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Sirtris co-founder fires back against resveratrol critics

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David Sinclair and his allies believe he has scored a major victory in the controversial--and complex--field of anti-aging science. With a new research paper, the Harvard genetics professor shows how the red wine chemical resveratrol and other compounds directly activate an enzyme called SIRT1, an activity on the target that has been hotly contested.

The paper appears in the March 8 issue of Science, but to understand or care about the findings, one must beef up on the scientific battle leading up to the present.

Studies from Sinclair's lab and others have linked SIRT1 activation to prolonging life spans and protecting organisms in lab experiments against diseases of aging. Based on his early research, he co-founded Cambridge, MA-based Sirtris Pharmaceuticals, which GlaxoSmithKline ($GSK) bought in 2008 for $720 million. And anyone who has followed the Sirtris saga since then knows that Sinclair's early resveratrol findings have been called into question in studies from outside labs that couldn't replicate his tantalizing results.

For instance, Pfizer ($PFE) scientists rained on the Sirtris party, concluding that resveratrol and other compounds from the biotech did not directly activate SIRT1, according to a 2010 paper in the Journal of Biological Chemistry. They also contended that SRT1720, a Sirtris compound, didn't perform as advertised in mice on a high-fat diet. 

Enter Sinclair et al and the latest Science article. The group found an SIRT1 mutant with complete immunity to activator molecules such as resveratrol and synthetic compounds from GSK/Sirtris. They tested resveratrol on muscle and skin cells with the mutant SIRT1 and others with normal SIRT1 in test tubes. The tests showed that the compound and others had no effect on the mutant-expressing cells, but the target jumped into action in the normal cells treated with resveratrol.

"I think that the resveratrol experiments as well as our synthetic compounds … clearly puts to rest a lot of the controversy, well, ultimately all of the controversy regarding whether these compounds are directly activating SIRT1," George Vlasuk, the CEO of Sirtris, told FierceBiotech.

As Sinclair explained in an interview, the paper also sheds light on the potential mechanism of resveratrol on the SIRT1 target and plugs holes in previous studies that detractors had highlighted in their own critical assessments.

"I hope it restores confidence in the field and the ability to activate SIRT1 in drug development as a way to treat diseases of aging," Sinclair, a Sirtris scientific advisor, said. "I'm advising [GSK] and my advice would be to continue being optimistic about clinical trials. That's where the next big discovery will come from."

About those clinical trials: GSK's massive investment in Sirtris has yet to lead to a drug or a prime-time drug candidate. Sirtris has ended clinical development of multiple synthetic compounds after initial human studies, Vlasuk said. And his team is hunting for the precise mechanism for activating SIRT1 in hopes of creating more potent compounds than resveratrol to treat diseases.

If history is any guide, Sinclair's recent findings are unlikely to silence skeptics. And Sirtris/GSK faces long years of rigorous research before this nook of the anti-aging field yields a marketed drug.

"We're working on other ways to delay aging and hopefully make drugs that treat multiple diseases," Sinclair said. "This is not the final piece to the story by any means."

- read the press release
- get the Science abstract

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