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As our understanding of the aging process grows, researchers keep testing new ways to extend life span. Yet, the most effective anti-aging intervention, at least in animals, remains the same as fifty years ago: caloric restriction, a.k.a. eating less. For instance, if you feed mice about 30-40% less (in calories) than what they consume when fed without restrictions, the animals live up to two times longer and remain healthy throughout almost the entire lifespan.
The results of caloric restriction in humans are likely to be less dramatic and there may be risks if caloric restriction is too severe and/or initiated too early in life. Yet, most experts agree that a properly administered, mild variant of caloric restriction is likely to benefit both human health and longevity.
Obviously, there is a catch. Humans tend to avoid things that are hard to do, even if they are beneficial. For most of us, dramatically cutting food intake makes life too miserable to be worth extending. To counter this problem, researchers have been trying to figure out how caloric restriction extends life and whether the same mechanism can be engaged by other means.
They started with an obvious theory that caloric restriction extends life by reducing cell damage from free radicals, which are generated when cells burn nutrients in the mitochondria to produce energy. Indeed, a reduction in free radical levels does appear to have some role. But there's more. Caloric restriction seems to trigger some very specific cellular mechanisms of self-preservation whose biological role is to extend survival of the organism until food intake increases sufficiently to ensure successful reproduction.
Caloric restriction and sirtuins
In particular, one biochemical pathway triggered by caloric restriction involves a class of enzymes called sirtuins (named after the corresponding gene sir2). The main role of sirtuins is to selectively regulate the activity of many key genes responsible for metabolism, cell defense, reproduction and other functions. In a way, sirtuins are involved in switching the body from reproductive mode to survival, self-preservation and stress-resistance mode. (A brief technical aside: sirtuins are NAD-dependent histone deacetylases, the enzymes which inhibit the activity of genes by making DNA more tightly packaged and thus less accessible for the cell's gene-copying machinery.)
The discovery that sirtuins are partly responsible for the longevity and health effects of caloric restriction quickly lead to the search for sirtuin activating substances. A sirtuin activator could theoretically deliver many of the benefits of caloric restriction without the concomitant hardships. In the ultimate "have your cake and eat it too" scenario, a sirtuin-activating drug could trick your body into thinking it is starving while you may be scooping a chocolate sundae.
Resveratrol, the sirtuin activator
The good news is that one potential sirtuin activator has been found. The not-so-good news is that it is unclear whether we can take advantage if it yet. This potential sprinkler of youth is resveratrol, a well-known substance found in grapes and red wine. Several studies showed that resveratrol can activate sirtuins and extend lifespan in various species, from yeast to worms to rodents.
A particularly interesting study (published the prestigious journal Nature in 2006) was conducted by a team of Harvard scientists who tested the effects of resveratrol on obese mice. The researchers put two group of mice on a high calorie, high fat diet. One of the groups also received resveratrol. The diet started when the mice were a year old (a middle age in mouse terms). As expected, overfed mice in the first group soon became overweight, developed diabetes, fatty liver and other health problems. The mice in the other group, who received the same unhealthy diet plus resveratrol, did much better. While also overweight, the mice on resveratrol did not develop any of the health problems seen in the first group. And they lived longer too. Essentially, resveratrol neutralized the negative impact of excess caloric intake on health and longevity.
Unfortunately, it is unclear how these promising data on resveratrol apply to humans. Many questions remain. Would humans respond the same as mice? If they do, what would be the optimal human dose? In the above Harvard study, mice received 24 milligrams of resveratrol per kilogram of body weight per day. For an average human, this would translate to about 1700 mg of resveratrol a day. Even after adjusting for slower metabolism of humans compared to mice, the comparable human dose would likely be hundreds of milligrams a day. This is a far greater amount than what can be realistically consumed by drinking red wine, which contains between 1 and 3 mg of resveratrol per bottle. The safety of high doses of resveratrol in humans has not been studied. Also, resveratrol is unstable and oxidizes easily, which makes the manufacturing of bioactive, high-dose resveratrol supplement a complicated and expensive process. All of these questions need to be addressed before sirtuin activation via high-dose resveratrol can become a viable option. Some companies are working in that direction. Others are trying to find more effective and stable sirtuin activators, whether derived from resveratrol or not.
What can you reasonably do in the meantime to activate your sirtuins? Probably not much. There are numerous resveratrol supplements on the markets but the dosages are likely to be too small to be effective. Besides, the stability and quality of most resveratrol supplements is at best questionable.
Resveratrol as a skin care ingredient
Some experts argue that despite the above uncertainties, there may already be a limited way to benefit from resveratrol's ability to activate sirtuins - by applying it topically to the skin. Small oral doses of resveratrol are known to be safe - after all people have been eating grapes and drinking red wine for millennia. When applied to the skin, even small amounts may create a high enough local concentration to produce sirtuin activation in skin cells. Whether they actually do so is unclear.
Unfortunately, topical application of resveratrol carries some uncertainties beyond its potential effect on sirtuins. On one hand, resveratrol is an antioxidant and anti-inflammatory, both of which is generally good for the skin. Indeed, in one study in mice, resveratrol reduced some indicators of free radical damage induced by ultraviolet light. However, in another study, in human epidermal cell culture exposed to ultraviolet light, resveratrol increased a certain type of harmful DNA mutations. More research is needed to determine the net effect of resveratrol on the skin as well as optimal ways to apply it (if any). Those who wish to try topical resveratrol despite the above concerns should be extra careful in avoiding sun exposure, at least until more is known about resveratrol's potential to increase UV-induced mutations.
Commercial creams with resveratrol do exist even though the choice is limited. However, the concentration of resveratrol in these products is typically unknown. Furthermore, the instability of resveratrol makes creating a cream with appreciable shelf life and good biological activity very difficult. A do-it-yourself approach is more likely to deliver a viable formula because one can purchase a stabilized resveratrol extract and add the desired amount to a topical vehicle just before use - thus reducing the risk of degradation. Using an anhydrous vehicle may further increase the chances of creating a formula capable of activating sirtuins. I have been receiving requests to include a DIY formula for a resveratrol cream in my DIY Skin Care Infopack. However, I am reluctant to do that until more research about the risks and benefits of topical resveratrol is available. (If you wish to make a suggestion and/or provide feedback regarding this issue, please contact me).
Some companies claim to make creams containing sirtuins, thus allegedly by-passing the need for sirtuin activator. Considering that sirtuins are large and relatively unstable proteins, it would seem very difficult to make this approach work in practice. At his point, there is no evidence that products claiming to contain sirtuins are effective.
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