Should you take resveratrol?

Resveratrol has been the most overhyped supplement of the last decade. It has also produced one of the more useful cautionary tales in modern translational science. Worth a clean look.

The setup

In the early 2000s, David Sinclair’s lab at Harvard published a series of papers linking resveratrol, a polyphenol found in red wine grapes, to activation of a class of regulatory proteins called sirtuins. Sirtuins, particularly SIRT1, had been implicated in the longevity benefits of caloric restriction in lower organisms. The pitch was that resveratrol would mimic caloric restriction without requiring you to eat less. A small molecule that lets you have your cake and live longer.

The marketing wrote itself. Resveratrol became, in different versions of the story, a fountain of youth, a telomerase activator, a telomerase inhibitor, an anticancer compound, and a heart disease preventive. Hundreds of millions of dollars in supplement sales followed. Dr. Oz did segments on it. Sinclair sold his company Sirtris to GlaxoSmithKline for roughly 720 million dollars in 2008, one of the largest payouts in biotech history.

What happened next

GSK ran the larger trials. The resveratrol effect did not replicate in humans at clinically relevant doses. Several of the original Sinclair lab findings on sirtuin activation by resveratrol were challenged in subsequent independent work. The proposed mechanism, direct SIRT1 activation by resveratrol, was reanalyzed and found to be largely an artifact of the fluorescent peptide substrate used in the original assays. GSK eventually shut down the Sirtris division in 2013. The dream of a small-molecule caloric-restriction mimetic via this pathway did not hold.

Some of the Sirtris executives, while still affiliated with GSK, were criticized for selling their own resveratrol product online during the same period the trials were underway. The optics were bad. The science was not what had been promised.

What resveratrol actually is

Resveratrol is a polyphenol with real antioxidant activity. It modulates a class of signaling molecules called adipokines, which influence energy metabolism, glucose handling, and stress response. It has cardioprotective signals in some studies and not others. It is not, as far as I have been able to verify, either a meaningful telomerase activator or a telomerase inhibitor at doses humans actually take. I have personally tested this question with help from Bill Andrews’ lab at Sierra Sciences. The signal was not there.

Could resveratrol have indirect benefits on telomere health via reduced oxidative stress and improved metabolic profile? Probably, modestly, in people who would benefit from any antioxidant supplementation. Is it the longevity molecule it was sold as? No.

What the sirtuin story tells us

The sirtuins are a real family of regulatory proteins. There are seven mammalian sirtuins, SIRT1 through SIRT7. They do real work in metabolism, DNA repair, and stress response. SIRT6 in particular has emerging human longevity associations from a few cohort studies. The connection between sirtuins and telomere length is also real, and the directionality has gone the other way from what was originally proposed. Telomere health appears to influence sirtuin expression, not the other way around.

This matters because it suggests that telomere maintenance is upstream of several of the pathways that the resveratrol story was trying to capture downstream. If you want to influence sirtuin activity at scale, addressing telomere health is probably more productive than chasing direct sirtuin activators.

Where this leaves a sensible adult

Resveratrol is fine as one piece of a polyphenol-rich intake. A glass of red wine, dark berries, dark chocolate, and a mix of colorful plants will get you more total polyphenol diversity than any single supplement. If you take a resveratrol supplement, it will probably not hurt you, and it will probably not produce the effects the early marketing promised.

What I would put my money on, in the same general anti-aging budget, is omega-3 status, vitamin D adequacy, a real multivitamin with active B vitamins, CoQ10 in ubiquinol form for people over 50, and for those for whom budget allows, TA-65. The case for those interventions has aged considerably better than the case for resveratrol.

That is not a knock on Sinclair’s work. The questions he was asking were good ones. The answers turned out to be more complicated than the headlines suggested. That is most of science.

— Doc