David Sinclair Found the Fountain of Youth? Not yet­!

Has Harvard’s David Sinclair Found the Fountain of Youth? Not yet­—but he sure is getting rich, famous, and having a blast while trying. by CATHERINE ELTON· 10/29/2019, 11:50 a.m. Read all about the latest gym openings, healthy events, and fitness trends in our twice weekly Wellness newsletter. EMAIL ADDRESS Portrait by Ken Richardson Like any dreamer, David Sinclair has a tendency to live in the future. The first time that thought crossed my mind, we were hurtling toward Worcester in his Tesla, on our way to visit one of his many companies working on an antidote to aging. Sinclair told me he’d recently discovered, using a health-tracking device, that he’s shaved a decade off his life: Biologically speaking, he is now 40, not 50. I took a good look at him. Except for the pillow he sat on while he drove, the wrinkles that formed around his eyes when he flashed his mischievous grin, and the note scrawled on the back of his hand (lest he forget something he has to do), there was no way in hell he looked anywhere near 50. He is slight of build, with nary a gray hair, and bears a passing resemblance to that forever child Alfred E. Neuman. He even says he feels like a kid, too. I had skipped breakfast that morning to get a feel for what it’s like to be Sinclair, whose habit of not eating anything until the afternoon—along with ingesting a mysterious medley of pills—is one of his many life-extending practices. When I asked about one of the drugs he takes, he reached into his pocket and pulled out a capsule filled with a white powder that he packages himself in his lab. He has told reporters that the substance inside is a miracle molecule. I plucked it from his hand and put it in my own. It felt so light in my palm. So easy to believe. And that is precisely the problem. ADVERTISING From time immemorial, people have been on a fantastical quest for a substance that would extend life, or even grant immortality. The medieval alchemists sought the elixir of life. Explorer Ponce de Leon looked for the fountain of youth in what is now the southern United States but, in an ironic twist of fate, found Florida, a place where people go to grow old and die. As the centuries wore on, traffic in life-extending substances and practices became the clear bailiwick of snake-oil salesmen, charlatans, and quacks. More recently, though, longevity has become the stuff of legitimate science. Sinclair is a superstar among a group of researchers who have harnessed science and technology’s latest advances in an effort to parse out, for the very first time, the biological mechanisms of aging in hopes of slowing or even reversing the process. The goal of this field is not to make us young for youth’s sake, but to address the single greatest risk factor for heart disease, cancer, diabetes, dementia, and many other forms of modern-day suffering: aging. This radical new thinking about medicine maintains that if we can address the upstream cause of these diseases, we can cure them all at once (instead of relying on the current Whack-a-Mole approach) and increase the number of years people live with good health. But it is also true, experts say, that eliminating all of these diseases of aging will make people live longer. “We are on the verge of a public health breakthrough of the kind we have never seen before,” says S. Jay Olshansky, a professor of public health who studies demographics and aging at the University of Illinois at Chicago. “It is not trivial. This is bigtime.” Sinclair deserves much of the credit for getting the field to where it is today. The Australian-born Harvard Medical School professor of genetics has had countless discoveries published in the most respected scientific journals in the world and has received dozens of scientific prizes and honors. Last year he was appointed an Officer of the Order of Australia for his contributions to humanity. Wealthy investors, including WeWork cofounder Adam Neumann, have bet hundreds of millions of dollars on his science and invested in the 17 companies he’s founded. When Sinclair’s book, Lifespan: Why We Age—and Why We Don’t Have To, was released in September, it reached number 11 on the New York Times bestseller list in just over a week. At the same time, Sinclair is one of science’s most controversial figures, regarded by many as a slick salesman who overhypes his work and its potential. Some critics cringe when he speaks of miracle molecules and everlasting life. Others whisper that his science may not be completely sound. Still others roll their eyes over his habit of taking drugs that haven’t been proven to delay aging in anyone who isn’t a mouse. The prevailing wish among his doubters is for him to simply keep his mouth shut. “He is a complicated guy,” says Steven Austad, a professor of biology who studies aging at the University of Alabama at Birmingham and is a friend of Sinclair’s. “He’s a superb scientist, as well as a superb salesman. You talk to him about science and you won’t find many more knowledgeable, incisive experimentalists as David. And then you can listen to the stuff he says on TV and be like, What the hell is he talking about? ” Sinclair’s bold statements and pill-popping habits have ruffled feathers closer to home, too—at the very institution that employs him. “He does do research and he gets it published in peer-reviewed journals, and if he just did that, it’d be fine,” says a Harvard Medical School professor who asked to remain anonymous. “But then he speaks out about how he makes himself young and says stuff that would be embarrassing for any normal scientist to say.” In other words, in an increasingly legitimate field of science desperate to distance itself from the alchemists and quacks of yore, Sinclair presents somewhat of a problem. As a brilliant scientist in the lab, he is a major asset to his field’s eternal quest for legitimacy. Let loose in the world, though, the self-described “Star Trek wannabe,” who’s eager for the future to arrive as fast as possible, is somewhat of a liability. He may very well be the man who will unlock the secret to extending life some 10, 20, or even 30 years—so long as he doesn’t get lost searching for the fountain of youth along the way. Sinclair can remember with startling clarity the day he first learned about death. He was with his beloved grandmother at her home in Turramurra, a leafy suburb of Sydney on the edge of the bush. They were seated on the floor playing when she told him his cat would only live to about 15. He was shocked. And the news only got worse. Everybody dies, she told him. It is not surprising for children to be disturbed when they learn about mortality, but most of them move on, squirreling away the fear and dread until it comes bubbling back to the surface with the appearance of gray hairs, knee pain, and mental lacunas. Sinclair’s trajectory was slightly different. In a sense, he never got over it. While his biochemist parents worked, Sinclair spent most of his childhood with his fun-loving, free-spirited grandmother, who admonished him to never grow up. By the time he enrolled at the University of New South Wales to study biochemistry, he was convinced that science would one day catch up with his grandmother’s ideas and people would be able to stay young forever. He believed, however, that he had been born too early to see it. He told his friends at school over coffee that they were likely to be the “last of thousands of generations to live the sad existence of such a short life.” But no sooner had he thought it, he says, than he considered the fact that maybe he was wrong. Maybe it could happen in his lifetime, and maybe he could be a part of it. Sinclair had found his life’s purpose. His next stop was 10,000 miles away at MIT, where at the tender age of 24 he became a postdoc in the lab of Leonard Guarente, who had just started studying aging in yeast. Sinclair’s colleagues remember him as someone who was aggressive, ambitious, and tireless: He was often the first to come into the lab and stayed as long as he could before dashing to catch the last train of the night. His colleague Shin-ichiro Imai, a professor of developmental biology at the Washington University School of Medicine who first met Sinclair in Guarente’s lab, says Sinclair had a “keen eye for capturing novel concepts and, based on that foundation, building new lines of research faster than anyone else.” At the time, aging research, once considered a fringe science, was still in its infancy, but Sinclair was determined to propel it to legitimacy. Three years into his time at MIT, he made a groundbreaking discovery that explained, for the first time, a mechanism of aging in yeast and opened up the possibility of one day manipulating the process in humans. From there, Sinclair’s career took off like a rocket. He soon left MIT to run his own lab at Harvard Medical School and became an assistant professor of genetics, continuing to build on discoveries made at Guarente’s lab about sirtuins, a family of proteins that exists in all living beings. These proteins are usually dormant, but when activated through stressors (such as restricting calories), they can enhance health and extend life in yeast. Sinclair was determined to find a substance that could mimic the effects of restricting calories in yeast, something that could one day be turned into a medicine that cures aging. True to form, he got to work, harder and faster than anyone else, Imai says. He screened some 20,000 substances until, one day, his collaborator called to say that he’d gotten a hit: resveratrol, a molecule found in red wine that has long been suspected to play a role in human health. Sinclair couldn’t believe what he was hearing and knew others wouldn’t, either. So he set out to disprove the finding right on his dining room table, where he lined up a series of petri dishes filled with yeast that had been fed different substances. When he discovered that the dish with yeast that lived 50 percent longer had been fed resveratrol, he cried out to his wife, “I think we have found something important here.” The discovery was the start of another phase in Sinclair’s career, one in which wealthy investors played as much of a role as the scientific community. In 2004, with the help of serial biotech entrepreneur Christoph Westphal, he founded a company called Sirtris Pharmaceuticals to pursue clinical-stage drugs inspired by the resveratrol molecule. At the time, it was almost unheard of for a scientist in the aging field to start a company. “David was a pioneer in merging academic and commercial research,” Austad says. “A lot of scientists would have liked to do what David did, but they didn’t know how, or have the appropriate skills to raise the money and convince the investors that this science was promising a revolution in health. David did.” Meanwhile, in his lab, Sinclair pushed his studies up the evolutionary chain into mice, and in 2006 published the paper that would change his life: a study showing that overweight rodents fed resveratrol aged slower and stayed healthier than ones that did not consume the substance. It was an instant sensation, landing on the front page of the New York Times. Sinclair gave a few dozen interviews before sitting down, relaxed and charming, for the Charlie Rose show. A 60 Minutes special on resveratrol wasn’t far behind, and soon he was telling Morley Safer we could expect an FDA-approved pill in five years’ time. Resveratrol, he once boasted to a reporter from the magazine Science, was “as close to a miraculous molecule as you can find.” In no time, Sinclair went from being a scientist toiling away in a lab to someone whom strangers recognized on the street. He became a longevity guru to legions of people hoping to glean insight about how to forestall their own mortality. And, he became rich. Sirtris went public in 2007, and one year later, pharma giant GlaxoSmithKline snatched it up for an astounding $720 million. Resveratrol had made Sinclair famous and wealthy beyond what he had ever imagined, but it was also about to turn him into one of modern science’s most polarizing figures. David Sinclair in his lab at Harvard Medical School. / Portrait by Ken Richardson Sinclair was sitting at his desk at Harvard one day in 2010 when a colleague called to offer his heartfelt sympathies: Pfizer scientists had just released a paper essentially saying that Sinclair’s work on sirtuins was bunk. When he finally got hold of the document himself, Sinclair couldn’t believe his eyes. “It wasn’t clear to me at all that we were wrong,” he told me. “We had data that showed we were right.” And yet, it wasn’t the first time Sinclair’s science had been challenged. A couple of years after his initial groundbreaking yeast study on resveratrol, two of his former colleagues from Guarente’s lab published a paper reporting on their inability to replicate it, suggesting his conclusions were wrong. A few years later, scientists from the pharma company Amgen also raised doubts, claiming Sinclair’s findings were erroneous. The Pfizer paper, though, was different. Not only did one of the biggest pharma companies in the world claim he was wrong on resveratrol, it also stated his entire theory on sirtuins was completely off. In response, Sinclair publicly questioned whether the Pfizer scientists had made mistakes running their experiment—which didn’t exactly go over well. “I was criticized for saying that Pfizer doesn’t know how to make a molecule right,” he explained. As the scientific community continued to raise doubts and gossip behind his back, Sinclair sank to a dark place. “I spent a week in bed,” he told me. “I couldn’t get out. My lab shrunk to, like, four people.” When I asked his assistant if she remembers what it was like when the Pfizer paper came out, she sighed, looked down, and shook her head from side to side: “That was devastating.” Still, it’s hard to keep Sinclair down for long; after all, he lives by the very idea of never say die. When he finally got out of bed, he went back into the lab to prove his naysayers wrong. The day I visited his lab, he stood with his arms crossed and a look of satisfaction on his face as he showed me a framed copy of a 2013 scientific paper that he says settled the debate and proved he was right about resveratrol activating sirtuins. In it, he showed that when scientists genetically engineered cells to change a single amino acid on a sirtuin, resveratrol had no effect on the cells. In the control cells with intact sirtuins, however, resveratrol did have an effect. Not everyone, though, was convinced. “There are lots of people in the field who harbor suspicions [about Sinclair’s science],” one researcher told me. “It is hard to explain how the same lab on multiple occasions over a decade or so can publish multiple pieces of data that other labs can’t reproduce.” What’s more, GlaxoSmithKline halted a Sirtris trial in humans because of potential negative side effects and then shut the company down altogether just five years after buying it. Today, resveratrol is known as the miracle drug that wasn’t. To Sinclair’s credit, none of his scientific papers have ever been retracted—and none of the people who spoke to me about their suspicions of Sinclair wanted their names used. One of them admitted that it might not be his data that critics object to, but rather the way Sinclair talks about his findings. While his colleagues in the aging field overwhelmingly stick to a safe script, describing their research as a quest to extend years of health, Sinclair talks freely and excitedly about extending mortality to 150 years by the end of the century—to say nothing of death eventually becoming a rarity—both of which critics say there is zero science to support. From his exalted platform as a scientist featured on TV and in the New York Times, Sinclair is promising the world that one day soon we’ll be able to get a shot that reverses aging, and when it wears off and the gray hairs sprout again, we’ll simply get a booster. “Does that sound like science fiction? Something that is very far out in the future?” Sinclair asks readers in his book. “Let me be clear: it’s not.” Even the title of his book—the part that says we don’t have to age—elicited an exasperated groan from the Harvard Medical School professor. “What is wrong with the guy that he is compelled to do this?” he asks. “Seen in the best possible way, he is totally convinced that he is the savior of mankind developing the fountain of youth. But you don’t have to hype to do that. Just let the facts play out.” Even his friends call him out for how he talks about his science. “David is a good friend,” Austad says, “but I do think he’s been guilty of making excessive claims.” Despite the resveratrol fiasco, Sinclair hasn’t shied away from making other grandiose promises. One of his more recent molecules of interest is called NMN. It is found in every living cell and boosts levels of something called NAD+, which regulates the mitochondria, or powerhouses, in all of our cells. NAD+ declines with age—unless, that is, scientists like Sinclair can find a way to increase it. Last year, he told Time magazine that NAD+ “is the closest we’ve gotten to a fountain of youth.” If Sinclair’s public comments push past the limits of what most scientists would say, it is also true that his accomplishments in the lab continue to push the limits of science itself. When I met with Sinclair, he told me he is gearing up to publish a paper about how his lab reversed aging in rodents. He described a series of experiments using gene therapy in which he and a group of scientists were able to restore vision in mice with glaucoma as well as in other mice who had their optic nerves (which cannot grow back after the newborn period) crushed. Sinclair’s team had made a handful of old mice young again. In light of the cutting-edge experiments and advances he is making in his lab, I was surprised that Sinclair also continues to study resveratrol. It seems so yesterday. When I asked about it, he assured me with a self-confident nod that he is still bullish on resveratrol. The 2013 paper, the one on his wall he believes vindicated him, didn’t get the word out far and wide enough, he says. That’s why his lab did another experiment—this time deactivating a spot on the sirtuin protein in mice—to show that resveratrol does, in fact, work. He tells me he’s really looking forward to that study coming out to restore faith in resveratrol. And, it seems, perhaps to restore faith in Sinclair, too. “When that one comes in,” he says of the forthcoming paper, “I’m going to drop the mike.” If Sinclair’s public comments push past the limits of what most scientists would say, it is also true that his accomplishments in the lab continue to push the limits of science itself. As Sinclair and I neared our destination in Worcester, I had my head down, furiously scribbling in my notebook, when I felt the car swerve abruptly to the right. I looked up to see Sinclair, visibly frustrated, struggling with the Tesla’s steering wheel. “My car appears to have been set to Mad Max mode,” he said in his pitch-perfect Australian accent. “I promise not to get us killed.” Then he added wryly, “That would be ironic.” It would, indeed. After all, Sinclair is planning on being around for a lot longer than most people think they will. He convinced his dentist to fix some wear on his teeth, a procedure that she told him she’d normally reserve only for teenagers. He dedicated his book to his great-great-grandchildren, whom he is very much looking forward to meeting. To make it until then, he practices calorie restriction, eats a mostly vegetarian diet, and tries to avoid sugar and carbs. On weekends, he exercises at the gym and then sits in a hot sauna before plunging himself into an ice-cold pool, because temperature extremes also kick our cells’ survival instincts into action, he says. Sinclair tracks his biomarkers regularly and takes vitamin D, vitamin K2, and aspirin. And he takes three other substances each morning: resveratrol, NMN, and metformin, a diabetes drug currently being studied for its potential anti-aging effects. The problem, critics say, is that unlike cancer drugs, for instance, nearly anyone can buy something close to the NMN and resveratrol capsules Sinclair is downing at places like the local GNC, where they’re sold as supplements alongside multivitamins and protein powder. Sinclair diligently points out that he is not a medical doctor; that he is not recommending anyone do what he does; and that there is no definitive evidence that any of it helps humans. Still, critics say that when a scientist such as Sinclair tells people what he is taking, it is nothing short of a celebrity endorsement, those caveats notwithstanding. In his defense, he told me he gets dozens of emails and messages every day from people asking him what they—or their pets—should be taking, and that he never makes recommendations. But it’s also hard to imagine people would write to ask him at all if he weren’t talking so publicly—and so often—about his daily regimen. “I like David a lot. We’re very good friends. However, I don’t think that what he’s doing is right,” says Felipe Sierra, the director of the aging biology division at the National Institute of Aging. “I don’t think that people should try it on themselves. And if they do, they shouldn’t publicize it. Researchers do have a responsibility toward the public, and we should be careful about what we tell the public.” Sinclair knows he ruffles feathers: At one point during our day together, I asked him where his family members get their pills from. He raised his eyebrows at me and then said in a Big-Brother-might-be-listening kind of whisper that we were in “territory that could get me called into the office, and it wouldn’t be the first time.” Still, he says he is prepared to deal with the consequences of being honest. What’s more, Sinclair says he has nothing to do with the supplement industry, a claim that is mostly true. All of the companies he has started are working on creating FDA-approved drugs, not supplements. True, years ago he did work as a paid adviser to a resveratrol supplement company, Shaklee, though Sinclair says he cut off that relationship when the company started using his name for marketing. Even if Sinclair isn’t directly profiting when people buy supplements after hearing him speak, he may still be benefiting financially from talking about what he takes. “Think about what the optics would be if someone says, ‘I’ve got this great potential therapeutic intervention,’ and then says they’re not taking it. Suddenly you are putting up red flags about your own science,” Olshansky, the Illinois professor, says. “So I can see why somebody who has a financial interest in a molecule would take it and brag about it. If it helps them get more money to do research, that may be one of the reasons they do it.” Sierra, for his part, admits that as much as he dislikes when Sinclair shares what he is taking, “it is probably good for commercial purposes.” Whether or not his personal habits have helped Sinclair’s bottom line, there’s no doubt he’s raised a ton of funding and used it to start a slew of companies. Seven of them fall under the umbrella of Life Biosciences, a Boston holding company he cofounded with Australian investor Tristan Edwards with the goal of building clinical-stage biotech companies by harnessing the best science in the aging field. Edwards had been interested in the longevity space and searched for a scientist to work with. He had a call with Sinclair and was so convinced by what he heard that before he got off the phone, he had already booked a flight to Boston. The firm raised $25 million while in stealth mode in 2017 and has since raised $500 million more. Another company, MetroBiotech (which falls under the holding company EdenRoc Sciences), is pursuing drugs inspired by the NAD+ booster NMN. That’s the one we were on our way to visit when Sinclair’s Tesla tried to kill us. Upon our arrival, two men looking slightly disheveled and both wearing Hawaiian shirts greeted us; these were the organic chemists tasked with developing molecules that may one day become an FDA-approved drug. As they took me back to their lab, I noticed the paunch on one of them, the wrinkles on the other, and the fact that what little hair either of them had left on their heads was somewhere between gray and white. I lowered my voice and asked, “So are you guys, you know, taking the stuff?” “Of course not. We are scientists!” one of them exclaimed, looking at me like I was the mad scientist in the room. It doesn’t take a PhD to know that the fact that two guys who aren’t taking NMN look old proves absolutely nothing. But it did make me feel a little more hopeful to learn that they were not. And the funny thing is that later in the day, when I asked Sinclair why he takes unapproved drugs knowing that there could be risks (and how much it pisses people off), he said the very same thing: “I take them because I am a scientist.” Then, in total deadpan, he gave me another reason. “And because I would like to outlive my enemies.” David Sinclair with his wife, Sandra Luikenhuis, at the Time 100 party after the publication named him one of the world’s most influential people in 2014. / Getty Images Sinclair and I were supposed to be at the gym at 5 p.m. to meet up with his 12-year-old son, Ben, and his about-to-be-80-year-old father. Because we were running late, he asked his wife to send his gym clothes with his dad. When we arrived, Sinclair came out of the locker room in his dress shoes. His wife, despite taking NMN herself, had forgotten to send his sneakers. Luckily, the trainer had an extra pair, and the Sinclair family got down to business. First up were dead lifts. Ben had a go and did pretty well for a kid his age. Then Sinclair went. He started to wince midway into the second set but made it through. Finally, his father had his turn, dead-lifting 95 and then 115 pounds like it was nothing. The trainer told me most of his 80-year-old clients are working on maintaining their balance and lifting themselves out of chairs. Sinclair’s dad is killing it in the gym. “Well, I suppose the only thing this proves is how useless I am,” Sinclair told me, frowning. Of course, he is hoping it means something else. His father has been taking NMN for two years, and since starting, Sinclair said, it has changed his life, his attitude, and his energy levels. It has returned to him his joie de vivre. When I asked Sinclair’s dad directly how the pills are going for him, I realized that Sinclair definitely did not get his salesmanship skills from his father. “Can’t tell,” he told me flatly, with a shrug. “But all my friends are dying or going downhill and I’m not.” Not only are Sinclair’s dad and wife taking NMN, but so are his two dogs. His younger brother grew gray hairs and developed wrinkles before he accused Sinclair of using him as a negative control in his little family experiment. Sinclair admits the thought did cross his mind, but blood is thicker than science, and now his brother is on the regimen, too. Even several of his graduate students are taking some of the pills. When the postmenopausal mother of one of those grad students also began taking it, she started menstruating again. (Perhaps unsurprisingly, Sinclair has a fertility company, too.) There was one person who never got the chance to take NMN, however, and it seems to haunt Sinclair. His mother was diagnosed with lung cancer at age 50 and had a lung removed. She managed to live another 20 years with one lung, which Sinclair says he would like to think had something to do with the fact that she took resveratrol. At the end of her life, when she took a turn for the worse, Sinclair packed some NMN in his suitcase and boarded a flight to Australia. When he got there, she started doing so much better that the doctors took her off her respirator, and she never took the NMN. She died unexpectedly 12 hours later. “I thought the NMN would save her,” he admits. “Wouldn’t anybody do whatever they can to try to save their mother?” As their workout wore on, Sinclair’s son Ben had something he wanted to tell me. He wanted me to know that he would like to continue his father’s work “if he ever dies.” I was distracted from the tenderness of this statement by the presence of a single preposition. “If?” I asked. “He may never die,” he said. I shrugged and smiled, but inside I was thinking that if he isn’t joking, someone is in for a real shocker. Earlier in the day, Sinclair told me he was such a straight-talker that he had ruined the illusion of Santa Claus for his children—and yet here his son could be thinking his father might never die. Such is life in the Sinclair household. Still, not everyone in the family wants to see people live forever. Sinclair’s oldest daughter doesn’t agree with his work and has zero qualms about letting her dad know it. She has asked him why, when previous generations have screwed up this planet so royally, he thinks it’s a good idea to have the people who did the damage hang around any longer. She is not the only one. Emory University bioethicist Paul Root Wolpe, for instance, has called the longevity field a narcissistic quest and points out that generational shifts are necessary for innovation, progress, and social change. As if in response, Sinclair’s book has an end section in which he delves into many ways to fix the world he wants to create. There is, he argues, a solution to everything in a reality where people live to 150—overpopulation, inequality, natural-resource limitations—if you are as hopeful as he is. Just as I was finishing up this piece, in fact, scientists published a study linking optimism to longevity—meaning Sinclair could stand to add even more years to his life. Indeed, if I squint hard enough, I can practically see him growing younger before my very eyes. Read More About: Harvard Medical School Health Long Reads You Might Also Like Kripalu Is Shutting Down until 2021 and Laying Off 450 Employees Is There Such a Thing as Healthy Tech Boundaries during Social Isolation? 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Bring your people on board with corporate change. People matter. Published Feb 26, 2020 + Follow I will preface this review with just one thought: if this is true, sooner or later longevity will COMPLETELY change who we are as humankind. My grade of the book: A+ (using the American grading system) - one of the best! Aging 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 all just one disease . . . . . . it all becomes clear: Aging is going to be remarkably easy to tackle... Easier than cancer. “Every death is violent,” he said in 2010. “There is no natural death, unlike the picture we like to paint of the father who dies quietly in his sleep, surrounded by his loved ones. I don’t believe in that.” Small numbers of senescent cells can cause widespread havoc. Even though they stop dividing, they continue to release tiny proteins called cytokines that cause inflammation and attract immune cells called macrophages that then attack the tissue. Being chronically inflamed is unhealthy: just ask someone with multiple sclerosis, inflammatory bowel disease, or psoriasis. All these diseases are associated with excess cytokine proteins. Inflammation 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 “inflammaging.” And cytokines don’t just cause inflammation; they also cause other cells to become zombies, like a biological apocalypse. When this happens, they can even stimulate surrounding cells to become a tumor and spread. 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 callous, but it works. WE ARE ANALOG, THEREFORE WE AGE. According to the Information Theory of Aging, we become old and susceptible to diseases because our cells lose youthful information. DNA stores information digitally, 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. Today, many of my colleagues 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. 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 will surely lead to our doom. “A new scientific 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 eventually die, and a new generation grows up that is familiar with it.” “Every aspect of job performance gets better as we age,” Peter Cappelli, the director of the Wharton Center for Human Resources, reported after he began to investigate the stereotypes that often surround older workers. “I thought the picture might be more mixed, but it isn’t. The juxtaposition between the superior performance of older workers and the discrimination against them in the workplace just really makes no sense.” Aging disables 93 percent of people over the age of 50, but in 2018 the NIH spent on aging less than a tenth of what was spent on cancer research. There are several ways to speed innovation to find and develop medicines and technologies that prolong healthy lifespan, but the easiest is also the simplest: define aging as a disease. Nothing else needs to change. Researchers working on aging will compete on equal footing with researchers working to cure every other disease in the world. This is what I want to change—more than anything else in the world. I want everyone to expect that they will meet not only their grandchildren but their great-grandchildren and their great-great-grandchildren. Generations upon generations living together, working together, and making decisions together. We will be accountable—in this life—for the decisions we made in the past that will impact the future. General advice 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. To engage our longevity genes fully, intensity does matter. Mayo Clinic researchers studying the effects of different types of exercise on different age groups found that although many forms of exercise have positive health effects, it’s high-intensity interval training (HIIT)—the sort that significantly raises your heart and respiration rates—that engages the greatest number of health-promoting genes, and more of them in older exercisers. Exposing your body to less-than-comfortable temperatures is another very effective way to turn on your longevity genes. 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 efficiently as the leading diabetes drug, while optimizing other health biomarkers, too. Diet Eating more vegetables, legumes, and whole grains, while consuming less meat, dairy products, and sugar. After twenty-five years of researching aging and having read thousands of scientific papers, if there is one piece of advice I can offer, one surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now, it’s this: eat less. On average, Americans consume more than three times the amount of food they need to survive and about 250 times as much water. Over time, some of these ways of limiting food will prove to be more effective 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. Study after study has demonstrated that heavily animal-based diets are associated with high cardiovascular mortality and cancer risk. Processed red meats are especially bad. Hot dogs, sausage, ham, and bacon might be gloriously delicious, but they’re ingloriously carcinogenic, according to hundreds of studies. Smoking We know that smoking accelerates the aging clock and makes you more likely to die than a nonsmoker—15 years earlier, on average. 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. The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke. Supplements People taking metformin were living notably healthier lives—independent, it seemed, of its effect on diabetes... Except for an extremely rare condition called lactic acidosis, the most common of the side effects is some stomach discomfort. 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 effect is due mostly to weight loss.17 Either way, that amounts to the equivalent of five 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-five showed protection from cancer. 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 small 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. The resveratrol-fed yeast were slightly smaller 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 cells with no SIR2 gene, and there was no effect. 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. When resveratrol is combined with intermittent fasting, it can greatly extend both average and maximum lifespan even beyond what fasting alone accomplishes. Resveratrol wasn’t very potent and wasn’t very soluble in the human gut, two attributes that most medicines need to be effective at treating diseases. We find NMN to be more stable than NR and see some health benefits 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 still being tested. So there’s no definitive answer, at least not yet. What Sinclair does • I take 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into my homemade yogurt) and 1 gram of metformin.7 • I take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin. • I strive to keep my sugar, bread, and pasta intake as low as possible. I gave up desserts at age 40, though I do steal tastes. • I try to skip one meal a day or at least make it really small. My busy schedule almost always means that I miss lunch most days of the week. • Every few months, a phlebotomist comes to my home to draw my blood, which I have analyzed for dozens of biomarkers. When my levels of various markers are not optimal, I moderate them with food or exercise. • I try to take a lot of steps each day and walk upstairs, and I go to the gym most weekends with my son, Ben; we lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool. • I eat a lot of plants and try to avoid eating other mammals, even though they do taste good. If I work out, I will eat meat. • I don’t smoke. I try to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans. • I try to stay on the cool side during the day and when I sleep at night. • I aim to keep my body weight or BMI in the optimal range for healthspan, which for me is 23 to 25. If I do take a supplement, I look for a large manufacturer with a good reputation, seek highly pure molecules (more than 98 percent is a good guide), and look for “GMP” on the label, which means the product was made under “good manufacturing practices.” Nicotinamide riboside, or NR, is converted to NMN, so some people take NR instead of NMN because it is cheaper. === Thanks for sticking till the end! I publish book reviews every Wednesday. Are you curious about what I do in my job as a startup CEO? We coach employees via Teams/Slack to drive agile and digital transformation, change management, learning, sales. Working with Bayer, Posti, Futurice. Winner of DigiEduHack and Sanako EdTech Hackathons. http://panda-training.com 9 3 Comments Like Comment Share Lauri Paloheimo Lauri Paloheimo What would you do with a thousand years for living? Like Reply 1 Like 2y Dima Syrotkin 🇺🇦 Dima Syrotkin 🇺🇦 Live 10 lives? :) Like Reply 2y Enzo Kanawati Enzo Kanawati Allow governments to stop spending on pension 😁 Like Reply 1 Like 2y To view or add a comment, sign inTo view or add a comment, sign in