Anti-aging drugs (cont.)

By David Stipp, Fortune

With the Renaissance man personality and the driving ambition, Westphal seems ready-made for the limelight. But he largely avoided the press until the recent news about resveratrol made that untenable. Recently he granted a few interviews, but his press persona has been low-key, guarded, almost professorial. It's not that he's shy. When a TV news team showed up one day, he put on a white lab coat and safety glasses before going on camera - a nerdy affectation that caused much mirth at Sirtris. Self-satire, he later commented, is part of his campaign "to keep us grounded. We're in trouble if we lose the ability to laugh at ourselves."

Rather, he's determined to avoid any whiff of "fountain of youth" hype - specifically, of giving the impression that Sirtris is a bunch of flakes chasing miraculous elixirs, which is the kiss of death for a startup trying to raise millions of dollars from hard-nosed money managers. He spends a lot of time explaining that his company is working to cure diseases of aging, not to cure aging itself. There's a difference, especially in the minds of regulators, who view aging as part of the human condition, not an illness warranting treatment.

Further, proving that a drug extends life span would require an impossibly long clinical trial. And then there's what Westphal calls the "vortex of inflated expectations," which invariably spins up around scientifically credible anti-aging research. "I don't want to get sucked in," he says.

But Westphal can't afford to steer Sirtris too far from the vortex. After all, it does have to impress those hard-nosed money managers in order to realize its drug-development dreams. And the possibility that its drugs actually will slow aging provides him with a very compelling case to put to potential investors and pharma partners - to wit, aging, when stripped to its dire essence, is simply a process that inexorably increases the risk of killer diseases. So a drug that retards that process should have across-the-board power to postpone such diseases' toll, making it an FDA-approvable blockbuster of unprecedented scope.

So Sirtris's star is hitched to perilously glitzy anti-aging science despite the fact that it isn't pursuing life-extension drugs per se. As a result, Westphal's media stance, like the man himself, is a study in high-speed motion as he alternately approaches and flees the vortex. In an interview last fall he enthused that "studies on long lived humans indicate there are four key predictors of longevity: low levels of blood glucose and insulin, little weight gain during middle age, and low body temperature. Our drugs positively affect these predictors in mice. That's very promising." Then he took pains to caution that "whenever Sirtris is mentioned" in the news, "it should be emphasized that it's going for FDA-approved drugs to treat diseases like diabetes, not anti-aging. No matter how often I say that, folks don't seem to listen."

Like most entrepreneurs, Westphal is fixated on the new. Ironically, however, the line of research that led to Sirtris dates from the 1930s, which is when scientists at Cornell University discovered the life-extending effects of calorie restriction, or CR. The researchers found that reducing normal calorie intake by about a third extends animals' life spans by 30 percent or more, keeping them sleek and vibrant when their normally fed peers look wasted, or are dead. In fact, CR is the only established way to slow aging in everything from guppies to dogs to, many scientists believe, humans. The big drawback, of course, is the not-eating part. CR's stomach-growling regimen requires the self-control of a Mahatma Gandhi. (It also tends to produce the great ascetic's half-starved look.)

And thus the appeal of a substance like resveratrol: Sinclair's research suggests it does many of the wonderful things CR does, including extending healthy life. Sirtris's goal is to develop medicines that function like resveratrol but are far more potent: in principle, people on the medicines could eat heartily while getting the pluses of CR. Further, they wouldn't have to gulp fistfuls of pills. (Heroic doses of resveratrol, comparable to a person's drinking hundreds of glasses of wine a day, were needed to elicit the remarkable effects seen in the high-profile mouse studies.)

The hubbub about resveratrol began with a 2003 study by Sinclair's group suggesting that the compound can mimic the effects of CR in yeast cells, boosting their life spans by 70 percent. The following year he and colleagues went on to demonstrate that resveratrol slows aging in roundworms and fruit flies. That made it the first compound to show anti-aging effects in widely divergent species. Then, last spring, scientists in Pisa, Italy, showed that its magic extends beyond creepy-crawlies: Large doses of the compound boosted life span more than 50 percent in a species of short-lived fish.

This is what happened to the mice that got Jay Leno so jazzed a few months ago: In one of the two mouse studies, conducted by Sinclair's group and the National institute on aging, high doses of resveratrol induced a number of CR-like effects, including significantly extending the life spans of mice on fattening diets while warding off diabetes and their ill effects of overeating.

In the other study, led by a French team and sponsored by Sirtris, even higher doses both protected mice against deleterious effects of rich diets - including keeping their weight down - and doubled their running endurance. All that is just what the doctor would like to order at a time when bathroom scales are groaning in terminal agony across the globe.

As for how resveratrol does its thing, therein lies a raging academic debate, Sinclair being one of the combatants. The dispute stems from the fact that resveratrol is a "dirty" drug, i.e., a blunt instrument that interacts with a complex array of molecules in the body. That makes its main mode of action, and link to CR, hard to pin down. It may be that resveratrol's effects spring from its ability to target many different molecules. Alternatively, it may be that just one of resveratrol's many targets is the really magical one - a kind of master switch that turns on CR-like effects all by itself. Sinclair is in the latter camp: he believes that an enzyme called siRT1 is resveratrol's key target, and that the compound works its magic mainly by activating that enzyme. (siRT1 is a member of the sirtuin class of enzymes, hence the company name.)

Sirtris has made a major bet that Sinclair is right about that by designing its novel drugs to activate siRT1. If it turns out that the enzyme isn't really a master switch for CR-like effects, the company's new medicines may not work. But there's growing evidence that Sinclair is right: Sirtris has already shown that its siRT1 drugs do nice things like lower blood sugar in overfed mice with diabetes, says Peter Elliott, the company's drug-development chief.

The mouse studies also gave hints that resveratrol induces basic metabolic changes akin to those that CR does. One of the most intriguing was the production of fresh mitochondria, the key components of cells that serve as power generators; they essentially burn sugar in slow motion to release energy. But like coal-burning power plants, mitochondria also pollute. In particular, they spew highly reactive chemicals called free radicals, which damage DNA and other important molecules in cells. Over time the radicals deteriorate the mitochondria themselves, which degrades their efficiency, causing yet heavier production of free radicals. The end result is a cell-degrading snowball effect that is thought to be a major cause of aging.

Resveratrol's ability to engender new mitochondria is especially exciting because it seems the fresh ones are more efficient than the worn mitochondria they replace, hence are less prone to churn out damaging radicals. CR appears to do the same thing - it's like replacing a smoky old coal burner with a cleaner burning gas-fired plant. Resveratrol's effect on mitochondria may be enough by itself to account for much of the compound's riveting effects in animal studies. In particular, the effect would seem to account for the abrupt Olympic-caliber running abilities observed in mice.

Again, that is the theory. The mouse studies didn't settle the debate over how resveratrol works, which probably won't happen until researchers with no ties to Sirtris confirm that Sinclair is right. So pursuing the siRT1 path is a gamble for Sirtris, one of many.