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 administration. Additionally, production of the pro-inflammatory cytokine endothelin-1 is suppressed, which helps retard plaque formation in the vessel wall. COX inhibition similarly slows plaque progression due to suppression of eicosanoid synthesis. Impairment of platelet aggregation via COX inhibition also provides an explanation for the clinical finding that myocardial infarction and stroke are less likely to occur if wine has been consumed within the previous 24 hours. Furthermore, resveratrol’s antioxidant capacity serves to lower levels of oxidized low-density lipoprotein. (It should be pointed out however that alcohol independently improves the HDL/LDL ratio so the beneficial effects of wine cannot be attributed solely to its polyphenol components.)
Resveratrol and Ischemia-Reperfusion Injury
Once an arterial clot is lysed and blood flow restored, a cascade of events ensues which may paradoxically hasten tissue damage. Much of this is mediated by oxidative mechanisms, and a growing body of experimental evidence indicates that there may be significant improvement in tissue survival with administration of resveratrol. (Clinically, this correlates to better outcomes after cardiac events among wine drinkers.) This effect has been reported in experimental models for intestine, brain, spinal cord, skeletal muscle, and heart muscle.9 A stroke model in gerbils demonstrated significant improvement in brain tissue with resveratrol following global ischemia induced by carotid clamping.10 Of particular significance to this study is that it also demonstrated that resveratrol could traverse the blood-brain barrier, with implications for its role in degenerative neurological diseases presuming that adequate blood levels could be achieved. However, the potential role of resveratrol for clinical use in treating ischemia-reperfusion remains to be studied.
Alzheimer’s Disease and Senile Dementia
It is difficult to overestimate the impact of Alzheimer’s disease (AD), with some 5 million cases in the U.S. and the “baby boom” demographic curve entering old age. The financial and social costs are incalculable, but certainly count in the billions of dollars. According to a recent consensus panel report from the U.S National Institutes of Health (NIH), “firm conclusions cannot be drawn about the association of any modifiable risk factor with cognitive decline or Alzheimer’s disease” and “evidence is insufficient to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimer’s disease.”
Progress has been made however in understanding the etiology of AD, notably the association of the apolipoprotein E (ApoE) gene variation, and misfolded beta amyloid plaques that characterize the neuropathology of the disease. Certain lifestyle factors have an association with lowered incidence of AD, including physical activity, higher educational
