Red Wine Chemical Redeemed?

Resveratrol, a natural product most famously present in red wine, has been in the headlines for a decade, ever since scientists reported that it activates a pathway linked to antiaging effects.

Whether and how the molecule elicits those effects is a controversial topic, however. And as efforts progress to make drugs that mimic resveratrol’s actions, the debate has heightened.

A new study shows that a much-maligned approach for finding res­veratrol mimics—an essential task for confirming the antiaging mechanism—actually does work (Science, DOI: 10.1126/science.1231097). The study was carried out by researchers with a significant financial stake in making resveratrol-like drugs, a group led by David A. Sinclair of Harvard Medical School. Coauthors include researchers from Sirtris Pharmaceuticals, the company Sinclair cofounded to combat cardiovascular, neurodegenerative, and other diseases of aging, and from GlaxoSmithKline, which bought Sirtris for $720 million in 2008.

Sinclair and others believe resveratrol’s benefits come from activating sirtuin enzymes, which clip acetyl groups from proteins, thus regulating a host of aging-associated genes. Much of the evidence came from a screen that used fluorescent peptide substrates for the enzyme.

But several groups have reported that resveratrol activates sirtuins only in the presence of fluorescent substrates, which are not found in the body. That cast doubt on whether this path is used in nature. Another group of researchers has reported that resveratrol uses a different route through phosphodiesterase enzymes.

“We hypothesized that the fluorescent groups were substituting for something natural in the body,” Sinclair says. “We just needed to find what that was.” Sure enough, he found that substrates with a large, hydrophobic amino acid such as tryptophan—which can resemble a fluorophore—help resveratrol activate a sirtuin called SIRT1.

However, “there are major questions about what the biological effects of resveratrol are and to what extent those are mediated by sirtuins,” and this study doesn’t really address them, says Matt R. Kaeberlein, a biologist who studies resveratrol at the University of Washington.

Sinclair’s team thinks resveratrol and synthetic activators induce a change in sirtuin shape that helps substrates bind to the enzyme’s active site. The exact mechanism isn’t clear, but they uncovered one glutamate residue on SIRT1 that is critical for resveratrol to work. They think pursuing this mechanism could lead to drugs for diabetes, inflammation, and beyond.

“With any drug program you’re going to be concerned about what the target is,” says Leonard P. Guarente of MIT. Guarente is a scientific adviser to Sirtris. This work, he says, convincingly shows that SIRT1 is the direct target of both resveratrol and synthetic activators. GSK halted clinical trials on resveratrol in 2010 after some patients developed kidney failure, but synthetic sirtuin activators are being evaluated in human volunteers as potential treatments for diseases such as Type 2 diabetes and psoriasis.

Skeptics, though, remain. Jay H. Chung, whose NIH lab showed resveratrol acts directly on phosphodi­ester­ases, not sirtuins, would like to see the team repeat their results with full-length SIRT1 substrates from nature. The peptides used in the current study may behave differently, he cautions.

Saying that sirtuins are or are not resveratrol’s target is an oversimplification, Kaeberlein adds. “The reality is probably somewhere in the middle,” with some biological effects because of sirtuin activation and some from other pathways.

“Does resveratrol activate SIRT1? A qualified yes,” says David R. Finkelstein of the National Institute on Aging. He commends the team for clarifying the confusion around their fluorescent assay. “Now, is that the only thing resveratrol does? I would be surprised.”