Scientists Reveal Molecular Secrets Behind Resveratrol’s Health Benefits

Resveratrol has been much in the news as the component of grapes and red wine associated with reducing “bad cholesterol,” heart disease and some types of cancer. Also found in blueberries, cranberries, mulberries, peanuts and pistachios, resveratrol is associated with beneficial health effects in aging, inflammation and metabolism.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have now identified one of the molecular pathways that resveratrol uses to achieve its beneficial action. They found that resveratrol controls the body’s inflammatory response as a binding partner with the estrogen receptor without stimulating estrogenic cell proliferation, which is good news for its possible use as a model for drug design.

The study was recently published as an accepted manuscript in the online journal eLife, a publication supported by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.

“Estrogen has beneficial effects on conditions like diabetes and obesity but may increase cancer risk,” said Kendall Nettles, a TSRI associate professor who led the study. “What hasn’t been well understood until now is that you can achieve those same beneficial effects with something like resveratrol.”

The problem with resveratrol, Nettles said, is that it really doesn’t work very efficiently in the body. “Now that we understand that we can do this through the estrogen receptor, there might compounds other than resveratrol out there that can do the same thing—only better,” he said.

“Our findings should lead scientists to reconsider the estrogen receptor as a main target of resveratrol—and any analogues,” said Jerome C. Nwachukwu, the first author of the study and a research associates in the Nettles laboratory. “It has gotten swept under the rug.”

In the new study, Nettles, Nwachukwu and their colleagues found that resveratrol is an effective inhibitor of interleukin 6 (IL-6), a pro-inflammatory protein that is part of the immune system (although IL-6 can be anti-inflammatory during exercise). High levels of IL-6 are also associated with poor breast cancer patient survival. According to the study, resveratrol regulates IL-6 without stimulating cell proliferation by altering a number of co-regulators of the estrogen receptor.

In addition to Nwachukwu and Nettles, other authors of the study, “Resveratrol Modulates the Inflammatory Response via An Estrogen Receptor-Signal Integration Network,” include Sathish Srinivasan, Nelson E. Bruno, Travis S. Hughes, Julie A. Pollock, Olsi Gjyshi, Valerie Cavett, Jason Nowak, Ruben D. Garcia-Ordonez , Patrick R. Griffin, Douglas J. Kojetin and Michael D. Conkright of TSRI; Alex A. Parent and John A. Katzenellenbogen of the University of Illinois; and René Houtman of PamGene International, The Netherlands. For more information, see http://elifesciences.org/content/early/2014/04/24/eLife.02057

The study was supported by the National Institutes of Health (grants PHS 5R37DK015556; 5R33CA132022, 5R01DK077085, 1U01GM102148, R01DK101871 and F32DK097890), the BallenIsles Men’s Golf Association, the Frenchman’s Creek Women for Cancer Research, the State of Florida and the James and Esther King Biomedical Research Program, Florida Department of Health (1KN-09).

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