Resveratrol Activity Not Limited to Sirtuin

BETHESDA, Md.Resveratrol, a component of red wine, may not confer its health benefits by just activating the longevity gene sirtuin 1, as previously thought. Researchers at the National Institutes of Health (NIH) found resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), which affect important energy-sensing metabolic regulators, including sirtuin 1 (Cell. 2012 Feb 3; 148(3): 387-89. DOI 10.1016/j.cell.2012.01.032).

Research on resveratrol shows it has anti-aging, anti-carcinogenic, anti-inflammatory and antioxidant properties; however, researchers have noted the effects of resveratrol supplementation on physiological responses in humans is still quite limited.

In this study, lead study author Jay H. Chung, M.D., Ph.D., chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood Institute, and colleagues suspected resveratrol's primary target was not sirtuin 1 when they found resveratrol activity required another protein called AMPK. This would not be the case if resveratrol directly interacted with sirtuin 1.

Therefore, the researchers traced out the metabolic activity in cells treated with resveratrol and identified PDE4 in the skeletal muscle as the principal target for the health benefits of resveratrol. By inhibiting PDE4, resveratrol triggers a series of events in a cell, one of which indirectly activates sirtuin 1.

To confirm that resveratrol attaches to and inhibits PDE proteins, Chung's group gave mice rolipram, a drug known to inhibit PDE4. Rolipram reproduced all of the biochemical effects and health benefits of resveratrol, such as preventing diet-induced obesity, improving glucose tolerance,and increasing physical endurance.

Chung noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities, particularly with long-term use. He added that the levels of resveratrol found in wine or foods are likely not high enough to produce significant health benefits or problems. Convincing clinical studies in humans have used about 1 gm of resveratrol per day, roughly equal to the amount found in 667 bottles of red wine.

"This result underscores the need for careful, well-controlled studies to illuminate how these natural products operate," said Robert Balaban, Ph.D., director of the NHLBI Division of Intramural Research. "As Dr. Chungs work suggests, the effects of resveratrol seem to be more complicated than originally thought. However, this new insight into the phosphodiesterases might prove an interesting avenue to pursue."