Resolving Confusion About Resveratrol

Chalk up the red wine compound resveratrol’s presumed health benefits to a direct blockade of phosphodiesterase enzymes, reports a multi-institution team (Cell, DOI: 10.1016/j.cell.2012.01.017). The researchers, led by NIH biologist Jay H. Chung, say their study clarifies confusing evidence about the biochemistry of resveratrol.

The study’s results point to new avenues of preventing age-associated metabolic diseases in people, says University of Wisconsin, Madison, calorie restriction researcher Richard Weindruch, who was not involved in the NIH research. In principle, preventing such diseases could extend human life spans.

Resveratrol is known to mimic the antidiabetic effects of calorie restriction in rodents, and it boosts life span in flies and worms. Whether resveratrol is beneficial to humans is not clear, but a recent study suggests it also mimics the effects of calorie restriction in obese people (Cell Metab., DOI: 10.1016/j.cmet.2011.10.002).

Resveratrol was thought to work in animals by directly activating sirtuin enzymes, which clip acetyl groups from proteins, researchers say. From that idea grew Sirtris, a biotech company that GlaxoSmithKline acquired for more than $700 million in 2008. Since then the sirtuin claim has come under heavy scrutiny as scientists have found that they can’t reproduce the earlier pro-sirtuin evidence.

Chung and coworkers previously learned that resveratrol also activates an important regulatory kinase enzyme but didn’t know how that occurred. From cellular assays and animal tests, they now show that resveratrol increases levels of cyclic AMP, which activates the kinase downstream. The cyclic AMP boost happens, they conclude, because resveratrol blocks phosphodiesterase enzymes that break down cyclic AMP. Resveratrol does indeed activate sirtuin enzymes, Chung says, but indirectly, further downstream in the phosphodiesterase-mediated pathway.

This work points to one pathway resveratrol may use to activate sirtuins but doesn’t prove it’s the only pathway, adds sirtuin expert and Sirtris scientific advisory board cochair Leonard P. Guarente at MIT.

Chung notes that it is impossible to prove that no other mechanism exists but says when his team blocked the key phosphodiesterase enzyme in muscle, it completely reproduced resveratrol’s effects. This strongly suggests that when it comes to metabolic effects, “the phosphodiesterase pathway is the major pathway,” he says.

The Chung team’s results come on the heels of a massive research misconduct investigation of University of Connecticut researcher Dipak K. Das, whose work reported definitive human health benefits from resveratrol.