The Fountain of Youth
David Sinclair believes age is a disease we can treat
Since my recent visit to the Harvard Medical School laboratory run by Australian geneticist David Sinclair, I’ve been struggling with a shamefully greedy impulse. How can I get my hands on the wonder molecules that Sinclair is trialling to amazing effect in mice, not only slowing down their ageing but reversing it? My fear of missing out has flared up since I learnt from Sinclair that he estimates at least a third of his scientific colleagues are taking some version of these “anti-ageing” molecules, just as he does, in the belief it will increase their health spans by as much as 10 years. This means not just having a chance at living an extra decade, but living it in good health, avoiding the age-related diseases and general frailty that can make those years harrowing. It becomes difficult to remain impartial when a respected scientist tells you he will soon turn 50, does not have a single grey hair and, according to regular blood and genetic tests, has the biological age of 31.4, even though he’s a workaholic and doesn’t exercise much. Or that he likes to think his mother prolonged her life – post lung cancer, with only one lung – for 20 years by taking the molecules he gave her, and that his 79-year-old father, who has taken several different kinds of them for years, currently lists whitewater rafting and mountaineering among his hobbies. Sinclair’s wife, Sandra Luikenhuis, even gives these molecules to the family dogs. (Luikenhuis, who has a PhD in genetics from Massachusetts Institute of Technology, only began taking the molecules herself after she noticed the irrefutably positive effect they’d had on their pets.) If all goes well, and these anti-ageing molecules live up to their promise, Sinclair and his family will be proof it’s still possible to be going strong on the other side of the private apocalypse each of us has to face, what Philip Roth famously called the “massacre” of ageing. Imagine if you could still be standing tall after the dust clears, not one of the walking wounded, not just surviving, but thriving. David Sinclair has made big promises before, and he’s suffered setbacks and triumphs in equal measure. No one knows if his predictions will turn out to be right; even for geneticists, it’s notoriously difficult to know what’s going on in the field of ageing research. In a 2017 New Yorker article, Tad Friend mapped out the different camps of longevity researchers – some closer to the “immortalist” extremes than others – and pinpointed why finding a solution to the biological problem of ageing is so complex: “Solving aging is not just a whodunit but a howdunnit and wheredunnit and a whyohwhydunnit.” (Also, mice are not men: a fact that has always bedevilled this kind of research. Medical breakthroughs in lab animals most often go nowhere in human trials.) For now let’s assume, given the increased interest in ageing research in recent years, that the end of old age as we know it is approaching – whether the breakthrough comes from one of Sinclair’s labs (he also heads an ageingresearch lab at his alma mater, the University of New South Wales) or from someone else’s. Sinclair describes how, when he went to uni in Sydney in 1987 at age 17 to study genetic engineering and molecular biology – then a brand-new field – ageing research was the “backwater of science”. There was nothing on ageing in textbooks or medical papers, because ageing itself wasn’t considered a disease and thus wasn’t seen as worthy of investigation (only age-related diseases were, such as heart failure or diabetes). He was told by senior academics that it was a mistake, a dead end, to pursue his obsessive interest in figuring out why we age. After Sinclair completed a PhD in molecular genetics at UNSW, he went to MIT on a postdoc to study the causes of yeast ageing at one of the only labs in the world looking at the genetic mechanisms of ageing at the time. His research took place under the supervision of Leonard Guarente, an established molecular biologist who ran the lab; Sinclair had been lucky enough to sit next to him at a group lunch while Guarente was on a lecture tour of Australia, and made an informal pitch to join Guarente’s team. Today, by contrast, there are hundreds of labs actively investigating the topic. “You can’t open the world’s leading scientific journals without seeing articles on age research breakthroughs,” Sinclair says. “All the leading academic centres – Harvard, Oxford, Stanford – are working on it.” This doesn’t mean there’s global consensus as to what ageing is, and why or how it happens. One of Sinclair’s researchers told me, “Every few decades a new theory of ageing comes around, and doesn’t wipe away the previous one but supersedes it.” If longevity scientists agree on anything, it’s that ageing has multiple causes, some major, some minor. What troubles Sinclair is that none of these causes is considered treatable. Instead, age-related diseases like Alzheimer’s, Parkinson’s, osteoporosis – which are symptoms of ageing – are treated one at a time. Sinclair is convinced that ageing should be considered a standalone, treatable disease. This is a more radical proposition than it may at first seem. It’s so radical, in fact, that no government in the world has endorsed this definition. Because ageing affects all of us, governmental regulatory authorities like the US Food and Drug Administration (FDA) and Australia’s Therapeutic Goods Administration won’t recognise it as a disease, and thus won’t approve any drugs designed to treat it. Sinclair is campaigning for Australia to become the first country to declare ageing a treatable condition. If it does, he has pledged to provide one of his longevity drugs to the government at cost for 10 years. Until this happens, pharmaceutical and biotech companies (Sinclair has founded several over the course of his career) can’t count on making money by developing drugs that treat ageing as a disease. They can only do so by treating age-related diseases and focusing on keeping individual organs healthy. As a result, “we’ve ended up with … a nation of elderly whose hearts are working well, for example, but their brains are no longer functioning,” Sinclair said in a 2013 TEDxSydney talk. By 2050,
the proportion of the global population aged 60 years and older will have nearly doubled. This isn’t necessarily a bad thing: as the World Health Organization’s ageing and health fact sheet states, “a longer life brings with it opportunities, not only for older people and their families, but also for societies as a whole”. The problem is that the extent of these opportunities “depends heavily on one factor: health”. And while our lifespans have increased, there is little evidence that the elderly are spending those extra years in better health than their own parents did at their end of life. Sinclair is also not in the traditionalist camp when it comes to interpreting the genetic components of ageing. Most of us have come to accept as a given that our individual ageing journeys are dictated by whatever is encoded in our DNA, as well as by irreversible changes, or mutations, to our genes. That’s why antioxidants became a thing for the health conscious: they’re supposed to mop up free radicals before they damage the DNA in our cells, or something like that. (According to Sinclair, if you think antioxidants work, you’re living in the Dark Ages.) He contends we should not picture ourselves as fatalistically bound to a genetic destiny that we can’t alter or reverse. We age, he believes, because of chemical signals that are sent to our genome (the complete set of an individual’s DNA, containing all genetic instructions for our bodies) by the “fabulously intricate, pulsating [molecular] structure that our genome is wrapped up in”: the epigenome. He uses a beautiful analogy to help laypeople comprehend the epigenetic theory of ageing. Think of your genome as a gigantic piano with 30,000 separate keys (genes). Sitting at that piano, deciding which of those keys will get played – expressed – or remain silent, is the epigenome, which is made up of chemical compounds and proteins. Not much was known about how exactly this music happened at a molecular pathway level until Sinclair and his colleagues began studying the process. Over the past two decades they’ve realised that, rather than focusing on changing or editing genes, the way to slow or reverse ageing may be to change what the epigenome tells certain genes to do. One of the key epigenetic pathways they’ve identified that can “change the song” the piano plays is via sirtuins: genes that make enzymes to control how a cell functions. As we age, more and more genes get switched on in our cells, altering the very nature of those cells and creating what Sinclair calls harmful “epigenetic noise”. This leads to identity loss in the cells themselves, like a microcosm of the identity loss of a person in extreme old age. Nerve cells begin to act like muscle cells or liver cells, and may degenerate to the point of becoming zombielike – a state described as “senescence” – at which point they do nothing except lurk there, ageing all the cells around them too. Yet when sirtuins are stimulated they turn off some of these genes that hasten the ageing process. Sinclair’s long relationship with sirtuins began while he was doing research in Guarente’s lab at MIT in the late ’90s. One of the other researchers there, Brian Kennedy, left a bunch of yeast cells, cold and starving, at the back of a refrigerator. When he finally got them out, he found that some of the ones that had survived ended up living much longer than unstressed yeast cells. Biological stress forces organisms to put their energy into maximising their own health in order to survive, rather than into reproducing. My favourite lines from Sinclair’s draft for a popular science book to be published next year (working title: “How To Start an Evolution”) put the latter observation more evocatively: “Stressed tomatoes have richer taste and reach a deeper shade of red. Stressed grapes make more intense wine.” Sinclair and others at the MIT lab figured out that it was this mysterious and newly discovered bunch of “silent information regulators” – sirtuins – that were behind this phenomenon. Nobody knew at that point if sirtuins existed in mammals. A few years later they discovered that they do, and are also activated by both calorie restriction and exercise. The next question, of course, was whether there might be other means of triggering sirtuins in mammals, thus mimicking the benefits of fasting and/ or extreme exercise, which are beyond the willpower of most of us mere mortals. Was there a way, in other words, to achieve the effects of a stressed organism without the stress, a way to make the human equivalent of a rich, red tomato? This became Sinclair’s research mission. The first major discovery he made was that a molecule called resveratrol, which comes from grape skins and is found in tiny doses in red wine, activates sirtuins in mice when administered in massive quantities. (Sinclair’s mother, after she was diagnosed with lung cancer, became one of the first humans to take a large dose every day; it’s this daily intake of resveratrol that he believes helped her live two decades longer than her doctors had forecast.) The tide had begun to turn: ageing research was suddenly no longer relegated to the scientific fringes. In 1999, Sinclair was recruited to start a new lab at Harvard Medical School, and in 2003 his resveratrol research was published in Nature. A few years later, the company
He contends we should not picture ourselves as fatalistically bound to a genetic destiny that we can’t alter or reverse.
The metabolisms of elderly mice that were given NMN in the Sinclair Lab were restored to youthful functioning within a week.
he’d founded, Sirtris Pharmaceuticals, was bought for US$720 million by GlaxoSmithKline (his less than 1 per cent ownership stake still netted him a tidy sum). During what should have been the happiest years of his career, he and Guarente had a falling out over disagreements about how sirtuins work and their separate efforts to commercialise their research. In a 2004 Science article about their “feud”, Sinclair is quoted saying, of Guarente’s company, “They’re doing exactly what we’re doing, and it’s a race.” Both Sinclair and Guarente now claim that the article overstates their rift, and they’ve continued to collaborate closely ever since. But the Science article is worth a read for an insight into this secretive, competitively charged world of laboratory research. (Sinclair, for example, is described as locking his research notebooks in a safe in his Harvard office after one of them went missing, suspected stolen by rival researchers.) There was yet more trouble ahead for Sinclair. As he puts it bluntly in his TEDxSydney talk, next thing “the bottom fell out”. In 2004, two of his former MIT colleagues published an article questioning the general thesis that calorie restriction activates sirtuins. Pharmaceutical company Pfizer went further, publishing a separate paper casting doubt on Sinclair’s claim that resveratrol activates sirtuins. “I had emails from top scientists sending me condolences,” he says. “The clinical trials were put on hold. I thought I’d let my lab down … Australia down … the whole world down. And there were days I really wanted to quit being a scientist.” Sinclair eventually assembled a team of scientists to try to prove his initial findings were correct. In 2013, he published the results of this research in Science, vindicating himself in the eyes of many of his peers by presenting evidence that resveratrol extends the health spans of certain organisms by activating sirtuins – though some scientists still don’t agree, or say the results can’t be replicated. Guarente has acknowledged that these “intensive controversies” about sirtuins are linked to scientific uncertainty, which means there’s an element of faithbased – rather than reason-based – support for the different theories (and the prophets who annunciate them). Sinclair’s colleague Brian Kennedy described the field in 2013 as “overly polarised”, and Stanford University scientist Howard Chang told The New Yorker that the longevity community is “the most difficult field I’ve ever worked in, and I didn’t want to define my scientific life with all these fights”. Sinclair has now moved on to bigger things than resveratrol. In recent years his research focus has shifted to molecules that boost the levels of a crucial compound in our bodies called oxidised nicotinamide adenine dinucleotide (NAD+), which he dubs the “fountain of youth”. NAD+ plays a role in regulating almost all the important biological processes in our bodies – including metabolism – but levels drop steadily, by almost 50 per cent, as we age. The renewed interest in NAD+ over the past decade (it was actually discovered more than a century ago) is because sirtuins are NAD+-dependent proteins. (Guarente co-authored a 2016 paper titled “It Takes Two to Tango” to describe this link; it was also in his lab, while Sinclair was a postdoc, that the dance between NAD+ and sirtuins was first observed.) Whereas resveratrol only works on one of the seven types of sirtuins in our bodies, NAD+ works on all of them. And NAD+’s health impacts could go beyond activating sirtuins, because of its involvement in hundreds of different reactions in and around cells. In a March article, Sinclair and his co-authors (among them Guarente) wrote that restoring NAD+ levels in mammals has a dramatically positive effect on the liver, heart, reproductive organs, kidney, muscles, and brain and nervous systems (since NAD+ itself is hard to administer directly, its precursors, among them one called nicotinamide mononucleotide, or NMN, are given instead). This is where we start tiptoeing into miracle territory. For example, the metabolisms of elderly mice that were given NMN in the Sinclair Lab at Harvard were restored to youthful functioning within a week. Even more astounding, Sinclair’s research team found that by administering NAD+ boosters they could make an old mouse run like a young mouse. An old mouse run like a young mouse. Not only that, but young mice given the same molecules exceeded the ability of the machine to measure their endurance, something Sinclair says hasn’t ever been done before. Humans have built entire cultural and spiritual belief systems around what we assume are our unchanging biological limitations. We’ve had a long time – all of human history – to get used to the idea that we will all age and die, and to adapt our sense of what it means to be human around these limits. We’ve cultivated certain coping mechanisms, turned them into virtues: graceful acceptance and gratitude for what we gain with age (wisdom, humility, resilience). Ageing has always been the great equaliser; as Thomas Mann wrote, “It will happen to me as to them.” To peek beneath this heavy veil of culturally endorsed forbearance is frightening, more frightening in a weird
way than the ideas of old age and death themselves. For Sinclair wants us to think of ageing not as something that makes us human but as something that makes us less than human. In his opinion, our docile acceptance of decline and ill health in old age is as barbarous as the people of the past once believing that it was normal and natural for women to die routinely in childbirth. Sinclair vividly recalls his first childhood intimations of the fate awaiting him and all those he loved, but, unlike most people, he refused to compartmentalise his horror as he grew up. Instead, it became the driving force for everything he did. From a young age he had an enquiring mind and was never one to swallow received wisdom; perhaps the result of being the child of two bioscientists. His parents worked at the same pathology lab, and he recalls going with them to work in the holidays, looking at body parts in buckets. Yet his contrarian response to the “fact” of ageing seems most closely linked to his deep emotional bond with his grandmother, Vera, and his distress when, at age four, he learnt that she would keep getting older, and one day would die. It’s late at night in Cape Cod when I ask Sinclair, over the phone from Sydney, about his grandmother. I’d expected him to sound weary at having to speak to a journalist while on a rare few days of family vacation. But he is expansive in his responses, and not in any rush to get off the line. His father is visiting from Australia, he tells me, and has been helping out with the kids and doing repairs on the holiday house. That afternoon, Sinclair and his co-author had finished the latest draft of their upcoming book, while in his Boston lab there’d been an exciting breakthrough (though not something he could tell me about). Vera – Sinclair’s grandmother – fled to Sydney with her young son (David’s father, Andrew) after the failed 1956 revolution against Soviet rule in Hungary. (Andrew later changed the family surname from Szigeti to Sinclair.) Vera was vivacious, courageous and a nonconformist; Sinclair says she was chased off Bondi Beach by the police for being one of the first women to wear a bikini. While Sinclair was growing up in St Ives, on Sydney’s upper north shore, Vera was a constant presence. She encouraged him to value the experience of childhood even as he lived it. “Never grow up,” she would say, and she loved to recite to him the A.A. Milne poem “Now We Are Six”: “But now I am Six, I’m as clever as clever. / So I think I’ll be six now for ever and ever.” She disliked being called Grandmother, so he called her Vera; she called him Professor David. He adored her, and as she aged he couldn’t bear to see her becoming a stranger to herself, to him. She lived until she was 92: on paper a decent innings, but in truth, he says, the spirited woman he’d known had been long gone by then. Sinclair’s relationship with Vera is his master narrative, what he reaches for every time he’s asked to account for why he is galvanised to buy humans more quality time on earth. His emotional vulnerability is palpable whenever he tells these stories about her. In his TEDxSydney talk, he says that seeing his grandmother suffer in old age made him wonder, “This thing we call ageing, why aren’t we up in arms about it?” This gets a laugh from the audience, but Sinclair is being totally earnest. “This once vibrant woman reduced to this. It’s incredible …” he continues, his voice wavering. “This is just my story, but it’s being played out every day, in everybody’s family … so why aren’t we doing more about it?” (During his talk, a slideshow plays behind him of overlapping photographs of Vera, morphing her too quickly from a child to a teenager, then a young woman, then an old one.) Like most longevity scientists, Sinclair is a “healthspanner” not a “lifespanner” (extra years must be good ones), and he’s certainly not an immortalist who thinks we should cheat – or hack – death itself. Yet it’s not a giant leap to imagine that once we start to add a healthy decade to our lives, we’ll soon be able to add two decades, then three, and then … On the phone, he mentions excitedly an article he’s just read in Science, which shows that the chances of dying become essentially constant beyond the age of 105 in humans. “They’re saying there is no natural limit to human lifespan,” he tells me. “Once we can make it past 105, our chances of dying don’t increase, they stay the same. I’m on the record saying the first person who will live to 150 has already been born. Anyone who says there is a limit built into our biology doesn’t know what they’re talking about. There’s no biological law for ageing. It’s not shocking that within our lifetime we could reset the body entirely.” Though Sinclair does not identify as a transhumanist, this doesn’t sound so different to something a transhumanist would say. Anya Bernstein, a Harvard anthropologist who studies transhumanism, describes it as a global “intellectual and cultural movement that aims to transform human nature by developing the tools to accomplish a ‘radical upgrade’ of the human being”. Most transhumanists share a commitment to the idea that humans should be able to “shape and direct one’s own evolution [through] self-mastery”, and that we should not only study ageing, but fight it.
“Anyone who says there is a limit built into our biology doesn’t know what they’re talking about.”
There’s already pushback from religious quarters to these ideas. Bernstein quotes a Russian Orthodox priest asking, in a 2014 debate on these issues, “Where is the border between improving human health and transforming into the posthuman?” For the secular, too, it’s a big deal to make the shift from embracing the human condition in all its pain and glory to trying to transcend it. The political philosopher Hannah Arendt anticipated this in her 1958 book, The Human Condition, writing that “the wish to escape the human condition, I suspect, also underlies the hope to extend man’s life-span far beyond the hundred-year limit”. She was concerned we’d lose hope if we lost the ability to let younger generations reinvigorate human affairs. In Arendt’s view, our saving grace as a species is that we’re forced by our biology to welcome new people constantly into the world, and to let others leave it once they’ve had their time. This means no matter what previous generations have set in motion, there is always the possibility of changing the course of human events. On the warm spring day I visited the Sinclair Lab, housed in one of the Harvard Medical School buildings in the Longwood Medical Area of Boston, my host for the morning was the lab manager, Luis Rajman (Sinclair was in Japan at the time). I was somehow comforted that Rajman wears spectacles and has a neat greying beard; he doesn’t take NMN or resveratrol like others in the lab, though he does take a drug called metformin because he’s diabetic. (Metformin is believed to have the added benefit of boosting longevity by increasing the activity of a protein called AMPK; elderly diabetics taking metformin outlive their non-diabetic counterparts, and Sinclair thinks all of us over 40 should be taking it even if we don’t have diabetes.) We sat at a table in Sinclair’s pleasantly cluttered office. On the bookshelves were bottles of red wine – all shout-outs for his resveratrol research – with playful labels suggestive of celebrations past (“Sirtris Pharmaceuticals, Appellation Start-up Contrôlée, 2003”). Articles about Sinclair – some fresh, some yellowing – were framed on the walls. The medals and awards stacked
along one shelf track how Sinclair’s star has risen. He’s shot from a successful Australian scientist (“Australia’s Top 10 Scientific Minds Under 45”) to one with global prominence, sharing space with Beyoncé in TIME magazine’s 100 most influential people in the world for 2014. Sinclair had told me over the phone that his “universe is big”. He can toggle comfortably between the research world (his Harvard lab employs 40 people and has a $4 million annual budget) and his for-profit companies (such as Life Biosciences, which employs 60 people and has an annual budget of $30 million). There was evidence in his office of the diverse demands of his working life. On the whiteboard were planning notes for his book, with intriguing headings like “Friday I’m in Love” and “How to Build a Utopia”. Among the books on his desk were The Essential Writer’s Companion, a Japanese scientific journal, Clive James’s Unreliable Memoirs, and a tome titled Annual Review of Pharmacology and Toxicology. Nearby were pottery objects made by his children, who are 15, 13 and 11. While his lab’s research projects vary in scope and nature, the unifying goal is to extend health in the elderly. “The ideal situation is you stay healthy and then get sick in the last few weeks of life,” Rajman told me. “You essentially die in good health.” The wider applications, and societal impacts, of the lab’s research became clearer as I chatted to some of the researchers who stopped by the office. Michael Bonkowski told me in his strong Boston accent that he’s working on a project for the NASA mission to Mars, figuring out how NAD+boosting molecules might be able to prevent and reverse the effects of cosmic radiation damage. Alice Kane, a friendly Australian postdoc recently arrived from Sydney, described a project she’s involved with on postradiation fertility (which would enable, for example, women who’ve had chemotherapy earlier in life to have their own children). I was at first confused as to how this relates to the lab’s mission, but of course one of the first impacts of ageing in women is fertility loss. Sinclair and his collaborator in this aspect of their research, Jonathan Tilly, suspect that it might not be true that women are born with their total allotment of primordial egg cells, which mature into eggs after puberty. In a mouse rendered infertile by chemotherapy, Tilly claims to have been able to induce ovarian stem cells in the lining of the ovary to produce new eggs, though other scientists have challenged the results. Sinclair and Tilly have since co-founded a company, OvaScience, which is commercialising aspects of this research through fertility treatments called “Augment” offered in Canada and Japan; at the moment it hasn’t sought US regulatory approval, and some critics claim that the zeal to commercialise has moved things too quickly out of the lab and towards the market. This isn’t something that seems to bother Sinclair, but an ethical scenario he is interested in discussing is what the acceptable upper age limit for women to have children might one day become: 50? 60? 80? “People have strong views about fertility research,” Kane admitted when I asked her opinion on this. “But you’re considered a geriatric pregnancy when you’re older than 35 … I’m almost that age. Maybe we wouldn’t want an 80-year-old to have a child, but what about someone in their 40s who has their career sorted?” Another potentially wide-reaching impact of increasing people’s health spans is that it could put pressure on global food supplies. Sinclair, anticipating this, has established a research project to improve food stocks by generating the first genome sequence for shrimp (to make them disease resistant and easier to farm), and to do the same for pigs. This isn’t “Frankenfood” genetic modification, he says; it’s about altering the epigenetics of the organism, not the genome itself. “There are scientists who just love the science, who are focused on the details,” Rajman said as I followed him towards the laboratory, passing drawings of famous male scientists in old age, including Charles Darwin (skinny, grey) and James Paget (stooping, frail). “Then there are scientists like David who still care about the minutiae but are also focused on the larger benefits the research can bring to society.” Rajman gave me a tour of the lab equipment: tissueculture incubators, cryostorage systems, polymerase chain reaction machines. He’s been there seven years, and started out as a researcher. “We’re all crazy masochists in here,” he said. “Graduate students work 60- to 80-hour weeks, take a few seconds to celebrate if they discover something important. Nobody would do it if they didn’t get great satisfaction just from the doing of it.” (In the Science article about Sinclair’s own time as a postdoc, he was described as “often the first to arrive, at 8:00 a.m., and the last to leave, at 12:30 a.m., running to catch the final subway train of the night.”) Satisfying a curious mind may be enough for the graduate students bent over their workstations. Yet given how lucrative a longevity pill would be, the commercial lure for Sinclair must be irresistible, too. In Tad Friend’s 2017 New Yorker article, a venture capitalist describes the longevity market as a “two-hundred-billion-dollarplus” opportunity.
A venture capitalist describes the longevity market as a “two-hundred-billion-dollar-plus” opportunity.
Leonard Guarente has already co-founded – without Sinclair – a company called Elysium Health to sell a daily nutraceutical supplement called Basis (a month’s supply costs around $50). Elysium Health’s website heralds that in 2017 it conducted the “first-in-humans study demonstrating clearly that Basis can increase NAD+ levels in the blood safely and sustainably”. This isn’t quite as reassuring as it sounds. The trial followed participants over only eight weeks; nobody has any idea what taking these supplements every day for decades could do. Some scientists have questioned whether it’s a conflict of interest for Elysium Health to do human trials on a product it already sells on the market; normally, it works the other way around. Also, Basis does not have US FDA approval; it’s sold as a nutraceutical supplement, not as a prescription drug. (As Rajman explained to me, the “FDA has a separate set of rules for supplements. Put simply, they are considered safe until proven otherwise.”) That’s also why resveratrol is widely available as a health supplement, but beware: when Sinclair tested a dozen samples from different purveyors, a while back, only one of them passed his effectiveness and purity test. Sinclair is aiming to get his own NAD+-boosting tablets on the market within three years. Unlike the other companies, he’s taking his research through the US FDA’s arduous drug-approval process so that, if clinical trials are successful, it can be sold not as a supplement but as a pharmaceutical drug, and prescribed by doctors. Since the FDA won’t approve drugs for treating old age, one of his companies, MetroBiotech, will market the boosters to treat rare diseases, and another, JumpStart Fertility, will sell them to reverse female infertility. The NAD+ booster furthest along in this process is called MIB-626; second-phase human trials are underway. I’m not alone, as it turns out, in my sudden anxiety to get access to the high quality stuff. His lab receives a call daily, often from somebody rich and famous, asking how they can get hold of Sinclair’s molecules or at least be selected for the clinical trials. Sinclair says he responds the same way to everyone: help fund the preclinical research in our lab, he tells them, and all this will happen faster. A third of the lab’s budget comes from private sources like the Glenn Foundation for Medical Research (years ago, Sinclair convinced the philanthropist Paul F. Glenn over a single lunch to put up $5 million) as well as from Sinclair’s own charitable trust (funded by his companies and patents), which helps explain why he’s constantly hustling on the venture capital circuit. The latest company Sinclair has co-founded, Life Biosciences, promises to treat multiple components of ageing through the work of a suite of six subdivisions, each with a slightly different focus. One, for example, will be devoted entirely to companion animal lifeextension research (which sounds like something Evelyn Waugh would have satirised but will no doubt be wildly popular among pet lovers). Sinclair is adamant that any drugs Life Biosciences develops will be within everybody’s reach. He read to me over the phone the company’s core values, displayed prominently on their new website, among them: “we are committed to making our biomedical breakthroughs accessible and affordable to all, regardless of age or background”. Several of his researchers told me during my lab visit that this isn’t just PR-speak. Rajman said that “when we started working on NMN, the cost was prohibitive, about $2500 a gram”. Over the years, they’ve found collaborators to produce it for them more cheaply, so that if it makes it onto the market for human consumption it will be affordable; currently they’ve got it down to one-tenth of that initial cost. “David always said this will not be a molecule just for rich people.” As Sinclair says goodbye over the phone to get ready for the late-night drive back to Boston – he needs to be at work early in the morning – he leaves me to chat to his dad. It’s a show of faith, since his 79-year-old father could easily go off piste in his conversation with me. Andrew Sinclair tells me that he stopped taking resveratrol recently because the powder tasted too bitter. He’s taken metformin since he was diagnosed with diabetes eight years ago, and now takes NMN every day, two white pills with breakfast. “David just gave me another handful of them. I don’t know where they come from. But I trust him,” he says with a wry chuckle. Sinclair had described his father to me as filled with energy: not only on his second career, doing bioethics non-profit work, but abseiling, climbing to the top of Cradle Mountain, going out every night. Yet his father downplays all this and is charmingly frank. “I can’t tell what difference it makes to take these things,” he says. “I haven’t changed my lifestyle, but there’s not a drastic improvement in anything. I’m not going downhill as fast as my contemporaries. But it’s hard to really know. A one-person clinical trial is not a clinical trial.” I ask if he’s proud of his son. “I don’t want to brag about him. I only mention what he does if somebody asks me about it. He’s the hardest worker I know. He never stops, he’s flat out all the time. I’ve lost track of how many companies he’s started up, 16 or something. But he’s humble. He has work and his family. That’s it.” I ask if Sinclair takes after him. “No, I was never as ambitious as he was; if things didn’t come, I didn’t push,” he replies. “He’s more like my mother, Vera. She was very bright though she never had any formal education. A self-made woman.” And then, after a pause, he says very softly, “David really could change the course of human history.”