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, the tetramers and pentamers believed to be most important. Although resveratrol may be the most thoroughly investigated molecule, others have revealed significant properties and some lines of evidence point to a synergistic relationship between wine compounds.
Resveratrol exists in two isomers, trans-resveratrol being the biologically active form. Exposure to light may cause the trans form to convert to the cis form, so storage conditions are important. Several related molecules in the stilbene family have been identified, many of which have biologic activity, especially tetrameric oligomers, which have been reported to be matrix metalloproteinase(MMP) inhibitors.2 As MMP’s activity contributes to collagen breakdown, this points to potential applications in anti-aging skin treatments and cancer therapy, though this remains to be explored further. In addition to the naturally occurring stilbenes, numerous synthetic derivatives have been developed, many of which have greatly increased potency for specific applications.
Figure 2. Isoforms of resveratrol
Biologic Activity of Resveratrol
Resveratrol has a unique range of documented biologic properties. It is a potent antioxidant, as are many polyphenols, though this is better documented in vitro than in human trials. The addition of whole red wine to the diet improves plasma antioxidant status.3 One randomized study compared a 40 mg daily dose of resveratrol for 6 weeks versus placebo, with 10 subjects in each group.4 Fasting blood draws were done at intervals for isolation of mononuclear cells which were tested for indices of oxidative and inflammatory stress, with significant reduction in generation of reactive oxygen species (ROS) observed. Additionally, production of pro-inflammatory cytokines and C-reactive protein (CRP), another marker of inflammation, were suppressed in the resveratrol group.
A partial list of additional properties of resveratrol is itemized below:
•Antibiotic
•Multiple enzyme inhibition including cyclo-oxygenase (COX-1 and COX-2)
•Multiple enzyme activation including mitogen-activated protein (MAP) kinase
•Phyto-hormonal
•Protection against ultraviolet radiation
•Anti-cancer: multiple pathways
•Ischemia-reperfusion
•Radiation fibrosis
RESVERATROL AND ANTI-AGING: THE EVIDENCE
Youthful Beauty: Resveratrol and Healthy Skin
Much of the clinical practice of anti-aging medicine is directed at appearance, and means of countering the visible manifestations of age. The cumulative effects of photodamage in addition to intrinsic aging contribute to an aged appearance, and botanical antioxidants are finding utility in reversing and preventing some of this damage. There is evidence that wine drinkers have fewer signs of photoaging such as actinic keratoses, and consumption of red wine high in polyphenols confers protection against UV damage as measured by minimal erythema dose.5 A topical preparation of 1% resveratrol was tested against 1% idebenone, previously advertised as the most potent antioxidant in a skin care product, with the resveratrol formula found to be 17-times more potent as measured by the Oxygen Radical Absorption Capacity (ORAC) test, an industry standard.6 Resveratrol appears to provide significant photoprotection though it may work best in combination with other wine polyphenols, as the oral dose from wine consumption would be inadequate to produce effective tissue levels in skin unless it is selectively taken up. Resveratrol appears to hold potential as a cosmeceutical skin care product.
Resveratrol and Cardiovascular Health
The original “French paradox,” a term from the ABC television show 60 Minutes in 1991, was based on the epidemiologic observation that citizens of southern France enjoy low rates of cardiovascular disease despite a lifestyle renowned for flaunting known risk factors such as smoking and high fat intake. The proposed explanation was their high level of wine consumption, a hypothesis initially met with much skepticism but now well-accepted. In fact, the idea was not new, having been documented as early as 19797, and wine consumption would later be recognized as a previously overlooked but central component of the Mediterranean diet. As a result of this new focus on the potential healthful properties of wine as a food, attention turned to the question of what chemical constituents of wine were responsible. Resveratrol, in addition to other wine phenolics, has been found to be involved in a number of specific processes that counter atherosclerotic disease.8
A primary action of resveratrol is up-regulation of nitric oxide (NO), a vasodilator. There is some clinical evidence that resveratrol produces a short-term relaxation of the arterial wall and lowers blood pressure after oral