A new study by nine universities and government organizations led by David Sinclair of Harvard Medical School supports the hypothesis that the metabolic benefits of the red wine ingredient known as resveratrol are largely due to its actions on the SIRT1 gene.

“Resveratrol improves the health of mice on a high-fat diet and increases life span,” said David Sinclair of Harvard Medical School. The question was how.

By producing mice in which the SIRT1 gene can be completely turned off in adults, the researchers discovered that those SIRT1-deficient adult mice don’t enjoy the benefits of resveratrol.

Dosage effects resolved

The study also provides insight into another important aspect of the resveratrol controversy. Doubts had arisen in part because the red wine ingredient seems to act in different ways at different doses. The study by Sinclair and colleagues clears those details up, too. They show that resveratrol targets SIRT1 directly at moderate doses and hits other targets at higher ones. Importantly, SIRT1 is required for resveratrol’s benefits irrespective of dose. Based on the findings, Sinclair emphasizes the value of finding the lowest effective dose of resveratrol, and perhaps any drug, to avoid off-target effects.

George Vlasuk, CEO of Sirtris, who was not involved in the new study, says the findings offer the “first definitive evidence” for a direct link between SIRT1 and the metabolic benefits of resveratrol.

“The work by Price et al. strongly supports the basic rationale being pursued at Sirtris, which focuses on the development of small-molecule compounds that directly activate the enzymatic activity of SIRT1 as a new therapeutic approach to many diseases of aging,” Vlasuk wrote in an email.

Ref.: Nathan L. Price, et al., SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function, Cell Metabolism, 2012; DOI:10.1016/j.cmet.2012.04.003