It has been known for years that caloric restriction, limiting an animal or person to 60% of its normal caloric intake while providing all essential vitamins and minerals, can promote a long life. In the modern era, where portion sizes are expanding, not getting smaller, putting people on such a restrictive diet would be challenging, though a few highly motivated people have maintained this type of diet long-term [1]. Fortunately, scientists may have uncovered an easier way to extend lifespan. Scientists first reported over fifteen years ago that the molecule resveratrol, present at low concentrations in red wine, mimicked the lifespan-extending effects of caloric restriction in yeast.

Figure 1. The chemical structure of resveratrol, a small molecule found in red wine and believed to prolong life. (Click image to enlarge.)

If resveratrol were able to mimic the lifespan-extending effects of caloric restriction in people without requiring such an extreme diet, it would be very popular, especially if it gives people an excuse to drink more wine! However, to consume enough resveratrol to benefit from the life-extending effects seen in yeast, the average person would have to drink 1000 bottles of wine per day, an endeavor with consequences that would far outweigh the lifespan-extending effects of resveratrol. To work around this problem, scientists have tried to package resveratrol as a concentrated pill. This would allow people to get the resveratrol dose needed for lifespan extension without consuming excessive amounts of wine. Unfortunately, resveratrol is not very potent and humans require high doses of it, even in a concentrated pill form. A clinical trial of resveratrol in humans was underway but was halted in late 2010 [2]. The clinical trial showed that calculating an appropriate dose of resveratrol that was both effective and stable in human blood proved too challenging for the drug to be feasibly used. More recently, scientists have set out to find resveratrol-like drugs that are active at much lower concentrations and more stable in the bloodstream over time. The pharmaceutical company Sirtis, based in Cambridge, MA, is the main developer of these new molecules.

Scientists have shown that resveratrol and resveratrol-like molecules may prolong life, but how might they do this? For many years, scientists believed these molecules worked by binding and activating a protein – part of the cell’s molecular machinery – known as SIRT1. Studies in model organisms like yeast and worms found that low-calorie diets stimulated activity of this protein. At first, it seemed that resveratrol-like molecules mimicked the effects of low-calorie diets using the same mechanism [2], but recent studies question this finding [3]. Two groups of scientists independently tried to replicate the experiment that had originally linked resveratrol and SIRT1, but both groups found that the experiment was flawed. What looked like an interaction between resveratrol and SIRT1 may have simply been an artifact of the way the original experiment was designed. There is insufficient evidence that resveratrol binds SIRT1, but scientists lack good alternative hypotheses for how resveratrol might work if it doesn’t work through SIRT1.

Whether or not we understand the mechanism, experimental evidence still suggests that resveratrol-like molecules prolong lifespan in healthy animals. Because these compounds seem to mimic the beneficial effects of caloric restriction in animals and allow them to live longer, healthier lives, scientists hypothesized that they might protect against the consequences of obesity and diabetes, two diseases associated with aging and high-calorie diets.

A recent study tested the effects of one of these resveratrol-like molecules (SRT1720) on mice that were fed a high-fat “Western” diet, and found that SRT1720 increased both the average and maximum lifespan of these mice [4,5]. Obese mice taking the compound fared better than obese mice not taking the compound, though even the “healthier” obese mice did not live as long as mice on a normal chow diet. Interestingly, mice on the high-fat diet gained the same amount of weight and consumed the same number of calories whether they were taking SRT1720 or not, which means SRT1720 does not prolong life by suppressing appetite. In comparison to previous studies that had cast doubt on the effectiveness of SRT1720 and similar compounds, these scientists reported no toxicity, and were able to see an effect at doses that could theoretically be effective in humans [6].

This most recent finding suggests that we may eventually be able to counteract some of the detrimental effects of obesity and diabetes by taking a pill, which could in turn have lifespan-extending benefits. But with new and contradictory reports appearing all the time, it will likely be years before the safety and effectiveness of such a “magic pill” are established. For now, moderation in diet and an active lifestyle may still be the best way to stay healthy.

Laura Strittmatter is a graduate student in the Harvard Chemical Biology program.

References

[1] “One for the Ages: A Prescription That May Extend Life” (Michael Mason, New York Times)

[2] “Doubt on Anti-Aging Molecule as Drug Trial Stops” (Nicholas Wade, New York Times)

[3] “The Sirtris Compounds: Worthless? Really?” (Derek Lowe, In the Pipeline)

[4] “Longer Lives for Obese Mice, With Hope for Humans of All Sizes” (Nicholas Wade, New York Times)

[5] “SRT1720 improves survival and healthspan of obese mice” (Robin K Minor et. al., Scientific Reports)

[6] “SRT1720: Good (And Confusing) News for Obese Mice” (Derek Lowe, In the Pipeline)