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					                                                           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 david_sinclair@hms.harvard.edu.

PIO Contact: Megan Homer at NIA, at (301) 496-1752, and
homerm@nia.nih.gov.
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