the Anti-Aging Revolution - May. 27, 2010

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By David Stipp, contributor June 4, 2010: 12:50 PM ET

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The anti-aging revolution

(Fortune) -- In early 1934, Depression-weary Americans were beginning tosee tendrils of hope poking out of the bleak landscape. President Franklin D.Roosevelt's New Deal was bringing the economy back from the dead.Galvanized by the sight of elderly women scrounging for food from garbage,California physician Francis Townsend had launched a crusade forgovernment-funded pensions that would soon spur the creation of SocialSecurity. Things were even looking up for the long-suffering WashingtonSenators, who had made it to the World Series the previous fall.

But one of the new year's most promising developments passed almostunnoticed. According to a brief article in the Jan. 13 Science News Letter,Cornell University researcher Clive McCay was nearing the end of afour-year study that showed that rats' life spans were greatly extended whenthey were put on near-starvation diets.

To many of his scientific peers,McCay's data made no sense at all.A glorious new chapter in nutritionscience had been opened not longbefore by the discovery of dietarydeficiencies behind scourges such asrickets, pellagra, and beriberi. In thewake of such progress, it seemedalmost subversive to suggest that abunch of rodent Oliver Twists, raised

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Transplant drug rapamycin has extended the life span of middle-aged mice like these,at the Barshop Institute, by 28% to 38%.

on such short rations that theirgrowth was stunted, could liveradically longer than well-fed ones.McCay sheepishly acknowledged inhis initial report that his resultsseemed "little short of heresy."

Over the next several decades, hisdiscovery was all but forgottenoutside of the back halls of science --a laboratory curiosity that didn'tactually spark much curiosity. Mostscientists were reluctant to riskwasting time probing an anomaly thatseemed as baffling as aging itself.

Calorie restriction (CR), as it's nowcalled, eventually was shown toextend many species' life spans by athird or more. Now that anti-agingresearch is hot, it seems bizarre thatCR spent decades on science's backshelf. Simply put, McCay showedthat the rate of aging is incrediblyplastic, and that it's supremely simpleto brake it in animals whose innerworkings aren't all that different fromours. No biomedical discovery of thepast century was more astonishing orsignificant.

So here's a prediction: McCay will someday be recognized as one of the lastcentury's most important discoverers. He wasn't a genius with a capital G.But his skinny rats had made history with a capital H.

The idea of mimicking CR with drugs -- and without the hunger pangs thatdiscourage most people from trying it -- finally got traction in the late 1990swhen scientists began getting hints on the kinds of compounds that mightwork. (It had always been clear that such medicines were needed to makeCR's broad health- and longevity-enhancing effects available to the masses,but before then researchers knew too little to get started.) Around 2000several biotech startups were formed to pursue CR mimetics, includingLifeGen Technologies of Madison, BioMarker Pharmaceuticals of San Jose,and GeroScience of Pylesville, Md. This first wave of CR-mimetic companieshave been low-profile affairs compared with Sirtris Pharmaceuticals, theCambridge, Mass., biotech juggernaut formed a few years later to developdrugs based on resveratrol, the famous red-wine compound shown toinduce CR-like effects in animals. (Sirtris was acquired by GlaxoSmithKlinein 2008.) They haven't been idle, though. GeroScience has worked withProcter & Gamble's (PG, Fortune 500) pet food unit, for example, on CRmimetics for pets, including a sugar in avocados called mannoheptulose. Iwouldn't be surprised to see Fido and Muffy launch the era of effectiveanti-aging medicines.

The startups also deserve credit for beginning to transform the anti-agingquest from a guessing game into a fairly routine exercise in drugdevelopment. Before the pursuit of CR mimetics took off, most anti-aginginvestigators were like blind magicians trying to pull rabbits from a barrel ofsnakes. Not surprisingly, even the serious scientists among them oftenwound up covered in snake oil, promoting "breakthroughs" such as monkey-testicle implants and radium-laced elixirs.

CR-mimetic developers don't have to solve the monster problem of howaging happens in order to devise interventions that oppose it. Evolution hassolved the problem for them. It did so while fashioning CR's machinery,which is poised to carry out all the intricate metabolic adjustments necessary

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to brake aging when activated by a true CR mimetic. Such drugs will bedesigned to switch on an ancient, enormously complex mechanismembedded in our genomes to postpone, and possibly attenuate, a myriad ofills brought on by aging: dementia, heart disease, cancer, as well aswrinkles, arthritis, age-related loss of muscle and bone, and the onset ofsenior moments. In effect, they'll represent the biggest free lunch in medicalhistory. And given that compounds capable of emulating key effects of CR inrodents have already come to light, it's arguable that the Great Free Lunch'sappetizers are now on the table.

Just a few weeks before his death in 1996 at age 100, George Burns wasstill enjoying life, cracking wise at a Christmas party thrown by Frank Sinatra.France's Jeanne Calment, who holds the record for longevity (she died in1997 at 122), was similarly droll and unsinkable. When a reporter at anannual party in her honor departed with the words "Until next year,perhaps?" she shot back, "I don't see why not! You don't look so bad to me."

Very old people with such élan are obviously rare. But I suspect that manywho retain mental clarity in late life make their way toward something likeBurns' and Calment's radiant rapprochement with old age. Surveys showthat self-reported happiness among older people in reasonably good healthis generally higher than among younger groups. I don't want to sugarcoat oldage -- it isn't for sissies, as they say. But I'd love to see more well-temperedsages like Burns in the world. Call it the George Burns scenario.

Some critics argue that developing anti-aging drugs is likely to engender adisastrous surfeit of needy oldsters gripped by greed and ennui. Leon Kass,a University of Chicago professor who chaired the President's Council onBioethics under George W. Bush, has asserted, for instance, that "the desireto prolong youthfulness [is] an expression of a childish and narcissistic wishincompatible with devotion to posterity." Some naysayers add that "greedygeezers" will rack up ruinous Medicare and Social Security bills. Worse, theyargue, the drugs may simply drag out late-life morbidity, recreating en massesomething like the Greek myth of Tithonus, who was granted eternal life butnot everlasting youth and wound up miserably withered forever.

I regard such visions as ill-founded. For one thing, there's evidence that CRmimetics would buy us quality time, not prolong misery. A study of CR'seffects in rhesus monkeys has shown that it reduces age-related diseasesby about a third in the primates during their later lives -- the calorie-restrictedmonkeys have greater lean muscle mass, significantly less age-related brainatrophy, half as much cancer, and half as much cardiovascular disease asdo peers on normal diets. The world's longest-lived human population,natives of Japan's Okinawa prefecture, whose scant traditional diets areregarded as tantamount to mild CR, have 80% less breast and prostatecancer at advanced ages than North Americans do, suffer about 40% fewerhip fractures, and experience half the rate of dementia between 85 and 90.

It's possible that anti-aging drugs would compress late-life misery, letting usreach a ripe old age in good shape before a speedy demise. That couldhave huge economic and social payoffs -- much greater, for instance, than amiracle cure for all cancers.

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Even if the medicines only postponed aging's deterioration, boosting lifeexpectancy by, say, a decade, the benefits would be monumental. AsRichard Miller, a University of Michigan gerontologist, says, "When you askpeople, 'Would you like to live to 100?' they picture what today's elderly,infirm person looks and feels like. But the proper question is a different one:'Would you like to add another 10 or 20 years to the middle of your life, soyou reach 80 or 90 in the same condition that people generally are today ataround 60 or 70?' "

A drug that increases healthy life-years would deliver large benefits acrossmany sectors of the economy. Healthier, longer-living people can stay in theworkforce longer, preserving skilled human capital that might otherwise belost. Healthier workers are physically and mentally more robust, makingthem more productive. They're motivated to invest more in developing theirskills, because they expect to reap the benefits of such investments forlonger periods. They save more for retirement, boosting capital formationthat fuels economic growth. They pose lighter burdens on federal entitlementprograms and contribute more in federal and state tax revenue. Such factorsprobably explain why per-capita incomes of nations around the world havelong risen in tandem with their populations' life expectancies.

Anti-aging drugs may well have downsides too. For instance, nest eggs thatonce seemed adequate may prove too small in an era of extended lifespans. But the drugs should also help with that problem by keeping usvibrant enough to work after 62, the average age at which U.S. workershave retired in recent years. Of course, it remains to be seen whether theeconomy will support demand for older workers' services. Still, surveys showmany baby boomers expect to work at least part-time in retirement for bothfiscal and personal-fulfillment reasons -- they apparently agree with a pieceof wisdom George Burns expressed late in life: "As long as you're working,you stay young."

Where does the anti-aging quest stand? As always with cutting-edgescience, the quest has had ups and downs. In 2008, Harvard's DavidSinclair and colleagues reported that resveratrol failed to extend the lifespans of mice on normal diets, suggesting that it is at best a partial CRmimetic -- the group had earlier made a splash by showing that thecompound induces CR-like effects in mice on high-fat diets. But last year amajor turning point was reached: Researchers showed for the first time thata drug could convincingly extend life span in mammals.

The drug was rapamycin, a medicine long prescribed to help preventrejection of transplanted organs. In parallel mouse experiments in threedifferent labs, scientists funded by the National Institute on Aging found thatrapamycin dramatically boosted longevity in mice on normal diets in a wayreminiscent of CR's effects. Stunningly, the study showed that when rodentswere first put on the drug at 20 months of age, roughly equivalent to 60years in humans, the life expectancies of males were boosted by 28%, andthat of females by 38%. Even CR itself hasn't been shown to exert suchlarge effects on animals so close to the end of their lives. Formerperma-bears about the anti-aging quest are now sounding upbeat.

Unfortunately, the drug industry has shown little interest in trying to translatesuch breakthroughs into anti-aging medicines. Both drug regulators and themedical establishment still essentially view aging as totally mysterious,inexorable, and intractable -- they wouldn't dream of adding it to the officiallist of drug indications. Thus, drug companies have no way to developanti-aging compounds as high-margin prescription drugs. And that meansthat spending many hundreds of millions of dollars on clinical trials of thedrugs' efficacy just doesn't compute. (The relatively small proceeds frommarketing them as low-margin dietary supplements can't justify such costly,high-risk trials either.)

Besides, vetting the drugs would require first developing reliable biomarkersof aging, telltale signs of normal bodily decline over time that could be usedto register how fast people are going downhill. Such biomarkers would

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enable the vetting of CR mimetics' efficacy in trials that last only a few years,rather than the impossibly long time it would take to assess their longevity-boosting effects in humans.

In short, the hugely promising anti-aging quest is now stuck between the Rand the D stages, and I fear it will stay there until the federal governmentgreatly steps up funding in the area. I, for one, don't plan to take purportedCR mimetics until there's some reasonably rigorous clinical trial datashowing that they're safe and effective. And until such data are available, theanti-aging revolution is likely to remain little more than the enthusiasticpursuit of placebo effects by wishful thinkers.

All this is terribly ironic. In effect, it means that authorities charged withpromoting public health are fatalistically standing and watching the "silvertsunami" of population aging -- with its huge economic and human costs --bearing down on us as if there were no way to shelter ourselves from its fullforce. Meanwhile, the authorities are perfectly willing to devote many billionsof dollars annually to the pursuit of ever costlier palliatives for diseases ofaging, which are typically applied when it's too late to do much good -- thefederal government now annually spends less than 0.04% as much onresearch about the biology of aging as it does on Medicare.

So here's the moral of the story: The George Burns scenario is within ourgrasp if we collectively recognize what has happened in aging science andseize the day. And while anti-aging drugs may not enable all of us to live aslong as Burns, they promise to let many of us age as gracefully as he didand thus aspire to our own version of his timelessness. As Burns oncequipped, "You can't help getting older, but you don't have to get old." Wordsto remember from a wise guy to the end.

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First Published: May 27, 2010: 7:26 AM ET

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Ester Coetzee Jul 19

We do not mind getting older, but we mind getting uglier...Message - Report

Dureen Coade Jul 16

Super article!!!Message - Report

Richard Bartholomew Jun 14

"Healthier, longer-living people can stay in the workforce longer,preserving skilled human capital that might otherwise be lost."

I hear a lot of complaining from the over 45 crowd (of which I am one)who have chronic trouble securing employment. Most of them don'treport any debilitating age-related conditions.

If employers don't value this kind skilled human capital now, why wouldthey start doing so just because a CR enhanced geriatric shows up atthe interview? More likely, the effect would be more and morepronounced age discrimination.

"...I fear it will stay there until the federal government greatly steps upfunding in the area."

It's hard to imagine a better reason for allowing it to remain indefinitelystuck between R and D.

"...the federal government now annually spends less than 0.04% asmuch on research about the biology of aging as it does on Medicare."

Eliminating Medicare would improve that ratio considerably.Message - Report

Bjarne Luther Frandsen Jun 6

Com on - bigger than big !!Message - Report

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