cognitive engagement behaviors, adequate folic acid intake, low dietary saturated fat, and high fruit and vegetable consumption. The NIH panel report does include a mention of low-to-moderate alcohol consumption as having a favorable impact on risk, but with a focus on wine specifically a clearer picture emerges. In fact, every large-scale epidemiologic survey that included a question on wine consumption has found a clear reduction in incidence among wine drinkers – up to 80% lower. A representative study is the Gruppo Italiano multicenter survey of more than 15000 subjects who underwent cognitive testing, with the highest scores in men drinking up to a liter of red wine per day and women consuming half that amount.11 The resulting J-shaped curve did not show an increase in cognitive decline until more than 2 liters daily consumption (for men) was reached. This dramatic relationship not only confirms the consistent relationship of wine consumption to lower incidence of AD, but suggests a powerful protective constituent to counter the adverse neural effects of high levels of alcohol consumption.
Resveratrol has emerged as a potential explanation for wine’s protective effects against AD, though other wine phenolics have been reported to have significant roles as well. In animal models, resveratrol has been shown to promote clearance of beta amyloid from neural tissues, and to be a potent inhibitor of beta amyloid deposition.12 Resveratrol is also a neuroprotectant, countering the toxic effects of beta amyloid in experimental models. This effect appears to be specific and unrelated to its antioxidant capacity. Whether or not therapeutic levels of resveratrol within the central nervous system can be achieved remains a matter of speculation however.
Via separate pathways, resveratrol may enhance neural function by up-regulation of MAP kinases active in the learning and memory centers of the brain. One small clinical study showed a dose-dependent increase in cerebral blood flow and increase in oxygen extraction by the brain with cognitive testing after taking resveratrol as compared to placebo, though no improvement in test scores was achieved.13 This, along with the findings in the gerbil global cerebral ischemia study, suggest that some degree of activity with central nervous system tissue can be achieved with resveratrol, though the cognitive testing results may be related to vasodilation rather than a neural effect. Long-term clinical trials will be required in order to obtain high-level evidence for a role of resveratrol in reducing age-related cognitive decline. A handful of these are underway, though results will likely be years off.
Resveratrol as an Antimicrobial
A primary function of phytoalexins is protection against environmental pathogens. For this reason, they may possess broad-spectrum antibacterial, antiviral, and antifungal properties, as is the case with resveratrol. In particular, resveratrol has been shown to inhibit proliferation of common bacteria and fungi on the skin, similar to the putative role it plays in grape skins. Additional targets are Streptomyces mutans, which contributes to dental disease, and Helicobacter pylori, which is associated with peptic ulcer disease. Isolated resveratrol is less effective than whole wine against Salmonella species and Escherichia coli, though it does possess a degree of activity independent of alcohol and other wine constituents.
For millennia, wine served as an important antibacterial, most especially on sea voyages and military campaigns, but its antiviral properties have not been studied until recently. An important clue comes from epidemiologic evidence that red wine drinkers have fewer and less severe colds, as compared to nondrinkers, and the benefit is greater with red than with white wine. Resveratrol has been demonstrated to have anti-rhinoviral activity in vitro, providing a plausible cause-effect explanation for the effect. A more dramatic finding comes from a mouse model of influenza type A, in which an LD50 dose (average inoculum required to produce 50% mortality in the test population) could be improved to 100% survival with the concurrent administration of resveratrol.14 It should be noted that quercetin also has a significant inhibitory effect on viral replication, so there may be synergies between the various wine phenolics in terms of antiviral activity.
Resveratrol and Cancer
Unlike beer or spirits, wine consumption follows a J-shaped curve for overall cancer mortality. Though this may be explained in part as a statistical marker for a healthier lifestyle, it has opened the door to a broad field of research into the role of wine phenolics as anti-cancer agents. The topic has been well-reviewed in recent years15 and clinical trials are in progress. Resveratrol has been proposed to unction at several stages including reduced risk of cancer (chemoprevention), anti-cancer therapy via several pathways, and in ameliorating some of the adverse effects of cancer treatments.
Early evidence for this came from studies of resveratrol on cancer cell progression in tissue culture. With several cell types, resveratrol was reported to exert a dose-dependent inhibitory effect, though in specific circumstances the effect is reversed and resveratrol promotes cell proliferation. Nevertheless, the array of cancer types that are inhibited suggest that resveratrol acts at a fundamental level.
These pathways can be understood by dividing cancer therapeutics into three categories according to the stage at which they exert their activity. At the first stage, anti-initiation, resveratrol functions as an anti-oxidant, suppresses mutations by supporting DNA stability, and inhibits activation of pro-carcinogens. Resveratrol has at least four distinct influences in the second stage of cancer, which is known as promotion. These are inhibition of COX-2, which is expressed in many, if not all, types of carcinoma; induction of apoptosis, which is suppressed in cancer cells; decrease in anti-apoptotic proteins, another mechanism by which cancer cells bypass regulatory processes; and down-regulation of cancer activation cellular pathways. The third stage, progression, is where the tumor becomes invasive and spreads. This requires activation of growth factor signaling pathways, on which resveratrol has a specific inhibitory effect. There are also specific effects via other mechanisms on cancer cell invasiveness and growth. A final requirement for tumor proliferation is angiogenesis, which has also been shown to be suppressed by resveratrol. (This latter property suggests other applications for resveratrol in wound healing and conditions such as rosacea.)
The nuclear signaling pathways by which resveratrol is involved have been mapped in considerable detail. Interestingly, many of the points of influence are also targets for curcumin (the spice turmeric), and epigallocatechin gallate (EGCG), a constituent of green tea. This would explain the similar epidemiologic patterns of tea and wine consumption as they relate to cancer.
Wine consumption has also been reported to be associated with less severe fibrosis from radiation treatment in women with breast cancer. As an added benefit, evidence indicates that resveratrol and other wine components help to sensitize tumor cells to radiation while protecting normal cells. A similar paradox applies to chemotherapy, at least in tissue culture and animal studies. This was dramatically demonstrated with doxorubicin and cisplatin in human gynecologic cancer cell lines and in isolated rat hearts.16 If confirmed in clinical trials, these would be very exciting findings but level 1 evidence has not been published so caution is in order.
Wine, Resveratrol, and Breast Cancer: Special Considerations
One of the first cell lines to be proven sensitive to resveratrol is breast cancer, and the effect applies regardless of ER status. However, the relationship of wine consumption and breast cancer has been problematically reported, causing confusion as to whether resveratrol is useful or even safe for breast cancer patients, and whether wine consumption has the same risk as alcohol. Several meta-analyses have been done on the subject of alcohol and breast cancer, with a linear dose-response correlation generally observed. More recent studies employ mathematical modeling to account for the well-known self-reporting bias on drinking levels, but the effect of moderate consumption remains at least in part a matter of extrapolation. Given the anti-cancer activity of resveratrol and other wine phenolics in vitro, the question of whether wine drinkers obtain any benefit in terms of relative cancer risk has been of intense interest.
Conflicting
