The Foun­tain of Youth

David Sin­clair be­lieves age is a dis­ease we can treat

The Monthly (Australia) - - FRONT PAGE - by Cerid­wen Dovey

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.”

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