Scientists Unlock Secret of Resveratrol

BETHESDA, Md.Scientists have discovered how resveratrol, a naturally occurring chemical found in red wine and other plant products, may impart health benefits, a finding that may one day lead to resveratrol-based medicines, according to a study published in the journal Cell.

National Institutes of Health researchers found evidence that resveratrol does not directly activate sirtuin 1, a protein associated with aging. Rather, resveratrol inhibits certain types of proteins known as phosphodiesterases (PDEs), enzymes that help regulate cell energy.

Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimers disease, and heart disease," said 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. However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells."

Previous studies suggested resveratrols primary target is sirtuin 1; however, the researchers found resveratrol activity required another protein called AMPK. This would not be the case if resveratrol directly interacted with sirtuin 1.

For the study, 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, the researchers 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.

The researchers noted that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause not-yet-known toxicities as a medicine, particularly with long-term use. 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.

Results also suggest that inhibitors of PDE4 may offer the benefits of resveratrol without the potential toxicities arising from resveratrol's interactions with other proteins. One PDE4 inhibitor called roflumilast has already been approved by the FDA for the treatment of COPD (chronic obstructive pulmonary disease).