National Institutes of Health researchers have identified how resveratrol, a naturally occurring chemical found in red wine and other plant products, may confer its health benefits.

The authors 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.

The findings may help settle the debate regarding resveratrol's biochemistry and pave the way for resveratrol-based medicines to combat diabetes, inflammation, and cancer.

"Resveratrol has potential as a therapy for diseases such as Type 2 diabetes, Alzheimer's disease, and heart disease," says Jay H. Chung, MD, PhD, 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."

Several previous studies suggested that resveratrol's primary target is rolipram. Chung and colleagues suspected otherwise when they found that resveratrol activity required another protein, AMPK.

In the study, the researchers methodically 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 notes that because resveratrol in its natural form interacts with many proteins, not just PDEs, it may cause unknown toxicities as a medicine, particularly with long-term use. He adds that the levels of resveratrol found in wine or foods are not likely to be 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.

The study 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.

The study appears in Cell.

Release Date: Feb. 2, 2012
Source: National Institutes of Health