Resveratrol is a naturally occurring polyphenolic compound found in various plants, including in the skins of grapes, blueberries, raspberries, mulberries, and peanuts. Its association with red wine has contributed to the illusion of the "French Paradox": the observation that French people have a relatively low incidence of heart disease despite a diet rich in saturated fats. If you were alive in the 2000s, you may remember cheering at the news that drinking red wine would protect your heart and help you live longer.

Unfortunately, this claim is not true. Matt, who describes resveratrol as the "most debunked longevity molecule in history", spent several formative years of his scientific career in the depths of the resveratrol saga. Together with colleagues, and in parallel with other independent labs, he demonstrated that the apparent miracle powers of resveratrol were likely an artifact of the experimental methods used to test resveratrol-induced sirtuin activation, and that resveratrol actually had no significant lifespan-extending effects in vivo. In this episode, Matt presents a comprehensive analysis of the existing resveratrol literature, transports us to his earlier years of figuring the story out piece by piece with colleagues such as National University of Singapore Distinguished Professor of Biochemistry and Physiology Brian Kennedy, and shares his views on how bad science can have a profound influence on scientific fields, funding allocations, and public behavior.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

This paper really kicked off the sirtuin story. The paper's authors developed an assay—a test or an analysis done to figure out the amount or presence of a specific substance or component in a sample—to identify drugs to activate the SIR2 gene and/or sirtuins, a family of proteins that help regulate important processes like metabolism, DNA repair, and stress response in the body. They found that resveratrol and several other compounds activated sirtuins and made yeast live longer.

The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms

Matt and his colleagues published this 1999 paper that laid some of the groundwork for the previous foundational resveratrol paper. They showed that over-expressing the SIR2 gene increased lifespan by about 30 percent in baker's yeast, and that SIR2 was a key lifespan regulator. Other research groups have since reproduced this result in yeast.

Substrate-specific Activation of Sirtuins by Resveratrol

Matt and colleagues examined the effects of resveratrol on yeast SIR2 and found that the resveratrol-induced activation of yeast SIR2 was entirely dependent upon the presence of a particular fluorescent group. Without that group, resveratrol no longer had a significant effect on yeast SIR2 activity.

Mechanism of Human SIRT1 Activation by Resveratrol

This paper independently reproduced the findings of Matt and colleagues that resveratrol did not, in fact, affect sirtuin activation. Researchers tested the effects of resveratrol on three enzymes—yeast SIR2, human SIRT1, and human SIRT2—using the same assay that the authors of the original yeast life-extension-by-resveratrol paper developed and presented. They found that resveratrol activated only one of the enzymes, SIRT1. Crucially, it seemed that removing a particular fluorescent group removed the effect of resveratrol on SIRT1, suggesting that the finding was an artifact. The rather mild title of both this paper and Matt's may have contributed to the resveratrol story's persistence in the public consciousness for many years after these findings should have called the molecule's effectiveness as a lifespan extension tool into question.

Is red wine actually good for your heart?

Key research and much of the resulting hype about the finding that compounds such as resveratrol that are present in red wine encourage slower aging came from Harvard Professor in the Department of Genetics David Sinclair. But several publications from Harvard, including this blogpost from Harvard Health Publishing, have questioned whether red wine actually provides substantial health benefits.