These results on obese mice reflect only one segment of the study. De Cabo and Sinclair are also studying the effects of resveratrol on mice on a normal diet and on mice on a calorie-restricted diet–a regimen of about 40 percent fewer calories than normal, but with adequate nutrition, which dramatically improves health and extends life span in mice and other animals such as fruit flies (see “A Clue to Living Longer”). The gene Sir2 is necessary for the benefits of calorie restriction in yeast, but the importance of its equivalents (called sirtuins) in mammals on the diet has not been demonstrated.
Sinclair says the hypothesis is that when given resveratrol, the health of mice on a normal diet will resemble that of mice on a calorie-restriction diet–just as the health of the mice on the high-fat diet resembles that of mice on a normal diet. Indeed, the health benefits of resveratrol in mice on a high-fat diet are in many respects similar to the health benefits of calorie restriction, although it’s unclear whether resveratrol and calorie restriction work by similar molecular mechanisms.
Weindruch, who heads a study of calorie-restriction diets in monkeys, says that although the study does not demonstrate a “100 percent creation of a calorie restriction-like state … it seems as if there is a significant overlap in the pathways that are being influenced.”
De Cabo says the National Institute on Aging will soon begin testing resveratrol on middle-aged rhesus monkeys on a high-fat diet. The study will not examine the compound’s effects on longevity (the monkeys live about 25 years in captivity) but will focus on health effects such as insulin sensitivity. Rhesus monkeys are much more closely related to humans than mice are, so if resveratrol has positive health effects in these primates, it probably will in humans, too.
The mice in the study were given high doses of resveratrol, but Sinclair says the levels given to the animals would be suitable for humans–although he says they are equivalent to hundreds of glasses of red wine. Resveratrol is currently available as a nutritional supplement, but because there hasn’t been much research on the compound in humans, it’s unclear whether there will be health benefits, and at what doses. Sinclair suspects that very high doses will be necessary.
Sinclair is a cofounder of Sirtris Pharmaceuticals (his research is independent of the company’s), which is conducting multiple clinical trials of resveratrol-like compounds for treating diseases including type II diabetes. Christoph Westphal, CEO of Sirtris, says that the research on aging processes by Sinclair and others “is now significantly mature to move into the clinic.” This was not the case only five years ago.
“In my short time as a gerontologist I have seen many compounds that look promising but that fall through in the end,” says de Cabo. He, like most others in his field, is “quite pessimistic about finding a golden bullet,” so he was skeptical when Sinclair approached him to collaborate on the resveratrol research. “But it has pluripotent [health] effects,” de Cabo says, and he has been pleasantly surprised by their results.