Volume 8 Number 1 July 2008 Red Wine Ingredient Wards Off Effects of Age on Heart, Bones, Eyes and Muscle Large doses of a red wine ingredient can ward off many of the vagaries of aging in mice who begin taking it at midlife, according to a new report published online on July 3 in Cell Metabolism, a Cell Press publication. Those health improvements of the chemical known as resveratrol—including cardiovascular benefits, greater motor coordination, reduced cataracts, and better bone density—come without necessarily extending the animals’ life spans. A particular strength of the study is that Sinclair and de Cabo’s team show evidence that resveratrol mimics the beneficial effects of eating fewer calories. Specifically, they found that resveratrol induces gene activity patterns in multiple tissues that closely parallel those induced by dietary restriction and every-other-day feeding. “ From a health point of view, the quality of life of these mice at the end of their days is much better,” said Rafael de Cabo of the National Institute on Aging. It suggests that resveratrol may “extend productive, independent life, rather than just extending life span.” “ I was most surprised by how broad the effects were in the mice,” added David Sinclair of Harvard Medical School. “Usually, you focus on slowing down or ameliorating one disease at a time. In this case, resveratrol influences a whole series of seemingly unrelated diseases associated with aging.” Sinclair said he expects some of the effect seen in the mice would have even greater impact if they hold in humans. That’s because, unlike people, mice usually don’t die as a result of heart disease or suffer from weakening bones. Earlier studies showed that reducing calorie intake by 30%–50%, or eating only every other day, can delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline, the researchers said. Although dietary restriction has beneficial effects in humans, such a diet is unlikely to be widely adopted and would pose a significant risk to the frail, critically ill, or the elderly. Therefore, the researchers are on a quest for “dietary restriction mimetic” compounds that provide some of the benefits without cutting calories. One contender has been compounds like resveratrol that activate SIRT1. SIRT1 and equivalent proteins have been linked to long life in many studies in yeast to mammals, although its role in prolonging life remains a matter of considerable controversy. Studies have shown resveratrol can extend the lives of yeast, worms, flies, and fish. It also improves the health and survival of obese mice fed a high- calorie diet. Now, de Cabo and Sinclair show that those effects do indeed seem to take place by inducing the physiology of dietary restriction. They placed 1-year- old mice on a standard control diet or every-other-day feeding with or without resveratrol. Resveratrol produced changes in the gene-expression profiles of key metabolic tissues, including liver and muscle, that closely resemble those induced by dietary restriction, they report. Overall, the animals’ health improved under all dietary conditions, as reflected by a reduction of osteoporosis, cataracts, vascular dysfunction, and declines in motor coordination. The mice did not live longer in general, although mice on a high-fat diet plus resveratrol did avoid the shortened life span that tends to come with such a fatty meal plan. “ In conclusion, long-term resveratrol treatment of mice can mimic transcriptional changes induced by dietary restriction and allow them to live healthier, more vigorous lives,” they wrote. “In addition to improving insulin sensitivity and increasing survival in [high-calorie fed] mice, we show that resveratrol improves cardiovascular function, bone density, and motor coordination and delays cataracts, even in nonobese rodents. Together, these findings confirm the feasibility of finding an orally available dietary restriction mimetic.” Resveratrol treatment is already being tested in clinical trials for type 2 diabetes, the researchers noted, and more potent molecules with effects similar to resveratrol are also under development. The new findings in middle-aged mice suggest that treatments with such drugs might have benefits for people who start taking them in their late thirties or forties. ### The researchers include Kevin J. Pearson, National Institute on Aging, National Institutes of Health, Baltimore, MD; Joseph A. Baur, Harvard Medical School, Boston MA; Kaitlyn N. Lewis, National Institute on Aging, National Institutes of Health, Baltimore, MD; Leonid Peshkin, Harvard Medical School, Boston MA; Nathan L. Price, National Institute on Aging, National Institutes of Health, Baltimore, MD, Harvard Medical School, Boston MA; Nazar Labinskyy, New York Medical College, Valhalla, NY; William R. Swindell, University of Michigan, Ann Arbor, MI; Davida Kamara, National Institute on Aging, National Institutes of Health, Baltimore, MD; Robin K. Minor, National Institute on Aging, National Institutes of Health, Baltimore, MD; Evelyn Perez, National Institute on Aging, National Institutes of Health, Baltimore, MD; Hamish A. Jamieson, Centre for Education and Research on Ageing, and the ANZAC Research Institute University of Sydney, Concord, Australia; Yongqing Zhang, Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD; Stephen R. Dunn, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA ; Kumar Sharma, Translational Research in Kidney Disease, UCSD, La Jolla, CA; Nancy Pleshko, Hospital for Special Surgery, New York, NY; Laura A. Woollett, University of Cincinnati Medical Center, Cincinnati, OH; Anna Csiszar, New York Medical College, Valhalla, NY ; Yuji Ikeno, University of Texas Health Science Center at San Antonio, and Research Service, Audie Murphy VA Hospital (STVHCS), San Antonio, TX; David Le Couteur, Centre for Education and Research on Ageing, and the ANZAC Research Institute University of Sydney, Concord, Australia; Peter J. Elliott, Sirtris Pharmaceuticals Inc, Cambridge, MA; Kevin G. Becker, Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD; Placido Navas, Centro Andaluz de Biologia del Desarrollo, and Centro de Investigacion Biomedica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Sevilla, Spain; Donald K. Ingram, Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA; Norman S. Wolf, University of Washington, Seattle, WA; Zoltan Ungvari, New York Medical College, Valhalla, NY ; David A. Sinclair, Harvard Medical School, Boston MA; and Rafael de Cabo, National Institute on Aging, National Institutes of Health, Baltimore, MD. This work was supported by grants from the American Heart Association, and from the NIH, and by the generous support of Mr. Paul F. Glenn and The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. Pearson et al.: “Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.” Publishing in Cell Metabolism 8, 1–12, August 6, 2008. DOI 10.1016/j.cmet.2008.06.011 www.cellmetabolism.org Author Contact: de Cabo, National Institute on Aging, National Institutes of Health in Baltimore, MD, at deCaboRa@grc.nia.nih.gov, and Sinclair, Harvard Medical School in Boston, MA at email@example.com. 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