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Sinclair’s and Auwerx’s success in extending the life span and improving the health of mice has partly assuaged critics’ doubts that resveratrol can work in mammals. “Both studies are extremely exciting,” says Kaeberlein; it’s “pretty clear” that resveratrol modifies certain proteins, such as mitochondrial proteins associated with energy production. ­Kaeberlein points out, however, that the tests involved mice on a high-fat diet and should be duplicated with mice on a normal diet.

And Kaeberlein is not yet convinced that resveratrol is an activator of the SIRT1 enzyme. “We were unable to reproduce the work from the Sinclair lab in yeast,” ­he says, adding that results have been mixed in flies, worms, and other animals. He also still disagrees that sir2 is the pathway by which caloric restriction increases longevity in yeast. “Sir2 regulates longevity, and caloric restriction regu­lates longevity,” he says. But it doesn’t follow that caloric restriction necessarily increases life span by activating sir2.

Critics point out, too, that no one yet knows whether resveratrol will work in humans. According to Harvard population biologist Lloyd Demetrius, the evolutionary forces determining life span are so radically different in mice and humans that mechanisms responsible for slower aging in mice are unlikely to have much effect in people. Demetrius has studied caloric restriction, not resveratrol, but he’s still skeptical of the chemical’s viability as a drug. “I think its effects on the maximal life span in humans will be almost zero,” he says.

A Believer
One convert to Sinclair’s views on the effects of resveratrol was Christoph Westphal, then a partner at Polaris Venture Partners, based in Waltham, MA. Though only 35 years old, Westphal had already cofounded two publicly traded companies, Momenta Pharmaceuticals and Alnylam Pharmaceuticals–both Cambridge, MA, biotech startups developing novel drugs. Westphal read the paper and e-mailed Sinclair, who was already working on starting a company. Sinclair had had someone else in mind as CEO, but he and Westphal hit it off.

“David was young and controversial,” says Westphal. “Half the people thought he was crazy, and they were pounding on him. But I saw something in him and believed in his science.” Westphal and Sinclair are now close friends, with adjacent desks in a small office at Sirtris. Sinclair spends his Saturdays at work, often bringing his two older children to play with Westphal’s two kids. ­Sinclair says that he and Westphal exchange 50 e-mails a day.

I accompanied Westphal one day last winter on his morning walk from his home in Brookline, MA, across the Charles River to Sirtris’s offices in Cambridge. He explained that Sirtris’s intention is not to produce drugs that extend life span. “That is not an end point recognized by the FDA,” he said. “Our end points will be specific diseases.” The company has developed a supercharged version of resveratrol, called SRT501. It has also discovered novel small molecules that are not related to resveratrol but, it claims, are a thousand times as potent in activating the ­sirtuins. So far, animal tests have shown that the drugs may help treat neurological disorders and diabetes.

This past spring, the company launched phase I human trials of SRT501 in patients with diabetes; it also plans human trials later this year to test the drug as a treatment for Melas syndrome, a rare disorder that hastens aging and causes fatal deterioration of the brain and muscles. Sirtris expects to begin human trials of its non-resveratrol compounds in the first half of 2008.

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Credit: Steve Brodner

Tagged: Biomedicine

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