Resveratrol (3,5,4′-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
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We thank H. Rasnow for his donation towards purchasing the mice; V. Massari for help with electron microscopy; W. Matson for HPLC assays of resveratrol; M. Chachich and M. Tatar for help with statistical analysis; W. Wood for microarray assistance; D. Phillips for animal care; J. Egan’s group for insulin measurements; the Sinclair laboratory, N. Wolf, P. Elliott, C. Westphal, R. Weindruch, P. Lambert, J. Milne and M. Milburn for advice on experimental design; and S. Luikenhuis and M. Dipp for critical reading of the manuscript. D.A.S. was supported by The Ellison Medical Research Foundation, J.A.B. by The American Heart Foundation, H.J. and D.LeC. by an Australian NHMRC project grant and an NHMRC post-graduate scholarship, and C.L. and P.P. by the American Diabetes Association and NIH. This research was supported (in part) by the Intramural Research Program of the NIH, NIA, a Spanish MCyT grant to P.N., NIH grants to D.A.S., and by the support of P. F. Glenn and The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging.
Author Contributions All experiments were designed and carried out by J.A.B., K.J.P., R.deC. and D.A.S. with the exceptions noted below. D.K.I. assisted with the design and interpretation of experiments. N.L.P., A.K., J.S.A., K.L. and P.J.P. assisted with the handling of animals and behavioural studies. Electron microscopy was performed by H.A.J. and D.LeC. Computational methods for analysis of microarray data were developed and applied by V.V.P. and K.G.B. Analysis of PGC-1α acetylation was performed by C.L. and P.P. Pathological assessments were made by S.P. (livers), M.W. and E.G.L. (hearts and aortas). In vitro AMPK reactions were performed by D.G. and R.J.S. Citrate synthase activity was measured by O.B. Cell-based mitochondrial assays were performed by G.L.L. and P.N. MRI images were obtained by S.R., K.W.F. and R.G.S.
This file contains Supplementary Figures 1–7. This file was updated on 2 November 2006.