immune function, and that he has been exercising more himself.

He offers one hypothesis, which he says is not proven: levels of NAD, a molecule needed for about 500 chemical reactions, fall with age, and viruses deplete it further; since two sirtuins control inflammation and depend on NAD, low NAD may contribute to the runaway inflammation that kills some patients. He says a clinical trial of an NAD precursor is under way in hospitals. When Howes asks about supplements, Sinclair says companies sell NAD precursors but "I don't hawk any molecules" and endorses none. On testosterone, he says expensive clinical trials showed no slowing of aging, though it builds muscle, and strength matters for avoiding falls and broken hips in old age.

Fruit, sugar and what centenarians eat

Howes raises two earlier guests, one who found grapes spiked her glucose and one who warned against large, sugary modern apples, and asks about fruit. Sinclair says his field studies sugar, not fruit, and that too much sugar is not good; glucose and fructose are the same chemicals whatever the source, and modern food supplies far more than people ate even 50 or 100 years ago. He eats fruit and encourages his children to, but looks for the most nutrition for the least sugar. He agrees grapes score poorly on that ratio, favors colored, polyphenol-rich fruits such as blueberries and blackberries, and believes cantaloupe has the best ratio of any fruit.

He is not strict, he says, and will eat a hamburger, but mostly focuses on plants and treats meat as a reward, noting that cultures with many people over 100 eat far more plants than meat. He says people in Okinawa stop eating before they are full, eat colorful, unprocessed foods, stay social and keep moving through gardening and walking. He also mentions that olive oil's oleic acid was recently shown to activate the same protective sirtuin enzyme that resveratrol does.

Resetting the clock

The question driving Sinclair's lab is age reversal. He explains that chemicals accumulate on DNA with age, like plaque on teeth, and form a clock that can be measured. His lab has a gene therapy that resets that clock so cells behave as young again; delivered to the retina, it restored vision in old, blind mice in three weeks, and it works in human cells in a dish. He hopes for clinical trials in two to three years. He believes "our cells have a backup copy of youthful information" and that the open problem is finding where it is stored and how cells know how far to go back without becoming a tumor.

He says such clocks can already predict lifespan; he credits Steve Horvath at UCLA with work that predicts, within a few years, when someone will die if their habits do not change, and says smokers and overweight people have faster clocks. "There's no doubt that you can control the rate of your aging with how you live your life." On vaping, he says the long-term effects are unknown, but as someone whose mother died of lung cancer from smoking, "putting anything foreign into your lungs to me doesn't make any sense".

Aliens and kindness

Sinclair says alien life is a certainty given the number of stars, though most would be too far away to contact. He speculates that other civilizations, like ours, evolved destructive traits and may wipe themselves out. Human traits, good and bad, exist because they once helped ancestors survive, but "we shouldn't be slaves to our DNA". His closing thought for a difficult, divided period is a single word: kindness.

Conclusion

Sinclair's position is that aging is not fixed. Immortality is out of reach, in his view, but longer lives spent in a youthful state look feasible, and the tools already within reach are plain ones: eat less often, avoid excess sugar, favor plants, keep moving and do not smoke. The more dramatic possibility, resetting the age of cells, has so far been shown in mice and in human cells in a dish, and he is clear that human trials are still ahead. Throughout, he separates what the published literature says from what he personally does, declines to endorse products, and ends by asking people to treat each other well.

This is a summary of "How to Stop Aging (Can Humans Become Immortal?) with Dr. David Sinclair" from The School of Greatness, giving you the GIST so you can decide if you want the REST.