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Low-dose resveratrol as a calorie restriction mimetic

Posted Jul 03 2008 4:12pm

Resveratrol, a natural product derived from grape skins and other plant sources, is widely (but notuniversally) believed to be an activator of the longevity assurance genes known assirtuins. Despite some debate about itsmechanism of action, the compound has received a great deal of attention as a possiblepharmaceuticalremedy for diseases of aging such as late-onsetdiabetes.

Most famously, resveratrol has been reported toincrease the median lifespanof mice fed a high-fat diet, but that study has been subject to numerous criticisms. The diet in question was so unhealthy it would have madeMorgan Spurlockblush, raising questions about its fairness as a model even for the most deranged Western diet. Furthermore, the quantity of resveratrol administered to the mice in the study corresponded to something like 1000 bottles of red wineper day. A skeptical reader could fairly claim that such a study, in which ridiculously high doses of a compound have an effect on an obscenely unhealthy animal, teaches us exactly nothing about what manageable doses of the same compound might accomplish in reasonably healthy people (which is, arguably, the point).

So: do manageable doses of resveratrol have health benefits — specifically, with respect to diseases of aging or aging itself? The first evidence in the affirmative has recently been published byBargeret al., who demonstrate that mice eating a normalad libitumcalorie-controlled* diet supplemented with resveratrol (at a much lower dose than in previous studies) undergo many of the same transcriptional changes as animals undergoing caloric restriction (CR):

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice

Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg/kg per day), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.

In addition to altered gene expression, the resveratrol-treated mice also exhibit delays in aging parameters (cardiovascular, endocrinological, metabolic) comparable to those caused by CR. The physiological and gene expression changes are observed in multiple tissues; taken together, they strongly support the hypothesis that resveratrol acts as a CR mimetic. Based on patterns of SIRT1 activity, however, the authors conclude that a subset of these changes (specifically, the delay in age-related cardiac decline) arenotdue to activation of SIRT1 by resveratrol.

The next question: Given that resveratrol and CR stimulate similar transcriptional changes, and that resveratrol yields some of the same physiological benefits as long-term CR, does low-dose resveratrol also have a favorable effect on median or maximum longevity? Based on these findings, I know how I’d bet, but for the ultimate answer, we’ll have to wait for the next paper.

*See Jamie Barger’s comment below.

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