1. Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
2. Laboratory of Experimental Gerontology,
3. Gene Expression and Genomics Unit,
4. Research Resources Branch,
5. Laboratory of Cardiovascular Science, and
6. Laboratory of Clinical Investigation, Research Resources Branch of the Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA
7. Centre for Education and Research on Ageing, and the ANZAC Research Institute University of Sydney, Concord, New South Wales 2139, Australia
8. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
9. Centro Andaluz de Biologia del Desarrollo, Universidad Pablo de Olavide-CSIC, 41013 Sevilla, Spain
10. Sirtris Pharmaceuticals, Inc., 790 Memorial Drive, Cambridge, Massachusetts 02139, USA
11. Molecular and Cell Biology Laboratory, The Salk Institute, 10010 N Torrey Pines Road, La Jolla, California 92037, USA
12. Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, Louisiana 70808, USA
13. These authors contributed equally to this work.

Correspondence to: Rafael de Cabo²David A. Sinclair¹ Correspondence and requests for materials should be addressed to D.S. (Email: david_sinclair@hms.harvard.edu) or R.deC. (Email: deCaboRa@grc.nia.nih.gov).

Abstract

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- coactivator 1 (PGC-1) 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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