Researchers have demonstrated what they consider conclusive evidence that the red wine compound resveratrol directly activates a protein that promotes health and longevity in animal models. Furthermore, the Harvard Medical School team uncovered the molecular mechanism for this interaction, and they show that a class of more potent drugs currently in clinical trials acts in a similar fashion.
Pharmaceutical compounds similar to resveratrol may potentially treat and prevent diseases related to aging in people, the researchers contend. Studies over the last decade have demonstrated that resveratrol, a compound found in the skin of grapes as well as in peanuts and berries, increases the activity of a specific sirtuin, SIRT1, that protects the body from diseases by revving up the mitochondria. Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging. In experiments with yeast, nematodes, bees, flies, and mice, lifespan has been extended.
"In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1," says David Sinclair, Harvard Medical School professor of genetics and senior author on the paper. "Almost all drugs either slow or block them."
The authors thus propose a model for how resveratrol works: When the molecule binds, a hinge flips, and SIRT1 becomes hyperactive. Although these experiments occurred in a test tube, once the researchers identified the precise location of the accelerator pedal on SIRT1—and how to break it—they could test their ideas in a cell. They replaced the normal SIRT1 gene in muscle and skin cells with the accelerator-dead mutant. Now they could test precisely whether resveratrol and the drugs in development work by tweaking SIRT1 (in which case they would not work) or one of the thousands of other proteins in a cell (in which they would work). While resveratrol and the drugs tested revved up mitochondria in normal cells (an effect caused activating by SIRT1), the mutant cells were completely immune.
"There is no rational alternative explanation other than resveratrol directly activates SIRT1 in cells,” says Sinclair. “Now that we know the exact location on SIRT1 where and how resveratrol works, we can engineer even better molecules that more precisely and effectively trigger the effects of resveratrol."