FYI: Resveratrol Question!

There has been so much “controversy” over the removal of resveratrol from TA Support Packs. With most issues that have to do with supplementation, health and wellness, there are always pro’s and con’s. In an effort to keep you abreast of the lastest information on these issues we will forward articles that have we think will be of interest to you and we will point out both the pro’s and the con’s where possible.

Herewith is an assortment of articles with varying slants on the resveratrol question.

"Life-Extending Protein Can Also Have Damaging Effects On Brain Cells"

July 2, 2008 (ScienceDaily) - Proteins widely believed to protect against aging can actually cause oxidative damage in mammalian brain cells, according to a new report in the July Cell Metabolism, a publication of Cell Press. The findings suggest that the proteins can have both proaging and protective functions, depending on the circumstances, the researchers said. "Sirtuins are very important proteins," said Valter Longo of USC. "Overexpression can protect in some cases, and in other cases, it may do the opposite. It has to do with the fact that they do so many things."

Sirtuins, or Sir2 family proteins, are found in organisms from bacteria to humans. Sir2 controls aging and lifespan in yeast, the worm C. elegans, and Drosophila fruit flies, earlier studies have shown. Studies have also implicated Sir2 in the life-extending effects of a calorie restricted diet in some, though not all, organisms. Notably, Longo's Lab showed that lack of Sir2 in Yeast further extended the lifespan of calorie-restricted cells. SirT1, the mammalian version of Yeast Sir2, controls numerous physiological processes including glucose metabolism, DNA repair, and cell death, the researchers added. In mammalian cells, SirT1 also controls several stress-response factors.

Now, the researchers show that cultured rat neurons treated with a SirT1 inhibitor more often survived treatment with oxidative stress-inducing chemicals. They further show evidence to explain the mechanism responsible for that effect. They also found lower oxidative stress levels in the brains of mice without SirT1. However, those SirT1 knockout mice didn't live as long as normal mice do on either a normal or a calorie-restricted diet.

These results are consistent with the existence of a prooxidative stress role for mammalian SirT1 similar to that described for Sir2 in Yeast but confirm that sirtuins can play both positive and negative roles, Longo said. Based on the new findings, Longo urges caution to those developing SirT1-boosting drugs intended for human consumption.

"[Such drugs] could have beneficial effects for certain diseases, but again, these proteins do a lot of things," he said. "I would say the idea that there is a conserved action of sirtuins to cause major lifespan extension -- the foundations for that are weak or very weak. Until we have more data to show that chronic treatment to increase SirT1 activity does not do damage, I don't think it's a good idea."


The researchers include:
Ying Li, Neuroscience Program, University of Southern California, Los Angeles, CA, Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA;
Wei Xu, Neuroscience Program, University of Southern California, Los Angeles, CA;
Michael W. McBurney, Ottawa Health Research Institute, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; and
Valter D. Longo, Neuroscience Program, University of Southern California, Los Angeles, CA, Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA.

VS.

"Caloric Restriction Comes in a Pill"

by Brandon Keim

July 3, 2008; Scientists have provided the strongest evidence yet that the anti-aging benefits of calorically-restricted diets can be duplicated -- minus the near-starvation -- by a pill.

Image: Courtesy of Harvard University; from an earlier study, livers of 18-month-old mice fed a (left) normal diet; (center) high-calorie diet; and (right) high-calorie diet plus Resveratrol.

In a study published today in Cell Metabolism, mice given Resveratrol -- the first of an eagerly-anticipated class of longevity drugs -- enjoyed dramatically improved health, even when they started taking the drug late in life. Resveratrol didn't extend the lives of normal mice, but it did protect them from the ravages of time. The rodents had stronger hearts, clearer eyes, more limber muscles, and firmer bones. Closer analysis revealed the same cell-level changes produced by caloric restriction, an extreme form of dieting that consistently lengthens the lives of lab animals but is impractical, if not dangerous, for people.

"For the first time, we can mimic caloric restriction in an otherwise healthy animal," said study co-author David Sinclair, a Harvard University biologist and co-founder of Sirtris Pharmaceuticals. "That's been the goal of the field for decades. We didn't know it was possible to let an animal eat whatever it wants, but still get the benefits. We now have evidence." Sinclair discovered several years ago that Resveratrol activates the SIRT-1 enzyme, one of an enzyme family known as sirtuins. Caloric restriction also activates sirtuins, which regulate cell function and rejuvenate mitochondria, the cellular components that convert glucose to chemical energy.

In 2006, Sinclair and National Institute on Aging gerontologist Rafael de Cabo, also a co-author of the Cell Metabolism study, used Resveratrol to improve the health and extend the lives of obese mice on high-calorie diets. The latest study involved both obese and normal mice, fed standard, low- and high-calorie fare. Regardless of mouse weight and diet, Resveratrol worked wonders. At two years of age, or the mouse equivalent of senescence, the mice were more coordinated than their non-dosed counterparts. Their bones were thicker and stronger, their eyes free of cataracts, their hearts beating strong. At the cellular level, tissues displayed gene-level changes almost identical to those produced by caloric restriction.

The mitochondria of Resveratrol-taking mice also proved healthy. Mitochondrial degeneration has been implicated in a variety of diseases, leading some researchers to believe that heart disease, cancer and dementia -- all the so-called diseases of aging -- have a common root. "The mice had tremendous health benefits from taking Resveratrol," said de Cabo. "If any of those parameters translate to humans, it will be tremendous."

When Sinclair and de Cabo's mice started taking Resveratrol they were one year old, roughly equivalent to 35 human years. The success suggests that the drug's benefits could be enjoyed by people who begin taking it during adulthood. The researchers are currently testing whether starting a resveratrol regimen earlier will provide the life extension seen in calorically-restricted animals, but de Cabo is not especially concerned with the outcome. "Would you rather live to be 122 and be wheelchair-bound for the last 50 years of your life, or live to 90 and be fully active?" he said.

Both de Caba and Sinclair caution that mouse results won't necessarily translate to human success. There is, however, reason for guarded optimism: mice are notoriously imperfect modelers of human neurological disorders, but fare much better as models of our metabolism -- the very metrics that de Caba and Sinclair analyzed.

Resveratrol has also proved non-toxic in mice, and human use has not revealed any glaring side effects. "It has been used for many years," said USC gerontologist Valter Longo, "and as far as I know has not been yet been associated with any toxicity." Longo was not involved in the study. Sirtris Pharmaceuticals has already started clinical trials of Resveratrol and a more-refined Sirtuin Activator. In June they were purchased for $720 million by Glaxo Smith Kline, signaling the seriousness with which academics and the pharmaceutical industry views the field.

"You've got to take aging research seriously if a company is willing to put down three-quarters of a billion dollars on it," said Sinclair. "One never knows," he continued. "But we're getting closer to knowing whether in our lifetime we'll be able to find drugs that treat diseases by targeting aging."


Cell Metabolism

"Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Lifespan"

Kevin J. Pearson (1)(17) Joseph A. Baur (2)(17) Kaitlyn N. Lewis(1) Leonid Peshkin(3) Nathan L. Price(1)(2) Nazar Labinskyy(4) William R. Swindell(5) Davida Kamara(1) Robin K. Minor(1) Evelyn Perez(1) Hamish A. Jamieson(6) Yongqing Zhang(7) Stephen R. Dunn(8) Kumar Sharma(9) Nancy Pleshko(10)(18) Laura A. Woollett(11) Anna Csiszar(4) Yuji Ikeno(12) David Le Couteur(6) Peter J. Elliott(13) Kevin G. Becker(7) Placido Navas(14) Donald K. Ingram(15) Norman S. Wolf(16) Zoltan Ungvari(4) David A. Sinclair(2) and Rafael de Cabo(1)

(1) Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224; USA
(2) Department of Pathology and Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston MA 02115; USA
(3) Department of Systems Biology and Center for Biomedical Informatics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston MA 02115; USA
(4) Department of Physiology, New York Medical College, Valhalla, NY 10595; USA
(5) Department of Pathology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48103; USA
(6) Centre for Education and Research on Ageing, and the ANZAC Research Institute University of Sydney, Concord NSW 2139; AUSTRALIA
(7) Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224; USA
(8) Cancer Genomics, Nucleic Acid/Microarray Facility, Kimmel Cancer Center, Thomas Jefferson University, 233 South Tenth Street, Suite 1009 BLSB, Philadelphia, PA 19107; USA
(9) Translational Research in Kidney Disease, 9500 Gilman Drive, MC 0711, UCSD, La Jolla, CA 92014-0711; USA
(10) Hospital for Special Surgery, 535 East Seventieth Street, New York, NY 10021; USA
(11) Department of Pathology and Laboratory Medicine, Genome Research Center, University of Cincinnati Medical Center, 2180 East Galbraith Road, Cincinnati, OH 45237; USA
(12) Barshop Institute for Longevity and Aging Studies and Department of Pathology, University of Texas Health Science Center at San Antonio, and Research Service, Audie Murphy VA Hospital (STVHCS),15355 Lambda Drive, San Antonio, TX 78245-3207; USA
(13) Sirtris Pharmaceuticals Inc, 200 Technology Square, Cambridge, MA 02139; USA
(14) Centro Andaluz de Biología del Desarrollo, and Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC, 41013 Sevilla; SPAIN
(15) Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808; USA
(16) Department of Pathology, University of Washington, Seattle, WA 98195-7470; USA

Corresponding Author:
Rafael de Cabo
deCaboRa@grc.nia.nih.gov

Corresponding Author:
David A. Sinclair
david_sinclair@hms.harvard.edu

Abstract:

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that Resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, Resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with Resveratrol beginning at 12 months of age. Our findings indicate that Resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Footnotes:

(17)These authors contributed equally to this work.
(18) Present address: Exponent, 3401 Market Street, Suite 300, Philadelphia, PA 19104; USA

Ref.: Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

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