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ABOUT THE AUTHORS
Robert L. Bard, M.D. is recognized as one of today's leaders in the field of radiology. His career began as an intern at Harkness Hospital (California, USA). He has served in the military, and has been head radiologist at several leading hospitals. Since 2001, Dr. Bard has been the Director of The Biofoundation for Angiogenesis Research and Development, an organization which researchers new therapeutic modalities in the treatment of cancer. Dr. Bard is currently in consulting practice in New York City (New York, USA).
Arthur W. Bartunek, M.A. is a senior member and instructor of The New York Institute for Gestalt Therapy (New York, USA) for 20 years, and a nutritionist. He received his Masters degree from the New School for Social Research, and continued advanced research work at Adelphi University. In his work with Dr. Bard, Mr. Bartunek pioneered the use of beta-sitosterol-based antioxidant nutrition for cancer patients. He maintains a nutritional consulting practice in New York City (New York, USA).
Chapter 3
Is Resveratrol a True Anti-Aging Compound?
Richard A. Baxter, M.D., FACS
ABSTRACT
As anti-aging science has progressed on both a molecular and clinical basis, resveratrol, a naturally occurring polyphenol antioxidant, has emerged as a candidate for comprehensive therapy. Laboratory evidence indicates that resveratrol protects skin against the effects of photoaging, and counters age-related diseases via protection against ischemia-reperfusion injury, Alzheimer’s disease, cancer, and diabetes. Resveratrol is a potent phytoestrogen and has potential related benefits and risks. Resveratrol has become a popular supplement in large part due to reports that it is a sirtuin activator, thereby acting as a caloric restriction mimetic and prolonging lifespan. However, questions about the bioavailability of resveratrol remain, clinical evidence is scant, and recent research indicates that resveratrol is not a direct sirtuin activator and does not extend lifespan in mammals. These controversies and the potential clinical role for resveratrol are reviewed.
Keywords: resveratrol, sirtuins, phytoestrogens, wine polyphenols, quercetin
INTRODUCTION
Resveratrol (trihydroxystilbene), a phytoalexin from red wine, has become a popular anti-aging supplement and the focus of escalating research efforts in recent years. Phytoalexins are naturally occurring compounds synthesized by plants as part of their defense against environmental challenges, such as microbial infection. Because of this, they possess antibiotic and antioxidant properties, and in the case of resveratrol, a long list of other potentially useful capabilities. These have been reported to include activation of sirtuins, the enzymes that mediate the metabolic shift that produces the increase in lifespan from caloric restriction. Resveratrol’s pleiotropic properties place it as a contender for a comprehensive anti-aging compound.
In order to consider the possibility of a “true” anti-aging intervention, a definition is needed. Though there are various ways to define anti-aging, for purposes of this discussion a comprehensive approach is taken, to include the following:
•Maintenance and restoration of youthful appearance
•Slowing of age-related cellular processes leading to reduced rates of degenerative diseases
•Lifespan extension
•Bioavailability
A Medline database search returns more than 3500 citations for resveratrol, with annual listings increasing exponentially. In 1991 there were only two articles in the biomedical literature on resveratrol, whereas there were approximately two each day in 2010, reflecting increasing interest on several fronts. However, only a few articles are based on clinical trials in human subjects, so if resveratrol is to be clinically useful a systematic approach is required.
Given that red wine is the primary source or resveratrol in the diet, the theory has been advanced that resveratrol provides the benefit attributed to regular wine consumption, a phenomenon characterized by a “J-shaped curve” of relative risk vs. disease incidence (moderate-consumption has a lower relative risk than non-consumption, high-consumption has a steeply rising risk.) The numerous other anti-aging benefits of red wine consumption also hold a potential relationship to resveratrol, so epidemiologic studies on red wine and health may serve as a useful starting point.
Once a clear relationship between wine consumption and a specific anti-aging benefit emerges, the next step is to formulate a plausible cause-effect explanation. Several lines of research support the role of resveratrol in specific mechanisms believed to be involved in wine’s healthful benefits, so experimental evidence for the proposed cause-effect relationship is also necessary. Ideally, this would culminate in clinical trial data leading to level I evidence as required for evidence-based practice. Recent publications have cast doubt on whether resveratrol functions at a biochemical level as previously reported, so clinical trial data is especially important.
Figure 1. Typical J-shaped curve
Resveratrol Chemistry
Resveratrol was first described in 19781 as an isolate from rhizomes of Rheum rhaponicum, a type of rhubarb. The best known source is red wine, which derives it from the skins of the grapes, where it serves to protect the fruit as it ripens from environmental pathogens and oxidative damage from ultraviolet light. Compounds present in the skin of wine grapes give what oenophiles call “structure” so vineyard management employs various techniques to encourage formation of these compounds by intentionally stressing the vines. Cultivars of wine grapes have been selected over the centuries to predispose to formation of these compounds, unlike table or juice grapes where they impart an undesirable astringent or bitter flavor. Furthermore, because red wine is made by fermenting the whole crushed grape (a process called maceration), the compounds are extracted more thoroughly than in white wine or pressed juice. As the alcohol develops it serves as a solvent for further extraction. Aging in oak may add additional phenolic compounds. For all of these reasons wine is a much more concentrated source of resveratrol as compared to table grapes or grape juice. Resveratrol is also made by other plants including the non-edible parts of the peanut plant and the Japanese giant knotweed, the latter is inedible but serves as a commercial source of resveratrol.
Resveratrol is a polyphenol, as are many other compounds in grape skins. Broadly, these are categorized into flavonoids including anthocyanins (which give the wine its color), tannins (many similar to those found in tea), other flavonoids such as quercetin, and non-flavonoids. This latter class includes stilbenes, such as resveratrol and benzoic, caffeic, and cinnamic acids. Some compounds derive from the seeds of the grape, including oligomeric proanthocyanidins,
