A compound found in red grapes called resveratrol improves the health and lifespan of mice on a high-calorie diet. This is potentially good news for overweight humans. Does it bode well for the rest of us too?
Bacchus (Dionysus to the Greeks) has been long out of style, but may be granting new favours — particularly if you long to be one of those people who can seemingly eat whatever they want, whenever they want, without having to worry about the consequences. A paper by Baur et al.1 on page 337 of this issue suggests that guilt-free gluttony might not be a fantasyFootnote 1.
In this report, mice fed a diet akin to coconut cream pie for every meal showed a striking increase in survival and health when their chow was supplemented with resveratrol, a polyphenolic compound found in red grapes or wine. Compared with animals fed a more standard diet, mice fed the high-calorie (60% from fat) diet without resveratrol had a shorter lifespan. They also showed many of the problems that plague humans who overindulge at the dinner table, including obesity, insulin resistance and heart disease. Baur et al. found that although resveratrol did not prevent obesity, it did prevent obesity-associated disease, at least in one strain of mouse, and conferred a nearly normal lifespan on these mice.
With the present epidemic of obesity in some Western societies, this could be very good news. But might resveratrol improve health or lifespan beyond that achieved with a healthy diet? The link between diet and longevity has been known to gerontologists since the discovery in the 1930s that reduced caloric intake can increase the lifespan of rodents by up to 50%. Dietary restriction has since been observed to have a similar effect on longevity in many different organisms, including yeast, worms, flies, spiders and fish. Importantly, dietary restriction not only increases lifespan, but it also delays the onset of nearly all age-associated diseases. For this reason, most gerontologists believe that dietary restriction affects the intrinsic ageing process at a fundamental level. The genetic pathways influencing this phenomenon are currently a hot topic of research and debate.
Like dietary restriction, resveratrol has long been known to have interesting properties. During the 1990s it was extensively studied as a potential link between improvements in a variety of health indicators and moderate consumption of red wine2. The antioxidant properties of resveratrol, in particular, have been suggested to account for many of its beneficial properties, including putative cardio-protective and anticancer activities, as well as providing protection against liver failure. Here it is noteworthy that Baur et al.1 show that resveratrol has a profound ability to prevent liver damage associated with the high-fat diet.
Resveratrol became of particular interest to gerontologists with the report3 that it can increase lifespan in yeast by activating particular enzymes (protein deacetylases) of the Sir2 family of proteins (sirtuins). Sirtuins are evolutionarily conserved mediators of longevity that might also play a role in lifespan extension through dietary restriction4. Although the results from the initial study of resveratrol in yeast remain controversial5, subsequent work has suggested that resveratrol has modest effects on lifespan in both worms and flies6, and a more substantial effect on lifespan in a short-lived fish7. Based on these findings, it has been proposed that resveratrol increases lifespan in several different organisms by a mechanism similar to dietary restriction8.
Baur et al.1 favour the view that many (perhaps all) of the beneficial properties of resveratrol are the result of increased sirtuin activity, and various studies have supported the idea that sirtuins underlie the effects attributed to resveratrol in vivo8. However, there is a surprising lack of biochemical evidence that resveratrol directly increases sirtuin-mediated deacetylation of biologically relevant substrates, and some evidence that it may not5,9. Resveratrol is also known to interact with numerous proteins and pathways, including mitochondrial ATP synthase and complex III, fatty-acid synthase, protein kinase C, p53, MEK1, TNF-α and NF-κB, all of which are candidates for mediating its in vivo effects. In particular, activation of AMP kinase by resveratrol protects against atherosclerosis and liver damage in diabetic mice10, suggesting a likely mechanism for the observations reported by Baur and colleagues.
Given the available data, it is difficult to predict the answers to a few key questions. Will resveratrol have an effect on health and longevity in mice fed a standard diet, rather than a high-calorie diet? Will it be effective in mice with genetic backgrounds other than the inbred strain used in the current report? Will it be effective in humans? Studies addressing these questions are under way: the answers will go some way towards determining whether or not resveratrol is a bona fide dietary-restriction mimetic.
Many people will wonder whether they should start supplementing their diets with resveratrol. After all, it is generally regarded as safe, and can be purchased over the Internet with promises of improved health and longevity. Our advice is to exercise caution. The safety of resveratrol at the high doses in humans comparable to those used by Baur et al.1 is unknown, especially over the course of years or even decades, when relatively modest side effects could have dramatic consequences. A logical next step would be to initiate controlled studies to find out whether resveratrol can safely reduce the ill-effects associated with diabetes or obesity in humans.
In the most optimistic assessment, a true mimetic of dietary restriction could be effective against many age-associated human diseases, including heart disease, diabetes, cancer and neurological disorders such as Alzheimer's disease. Even if resveratrol doesn't make the grade, it is not the last hope of gerontologists, or necessarily even the best. Studies of several other compounds are under way in multicentre studies of mouse ageing sponsored by the National Institute on Aging11. These include potent antioxidants and compounds targeting other pathways thought to influence lifespan extension through dietary restriction.
For now, we counsel patience. Just sit back and relax with a glass of red wine — which, alas, has only 0.3% of the relative resveratrol dose given to the gluttonous mice (note also that increasing the dose via wine will not be healthy). But if you must have a Big Mac, fries and apple pie, we may soon know if you should supersize that resveratrol shake.
*This article and the paper concerned1 were published online on 1 November 2006.
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