Editors' ChoiceMetabolism

Resurrecting Resveratrol

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Science Translational Medicine  07 Dec 2011:
Vol. 3, Issue 112, pp. 112ec197
DOI: 10.1126/scitranslmed.3003536

Although a glass of wine a day might not keep the doctor away, a compound found in grapes and red wine called resveratrol might mimic the health effects of calorie restriction. Indeed, a 30 to 50% reduction in caloric intake significantly decreases the risk of cancer and cardiovascular disease in a variety of model systems. Resveratrol is thought to have an effect on the expression of sirtuin 1 (SIRT1), which encodes a protein deacetylase and plays a role in a variety of metabolic pathways. With pleiotropic effects that range from improved endothelial function and insulin sensitivity to reduced blood pressure, resveratrol has generated tons of attention as a potential antiaging compound. Recently, however, conflicting data have cast doubt on the clinical utility of this highly touted and widely used supplement. In an effort to add clarity, Timmers et al. now measure the metabolic effects of resveratrol on 11 healthy obese male patients.

The 4-week crossover design of the study enabled each subject to serve as their own control, limiting the confounding heterogeneity between control and treatment groups that is inherent in typical clinical studies. Adequate plasma concentrations of resveratrol were confirmed to ensure regimen adherence and appropriate bioavailability of the drug. Notably, resveratrol treatment resulted in a drop in systolic blood pressure, improved insulin sensitivity, and reductions in serum concentrations of triglycerides, glucose, and common inflammatory cytokines. Muscle, adipose, and liver biopsy specimens from subjects revealed a decrease in liver fat accumulation and an increase in fatty acid catabolism, metabolic effects that also are seen in patients who have undergone significant weight loss. Gene expression data from muscle biopsies showed up-regulation of numerous mitochondrial oxidative phosphorylation genes. In addition, resveratrol-treated subjects showed an increase in phosphorylation of adenosine 5´-monophosphate–activated protein kinase (AMPK); this finding is consistent with previous studies that demonstrate that phosphorylated AMPK mediates the pleotropic effects of resveratrol on mitochondrial function.

Although encouraging, these data only partially address the glaring deficiencies in the scientific literature on resveratrol’s effects on health span. Foremost, the authors fail to state whether statistical correction for multiple hypotheses was performed, which would involve a simple division of the P value of the phenotype tested by the number of tests performed. Accordingly, several of the P values that showed statistical significance may be false positives. Further, findings such as reduced energy expenditure in resveratrol-treated patients are in opposition with earlier data from mouse models. Last, the small number of patients and short study duration further skew the data and call into question the study results. Therefore, additional large-scale data will be required before we can resurrect resveratrol from the pharmaceutical graveyard.

S. Timmers et al., Calorie restriction–like effects of thirty days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metabol. 14, 612–622 (2011). [Abstract]

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