Cosmos - - Front Page - EL­IZ­A­BETH FINKEL is ed­i­tor-in-chief of Cos­mos Mag­a­zine.

It’s no longer snake oil. Sci­en­tists have a pipe­line full of promis­ing anti-age­ing com­pounds just wait­ing for hu­man tri­als. EL­IZ­A­BETH FINKEL re­ports.

“I NEED TO LAST LONGER,” the pro­fes­sor tells me. He lets my quizzi­cal look hang for a mo­ment, then quickly ex­plains. “I’m on my sec­ond mar­riage and my wife is ex­pect­ing twins.”

SOON TO BE 50, the re­spected head of an Aus­tralian med­i­cal in­sti­tute is con­tem­plat­ing the lat­est of­fer­ing from the anti-age­ing in­dus­try. It’s a prod­uct that tops up the lev­els of nicoti­namide ade­nine din­u­cleotide (NAD+), a com­mon­place chem­i­cal made by our bod­ies that is cru­cial for our me­tab­o­lism.

He’s not alone. Leonard Guar­ente, a pro­fes­sor at Mas­sachusetts In­sti­tute of Tech­nol­ogy, has been tak­ing NAD+ boost­ers for years; and in 2015 started a com­pany, Ely­sium, to mar­ket them. There are likely thou­sands of users by now. Even NASA has been se­duced. It hopes to use NAD+ to re­pair the DNA of as­tro­nauts bom­barded by cos­mic rays dur­ing the year­long tip to Mars. DNA dam­age is one of the fac­tors linked to age­ing.

Some­thing has changed in the anti-age­ing field. Ec­centrics and gullible-types have al­ways availed them­selves of anti-age­ing reme­dies. Du­bi­ous sup­ple­ments from gingko to hor­mones feed a mush­room­ing $30 bil­lion in­dus­try. But when ev­i­denceclam­our­ing sci­en­tists start pop­ping a pill, you sit up and take no­tice. Like the soon-to-be-50 Aus­tralian pro­fes­sor, most aren’t aim­ing to ex­tend their life­span; they are aim­ing to ex­tend their “health span” – the pe­riod of time be­fore the dis­eases of age­ing catch up with them: heart dis­ease, arthri­tis, can­cers, kid­ney dis­ease and de­men­tia.

This seal of ap­proval from sci­en­tif­i­cally lit­er­ate cus­tomers re­flects a rev­o­lu­tion in the sci­ence of age­ing. Thirty years ago, there was none. Most sci­en­tific think­ing held that age­ing was not amenable to tweak­ing. No more than pre­vent­ing wear and tear on your car. Yet an­i­mals do age at dif­fer­ent rates – a lab rat lives for three years, but a mole rat for 40. Rather than a ran­dom process of degra­da­tion, this surely sug­gests some un­der­ly­ing pro­gram, one that might be hacked.

In the late 1980s, sci­en­tists proved that was in­deed the case – at least in yeast and round­worms. They tin­kered with the genes of these crea­tures and ex­tended their life­spans and healthspans. In the case of round­worms, life­span could be dou­bled by al­ter­ing a sin­gle gene!

Sud­denly sci­ence had some levers to push – and in a com­pelling demon­stra­tion of how the fun­da­men­tals are con­served through evo­lu­tion, the same ge­netic levers were iden­ti­fied in mice and hu­mans. But al­ter­ing the genes of hu­mans is not on the cards. So for more than a decade now, re­searchers have searched for drugs to tweak those same genes.

NAD+ boost­ers have now be­come the party favourite. In part be­cause they’re not drugs; they are nat­u­ral prod­ucts that re­store body chem­istry to a more youth­ful state. By age 50, NAD+ lev­els are half what they were at 20. Top up NAD+ lev­els in el­derly mice and their mus­cles be­comes like those of young­sters, their stem cells get more oomph and they live longer.

So have sci­en­tists fi­nally found the foun­tain of youth? And if it’s good enough for sci­en­tists, should the rest of start tak­ing NAD+ sup­ple­ments?

I FEEL A BIT like the char­ac­ter Mor­pheus in the movie The Ma­trix, in the scene where he of­fers Neo ei­ther the blue pill or the red pill: “You take the blue pill – the story ends, you wake up in your bed and be­lieve what­ever you want to be­lieve. You take the red pill … and I show you how deep the rab­bit hole goes.”

I had a sim­i­lar ex­pe­ri­ence re­search­ing this story. Some re­searchers I in­ter­viewed were in the blue-pill camp: they felt that we prob­a­bly know enough about age­ing to in­ter­vene. Oth­ers were red-pill types. The rab­bit hole was too deep, they didn’t think we knew enough to start in­ter­ven­ing.

So I’ll give you the Mor­pheus choice here. BLUE PILL: TAP­PING THE FOUN­TAIN OF YOUTH

The rea­son some se­ri­ous sci­en­tists are tak­ing NAD+ sup­ple­ments is be­cause of a se­ries of epipha­nies, which have erected a glit­ter­ing sci­en­tific ed­i­fice on what just three decades ago was just a swampy back­wa­ter.

Just about ev­ery univer­sity now has a depart­ment for age­ing re­search; and it’s not just aca­demic in­sti­tutes. Google en­tered this space in 2015 with its se­cre­tive sub­sidiary Cal­ico, which is bring­ing big data to bear on the prob­lem. Craig Ven­ter, who pi­o­neered the read­ing of the hu­man genome, started the com­pany Hu­man Longevity to de­code the genes for long life.

Cal­i­for­nia-based Alka­h­est is min­ing the re­gen­er­a­tive fac­tors in youth­ful blood, and there are plenty more vari­a­tions on theme from start-ups such as Pro­gen­ics and Unity.

But roll back 30 years and study­ing age­ing was ca­reer sui­cide for any se­ri­ous sci­en­tist. Mean­while at the other end of the bi­o­log­i­cal spec­trum, the sci­ence of em­bryo de­vel­op­ment was boom­ing. Just how the mush of an egg turned into an em­bryo had long been bi­ol­ogy’s great­est mys­tery. By the late 1980s, re­searchers had un­cov­ered a ge­netic pro­gram that ran the process in ev­ery­thing from round­worms to hu­man be­ings. These lessons from em­bryos would help pro­pel the study of age­ing into the main­stream.

Les­son num­ber one was that the fun­da­men­tals of bi­ol­ogy are pre­served across the species. In the late 1980s Cyn­thia Kenyon was com­pelled by this les­son. She was a 30-some­thing slim blonde, pos­sessed of ex­cep­tion­ally youth­ful fea­tures and an in­fec­tious en­thu­si­asm for sci­ence. Her model or­gan­ism was the one-mil­lime­tre-long, 959-cell-strong round­worm, Caenorhab­di­tis el­e­gans. Kenyon was struck by its very ob­vi­ous age­ing. In two weeks it went from ag­ile slith­erer to a de­crepit crea­ture barely able to drag it­self across the cul­ture dish.

She felt sorry for the worms. She was also in­trigued. Per­haps, like de­vel­op­ment, age­ing was also a process un­der some sort of con­trol. She set out to see if tweak­ing genes, by bom­bard­ing the worms with mu­ta­genic chem­i­cals, might af­fect their life­span. Her hunch was re­warded by a re­mark­able mu­tant. At four weeks of age it was still slith­er­ing like a teenager. Tweak­ing a sin­gle gene more than dou­bled its life­span.

In 1993 Kenyon pub­lished a pa­per in Na­ture re­veal­ing the iden­tity of that gene as “daf-2”, which may not mean all that much to you; but there was a rev­e­la­tion lurk­ing be­hind the name.

One of the big lessons of the 1980s was that genes don’t change all that much dur­ing evo­lu­tion. They ac­quire some code changes and get re­pur­posed, but it’s still pos­si­ble to recog­nise them. Sort of like the way words change in lan­guage – you can still pick out the an­cient Greek roots.

So it wasn’t sur­pris­ing that mam­mals turned out to have two genes that re­sem­bled daf-2. The sur­prise lay with their job de­scrip­tion. In hu­mans, the coun­ter­parts of the worm’s life-ex­ten­sion gene are the in­sulin re­cep­tor gene and its close rel­a­tive, the in­sulin-like growth fac­tor 1 re­cep­tor gene (IGF1R).

To un­der­stand why this was such a rev­e­la­tion, you need to know a cou­ple of things.

In­sulin’s job is to mo­bilise the body to re­spond to food in­take. Like a ware­house over­seer re­ceiv­ing a stock de­liv­ery, the hor­mone is re­leased into the blood to en­sure many sys­tems are quickly mo­bilised. The in­sulin ‘re­cep­tor’ con­veys these sig­nals to the body tis­sues so nu­tri­ents are used as needed or stored as fat.

Round­worms showed that sig­nals about food avail­abil­ity also had a link to age­ing. But even be­fore the worm dis­cov­ery we knew that.

Back in the Great De­pres­sion of the 1930s, many peo­ple went hun­gry. Won­der­ing about the ef­fect on growth and long-term health, Cor­nell Univer­sity nu­tri­tion­ist Clive Mckay set up rat ex­per­i­ments to mimic calo­rie re­stric­tion. To his sur­prise the rats, so long as they re­ceived ad­e­quate nu­tri­ents, ac­tu­ally lived

longer. The ex­per­i­ment has been re­peated in yeast, worms, flies, mice and pri­mates. The rough rule of thumb is: re­strict calo­rie in­take by 30% and see up to a 30% in­crease in life­span. The ef­fects are smaller in mice and even smaller in pri­mates.

Not many peo­ple have the willpower to ad­here to a life­long diet, though oc­ca­sional “fast­ing mim­ick­ing di­ets” de­vel­oped by Wal­ter Longo at the Univer­sity of South­ern Cal­i­for­nia seem to have ben­e­fi­cial ef­fects. Nev­er­the­less the holy grail has been to find a drug that could mimic fast­ing.

Kenyon’s iden­ti­fi­ca­tion of the daf-2 gene pro­vided an en­try point into the cir­cuit link­ing food in­take with life ex­ten­sion. In the fol­low­ing years, she and oth­ers teased out more key com­po­nents. Re­search showed the same com­po­nents played a role in the age­ing of dif­fer­ent species. Long-lived dogs and long-lived peo­ple showed ev­i­dence of tweaks to their IGF1-R gene. An­other ge­netic tweak that dou­bled a worm’s life­span, daf-16, turned up in long-lived men. They were more likely to carry a par­tic­u­lar variation in a gene called FOX0-3A, which har­boured within it the recog­nis­able code of daf-16.

AN­OTHER EN­TRY POINT into the age­ing cir­cuitry came from the yeast Sac­car­omyces cere­visiae. It might seem ab­surd to go look­ing for the se­crets of age­ing in a sin­gle-celled yeast, but this cell re­sem­bles one of our own in that it has mul­ti­ple chro­mo­somes housed in a nu­cleus. Re­mark­ably the yeast also pos­sesses many recog­nis­able fea­tures of age­ing. A sin­gle yeast cell will even­tu­ally age and die af­ter a cou­ple of days. If coaxed to bud off daugh­ters, it will un­dergo a kind of menopause; spawn­ing so many daugh­ter cells and no more. It also demon­strates the uni­ver­sal fea­ture of age­ing: de­prive yeast of calo­ries and it lives longer.

Just as with round­worms, the search for mu­tants de­liv­ered. In 2000, Leonard Guar­ente’s lab at MIT found yeast mu­tants that con­tin­ued to spawn for about about 30% longer than nor­mal. The gene re­spon­si­ble was named Sir­tuin 2 (Sir 2). It was a com­pletely dif­fer­ent com­po­nent of the age­ing cir­cuit to any­thing un­earthed in the worm. It made parts of the DNA code in­ac­ces­si­ble or “silent” – the pre­fix Sir stands for “silent in­for­ma­tion reg­u­la­tor”.

Sir­tu­ins work by in­creas­ing the stick­i­ness of the hi­s­tone pro­teins that wrap up DNA. Worms, flies, mice and hu­mans all have them – and ex­per­i­ments with worms, flies and mice in­di­cates that in­creas­ing sir­tuin ac­tiv­ity mod­estly ex­tends life­span.

Yeast stud­ies also de­liv­ered an­other wind­fall. Like other or­gan­isms, yeast life­span in­creases when calo­ries are re­stricted. As yeast doesn’t have in­sulin or IGF1 re­cep­tors, some other ge­netic com­po­nents must be re­spon­si­ble for sens­ing calo­ries. In 2005 re­searchers found that role was played by a cu­ri­ous gene known as the “tar­get of ra­pamycin” or TOR (in mam­mals the gene is called MTOR). When the TOR gene senses low lev­els of calo­ries, it re­sponds by slow­ing down protein syn­the­sis. It also stim­u­lates re­cy­cling of a cell’s com­po­nents, a process known as au­tophagy.

It seemed to make sense. Calo­rie re­stric­tion flips a meta­bolic switch from “abun­dance” to “aus­ter­ity”. Like when you get a big salary cut, you don’t go adding ex­ten­sions to the house; you hun­ker down, live mod­estly, re­cy­cle your old things and de­lay your plans to have ba­bies. Some­how re­spond­ing to this stress also length­ens life­span.

These days re­searchers think au­tophagy plays a big part in the length­en­ing. For in­stance, Wal­ter Longo’s re­cent stud­ies on mice and hu­mans shows that fast­ing ac­cel­er­ates the re­fur­bish­ing of tis­sues, clear­ing away dam­aged “senes­cent cells” while turn­ing on re­new­ing stem cells.

The name “tar­get of ra­pamycin” is an ac­ci­dent of his­tory. Ra­pamycin was dis­cov­ered in a bac­terium that grows in the soils of Rapa Nui, bet­ter known as Easter Is­land. Ra­pamycin’s abil­ity to flip the TOR lever makes it a drug with pro­found ef­fects. Un­til now, its ma­jor med­i­cal use has been to stop the re­jec­tion of for­eign tis­sues in trans­plant pa­tients by ton­ing down their im­mune sys­tems. But it was des­tined for greater things.

BY THE EARLY 2000s, the sci­ence of age­ing was buzzing. Worms and yeast had pro­vided threads that re­searchers fol­lowed to re­veal an en­tire cir­cuitry of age­ing. In lab an­i­mals these com­po­nents could be tweaked to in­crease life­span. But that in­volved al­ter­ing genes – not pos­si­ble for hu­mans. Could chem­i­cals achieve the same hack?

En­ter Syd­ney-born David Sin­clair. He had long been com­pelled by the lessons of age­ing learnt from yeast. In 1997at Lenny Guar­ente’s lab he had found a mu­tant yeast that aged faster. The faulty gene, SGS1, was re­lated to one caus­ing Werner syn­drome. Just like yeast, af­fected peo­ple age faster.

But it was yeast’s Sir 2 gene that cap­ti­vated him. It ap­peared to be a lever that flipped dur­ing calo­rie re­stric­tion. Per­haps chem­i­cals could do the same thing. In 2003 he hit pay dirt with a plant-de­rived com­pound called resver­a­trol. To ev­ery­one’s de­light, it was found in red wine – though you’d have to im­bibe litres to get an ac­tive dose. Soon af­ter, he spun off the com­pany Sir­tris to com­mer­cialise com­pounds like resver­a­trol; it was bought by Glax­osmithk­line in 2008.

Sin­clair, who now heads labs both at the Univer­sity of NSW and Har­vard Med­i­cal School, says GSK has a

whole sta­ble of sir­tuin-ac­ti­vat­ing com­pounds in test­ing, some of which are 1,000 times stronger than resver­a­trol.

His at­ten­tion, in any event, has shifted to NAD+. The chem­i­cal had been hid­ing in plain sight since 2000, when sir­tu­ins were iden­ti­fied as an anti-age­ing lever in yeast. It was clear NAD+ acted like a grease for the sir­tuin mech­a­nism. Since its dis­cov­ery some 100 years ear­lier as a yeast co-fac­tor that stim­u­lated fer­men­ta­tion, NAD+ had been found to grease a mul­ti­tude of meta­bolic re­ac­tions – but few thought of it of­fered a po­ten­tial treat­ment. It was, as Sin­clair put it, “the most bor­ing mol­e­cule in bio­chem­istry”. How could rais­ing the lev­els of such a com­mon­place sub­stance have any ef­fect?

Fur­ther­more, it was also not clear how to raise its lev­els: NAD+ it­self is very un­sta­ble, and can’t ac­tu­ally get in­side cells where it is needed.

Two things changed the game. One was that re­searchers dis­cov­ered NAD+ lev­els de­cline with age but are raised by calo­rie re­stric­tion and ex­er­cise. The other was iden­ti­fy­ing sev­eral nat­u­ral pre­cur­sors of NAD+ – nicoti­namide mononu­cleotide (NMN) and nicoti­namide ri­bo­side (NR) – that were much more sta­ble, could en­ter cells and raised NAD+ lev­els when given to an­i­mals.

Jo­han Auw­erx’s lab­o­ra­tory at the Swiss Fed­eral In­sti­tute of Tech­nol­ogy in Lausanne showed in 2016 that NR boosted the mul­ti­pli­ca­tion of skin, brain and mus­cle stem cells, and slightly in­creased the longevity of mice, even when given in mid­dle age.

Sin­clair’s lab showed in 2013 that mice treated with NMN boost­ers had im­proved mus­cle strength, and ear­lier this year that mice treated with NMN had su­pe­rior abil­ity to re­pair their DNA – the rea­son NASA is now en­gaged in talks with Sin­clair’s lab.

As well as as­tro­nauts, chil­dren who have un­der­gone ra­di­a­tion ther­apy for cancer might also ben­e­fit from this treat­ment. Sin­clair is plan­ning clin­i­cal tri­als us­ing NMN or a closely re­lated com­pound.

What’s miss­ing is a proper con­trolled trial to see if NAD boost­ers will ac­tu­ally do any­thing to fore­stall hu­man age­ing. Get­ting a trial off the ground for any anti-age­ing com­pound turns out to be ex­tremely dif­fi­cult. (See ‘ Go­ing to trial’ on the pre­vi­ous pages.)

WHICH BRINGS US back to NAD+ boost­ers. The ex­cite­ment is that NAD+ boost­ers are not drugs. So you needn’t wait; there are com­pa­nies will­ing to oblige by pro­vid­ing NR sup­ple­ments, such as Guar­ente’s startup, Ely­sium. It has some cred – no less than five Nobel prize win­ners on its ad­vi­sory board. In lieu of a trial, Guar­ente says the com­pany will fol­low up re­sults with clients over time. There are con­cerns as to whether NAD+ lev­els are truly raised by the sup­ple­ment but, for what it’s worth, have a google and you’ll find anec­do­tal tes­ti­mo­ni­als from peo­ple say­ing they feel pep­pier for tak­ing it.

So what do you do? Just be­cause some­thing is a nat­u­ral com­pound doesn’t guar­an­tee that boost­ing its lev­els in mid­dle age is a safe thing to do. As Sin­clair re­ported at a re­cent con­fer­ence in Syd­ney, NMN not only helped aged mice de­velop stronger mus­cles but also trig­gered the growth of tiny blood ves­sels. That might flag a risk, since cancer cells rely on newly formed blood ves­sels to spread.

On the other hand, it’s pretty clear what the ef­fects of age­ing are – a dra­mat­i­cally in­creased like­li­hood of de­vel­op­ing all sorts of dis­eases.

De­pends if you’re the punt­ing type.


You might think with all the epipha­nies of the past 30 years, surely we know enough about age­ing to go full speed ahead with in­ter­ven­tions? All the can­di­date com­pounds, so far, seem to hack into the same path­way trig­gered by calo­rie re­stric­tion. Well, yes – but this rab­bit hole goes very deep. Take calo­rie re­stric­tion, the sup­pos­edly iron-clad way to trig­ger life­span ex­ten­sion. In fact, stud­ies in mice show very dif­fer­ent ef­fects, de­pend­ing on their breed, gen­der and even what they are fed. Rafael da Cabo, who runs the long-term calo­rie re­stric­tion study on rhe­sus mon­keys at the US Na­tional In­sti­tute of Age­ing, told me some breeds of mice ac­tu­ally live shorter life­spans when calo­rie-re­stricted; and fe­males may re­spond bet­ter than males or vice versa. Nor is it just about calo­ries: sorry pa­leo di­eters but high-protein di­ets shorten life­span in mice. So go fig­ure where you as an in­di­vid­ual, en­dowed with a spe­cific gen­der and a unique set of genes, fit into all this.

And while it’s all very well to con­cep­tu­alise the bi­ol­ogy of age­ing as a cir­cuit, cir­cuits end up con­trol­ling some­thing. So what ex­actly does this cir­cuit con­trol?

Over the years, one com­pelling the­ory has been that it con­trols the in­tegrity of mi­to­chon­dria, the en­gines of our cells which clearly de­gen­er­ate as we age. Ac­cord­ing to the the­ory, the cor­ro­sive by-prod­ucts of cel­lu­lar com­bus­tion – free rad­i­cals – cause on­go­ing dam­age as an in­evitable con­se­quence of be­ing alive. But nu­mer­ous re­cent ex­per­i­ments show that slow­ing the gen­er­a­tion of free rad­i­cals in mice or flies, doesn’t ac­tu­ally slow the age­ing process. In fact, it seems to have the op­po­site ef­fect. Nowa­days the paradigm shift is that stress sig­nals like those from free rad­i­cals, fast­ing or ex­er­cise trig­ger an adap­tive anti-age­ing re­sponse.

It doesn’t mean past the­o­ries are en­tirely wrong. As da Cabo says: “Noth­ing has been dis­proven.” It’s just

that there is a lot of other stuff go­ing on in age­ing as well. At least nine tar­gets ap­pear to be con­trolled by the age­ing cir­cuitry, rang­ing from the fray­ing of telom­eres on the tips of chro­mo­some to ‘epi­ge­netic’ dis­tur­bances that change how the DNA code is read.

Kenyon’s epipha­nies with worms sug­gested for a while that tweak­ing the con­trols for age­ing might be sim­ple. In­deed these days it’s pos­si­ble to ex­tend the life­span of worms ten-fold. But mam­mals are com­plex. Da Cabo of­fers the metaphor of a Model T Ford com­pared to a mod­ern Tesla. Back in the 1920s you could tune the en­gine with a few tweaks from a span­ner. Good luck try­ing that with a Tesla!

Luck­ily, just like to­day’s car me­chan­ics, re­searchers now have mind-bog­gling tools to deal with mind­bog­gling com­plex­ity – they can mon­i­tor the ac­tiv­ity of ev­ery gene and the out­put of me­tab­o­lism –with so­called ‘omics tech­nolo­gies’ – and leave it to ma­chine­learn­ing al­go­rithms to fig­ure out what’s go­ing on.

This is the sort of big data ap­proach that Google’s sub­sidiary Cal­ico is ap­ply­ing to the bi­ol­ogy of age­ing. The com­pany’s chief sci­en­tific of­fi­cer: Cyn­thia Kenyon.

None of this means the era of anti-age­ing medicine has to wait for us to ex­plore ev­ery blind al­ley of the rab­bit hole. In­deed, most of the re­searchers I spoke with pas­sion­ately be­lieve they are more than ready to start test­ing the plethora of promis­ing new com­pounds in their pipe­lines.

What’s needed is the faucet at the end – the reg­u­la­tory frame­work that will in­cor­po­rate “age­ing” as a med­i­cal in­di­ca­tion. So that peo­ple who need to last longer don’t have to be pun­ters.

IMAGES 01 Mario Castello / Getty Images 02 Steve Gschmeiss­ner / Getty Images 03 Sci­mat / Getty Images 04 Fran­cis Dean / Getty Images

Less is more: restrict­ing calo­rie in­take has been shown to in­crease life­span in ev­ery species stud­ied.


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