By Chris Nelson with contribution from Brandon Tavshanjian
Resveratrol is a compound that gained a lot of notoriety in the mid-2000’s as sort of a multipurpose pro-health molecule. Early studies showed anti-aging, anti-inflammatory, and anticancer effects. Chemically, resveratrol (3,5,4′-trihydroxystilbene, shown below) belongs to a class of compounds called polyphenols, which are abundant in all kinds of plants; however, resveratrol is particularly rich in already popular foods like wine, chocolate, and peanuts. In its heyday, it spawned companies and a plethora of enthusiastic articles that recommended binging on resveratrol-containing chocolate and red wine as an all-purpose health enhancement. Interest has since waned on this compound, but it’s worth revisiting the story to see how an exciting, trendy scientific discovery can lose steam when scientists better understand its limitations.
A first hint of Resveratrol’s pro-health effects came in 2003 out of the lab of David Sinclair, a young investigator at Harvard. Sinclair’s lab found that resveratrol could extend lifespan in yeast. The extension was thought to be dependent on the protein Sir2, the founding member of a family of related proteins called sirtuins. There is a large body of literature on sirtuins in different organisms, and their mechanisms of healthspan extension in mammals are still actively researched and debated. Shortly after publishing the yeast lifespan extension, Sinclair launched Sirtris Pharmaceuticals, a company dedicated to producing sirtuin activators. A major landmark for resveratrol came when Baur et al. 2006 (with Sinclair as last author) reported that resveratrol could extend lifespan by 15% in obese mice.
The idea that small molecules could be used to extend healthspan was gaining excitement and attracting funding. A year later, Sirtris went public, eventually being bought up by pharma giant GlaxoSmithKline. The resveratrol supplement industry grew to have annual sales of $30 million in the US, with Dr. Mehmet Oz recommending a diet consisting of resveratrol-rich foods.
A wide array of potential benefits in humans have been posited, including cardiovascular benefits and reducing cancer risk. However, later reports led to questioning resveratrol’s benefits. Work out of the lab of Linda Partridge, a well-respected Drosophila researcher, was unable to reproduce earlier findings of lifespan extension in Drosophila and produced only variable effects in C. elegans. There has also been a broader controversy over the role of resveratrol’s reported target SIRT1. The same Partridge study found the variable lifespan extension in C. elegans happened independently of worm SIR-2.1.
A major stain on the field came in 2012, when resveratrol researcher Dipak Das was fired from UConn for allegedly committing 145 instances of scientific fraud including “fabrication and falsification of data”. At least 20 of Das’ papers have since been retracted. Much of Das’ work formed the basis for supposed cardioprotective benefits of resveratrol. As a result, resveratrol’s efficacy for this application is now in serious doubt, especially since Das’ death in 2013 makes it difficult to ever know the full extent of his fraud.
But even before the Das controversy, there were indications that people in the know had cooled on resveratrol related formulations as therapeutics, possibly due to inherent limitations with the compound. One of the co-founders of Sirtris left the company in 2011, and GlaxoSmithKline eventually shut down Sirtris and folded it into its broader business. This diminished industry interest in resveratrol may stem from two unfortunate issues: 1) research suggesting resveratrol does not act via SIRT1 makes it difficult to develop resveratrol into a drug; and 2) resveratrol is rapidly degraded by the liver after ingestion, making it naturally a poor drug. The first is an even bigger problem than it seems because FDA approval of new drugs requires knowing their mechanism of action. The second is a problem because it means it’s difficult to increase the levels of resveratrol in the body by taking a pill, and medicines usually need to be administered by pill for average patients to be able to use them.
To be fair, there is still a lot of literature published on resveratrol ( >1000 PubMed entries last year). For example a 2014 meta-analysis from Liu and colleagues suggests that high dose (>150 mg/d) resveratrol may lower systolic blood pressure. Unfortunately, much of this literature “is still as clear as mud”, according to aging researcher Brian Kennedy. The controversy and fraud allegations may always contribute to the lack of clarity on resveratrol’s effects and mechanism of action.