A Life-Extending Pill for Fat Mice
A compound found in red wine keeps middle-aged mice on a high-fat, high-calorie diet as healthy as mice on a healthy diet, according to research at the National Institute on Aging and Harvard Medical School.
The compound, called resveratrol, also improves the mice’s survival rates, extending them to the same lengths as those of mice on a healthy diet. These preliminary results may demonstrate resveratrol’s ability to activate molecular pathways thought to be critical regulators of the aging process. Indeed, the researchers say the mouse study is the first demonstration in mammals of the activation of known genetic pathways affecting life span by a drug–a good sign for researchers and pharmaceutical companies that hope to treat the diseases of aging by developing drugs that intervene in these pathways.
Human obesity is associated with a higher risk of diabetes and heart disease, and of age-related diseases such as cancer. Mice on a high-fat, high-calorie diet have similar problems: the control group in this study exhibited elevated blood levels of glucose and insulin (early signs of diabetes), fatty livers, unhealthy hearts, relatively poor motor coordination, and changes in gene-expression patterns that correlate with unhealthy diets.
Treating mice on such an unhealthy diet with resveratrol starting in middle age appeared to alleviate the negative health effects of obesity, although the mice did not lose weight. They have healthy livers and hearts, and their insulin sensitivity is comparable to that of mice on a healthy diet, as are their motor skills. And “most amazingly,” says Rafael de Cabo, a head researcher on the project and also a researcher in gerontology at the National Institute on Aging, resveratrol reverses almost all of the diet-induced changes in gene expression–changes that may contribute to heart disease, cancer, and other maladies.
While the life-extending effects of resveratrol have previously been demonstrated in yeast, roundworms, fruit flies, and fish, this is the first comprehensive demonstration of the compound’s health benefits in mice. The mice in the study are currently 27 to 28 months old; their life expectancy is 32 to 36 months, and time will tell whether resveratrol increases the maximum life span of the mice on the high-fat diet. However, according to research published in the journal Nature, the survival rates of the resveratrol-treated mice on the high-fat diet are comparable to those of mice on a normal diet (at 114 weeks old, 42 percent of both groups had died), while more mice in the high-fat, no-treatment group have died (at 114 weeks old, 58 percent had died).
“Overall, the results are quite striking,” says Richard Weindruch, professor of medicine at the University of Wisconsin-Madison, who studies the effects of low-calorie diets on life span and health (see “The Fountain of Health” and “Do Dieting Monkeys Live Healthier and Longer Lives?”). He says the study demonstrates “a rather remarkable effect of resveratrol to oppose a highly toxic diet.”
There have been some previous scientific reports of the beneficial health effects of red wine and resveratrol supplements in humans. “This was not a molecule we just pulled off the shelf,” says David Sinclair, the associate professor of pathology at Harvard who headed the study with de Cabo. Sinclair’s previous research has demonstrated that in yeast, resveratrol extends life span, and that it activates a gene called Sir2, a master regulator of aging in these organisms. The mouse study takes the next step, says Sinclair, asking, “Is there any hint [that] resveratrol can improve health in mammals?”
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.
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