Resveratrol, a compound found most famously in grapes and red wine, seems to ward off several age-related diseases. However, its mechanism of action has been elusive. Researchers have now found a direct molecular target for the compound. The finding may lead to drugs that can prevent certain age-related health problems.

People can develop a variety of metabolic diseases as they age, including type 2 diabetes and heart disease. In animal studies, severely restricting calories can help prevent these diseases. Over the last decade, scientists have found that resveratrol mimics calorie restriction in some ways. It seems to affect the activity of proteins called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process.

Recent studies uncovered intermediate steps between resveratrol and sirtuins. A key step in this pathway is an enzyme called AMPK, which regulates energy levels in the cell. However, the link between resveratrol and AMPK has been a mystery. To investigate, a research team led by Dr. Jay H. Chung of NIH's National Heart, Lung and Blood Institute (NHLBI) set out to find resveratrol's target.

The researchers methodically traced metabolic activity in cells treated with resveratrol. They were able to identify an enzyme called PDE4 in the skeletal muscle as the principal target for the health benefits of resveratrol. Resveratrol inhibits PDE4, which raises levels of an important cell signaling molecule called cAMP. Levels of cAMP normally rise when cells get the signal that blood glucose levels are low. Resveratrol thus activates one of the same biochemical pathways as a low-calorie diet. This pathway ultimately activates AMPK and sirtuins.

To confirm their findings, the scientists gave mice rolipram, a drug known to inhibit PDE4. Like resveratrol, the drug protected mice from the ill effects of a high-fat diet. Mice on a high-fat diet normally become obese and develop glucose intolerance, a hallmark of type 2 diabetes. Mice given the drug stayed healthy.

As this study shows, the biochemical pathways affected by resveratrol are complex and far-reaching. As a natural product, resveratrol likely has additional targets, which could lead to side effects. These findings may now help researchers design effective drugs without those potential problems.

Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimer’s disease and heart disease,” says Chung. owever, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells.

A PDE4 inhibitor that is 30,000 times more potent than resveratrol has recently been approved by the FDA for treating chronic obstructive pulmonary disease. Chung's group is now planning a clinical trial to test the inhibitor in obese people at risk for developing type 2 diabetes.

• 
  http://www. nih. gov/researchmatters/november2006/11102006mice.
• 
  http://www. nhlbi. nih.
• 
  http://www. nih. gov/news/radio/feb2012/20120202NHLBIresveratrol.