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By Ted Wissink, MD, and Matt Stevens, MD
Dr. Wissink is Attending Physician, Family Medicine Residency and Integrative Medicine Department, Maine Medical Center, Portland, ME. Dr. Stevens finished his Family Medicine residency in 2013 at Maine Medical Center in Portland, ME. He is the currently completing an integrative medicine fellowship through the University of Arizona and Maine Medical Center.
Dr. Wissink and Dr. Stevens report no financial relationships relevant to this field of study.
Synopsis:Resveratrol has substantial potential to improve health in different ways based on the research. Enough beneficial physiologic responses have been seen in numerous animal models and in limited human studies to warrant long-term human trials studying whether resveratrol supplementation ultimately has a true impact on chronic disease.
Red wine is widely recognized around the world for its cardiovascular benefits, and resveratrol has gained attention as a key ingredient in red wine that looks promising to offer a variety of health benefits. Resveratrol is one of the most biologically active polyphenols in red wine. It has gained progressive interest in the scientific and medical community since 1992, when the "French Paradox" highlighted the potential link between red wine and heart health by reporting that people in France had relatively low incidence of heart disease despite a diet high in saturated fats.1
However, long before this in various parts of the world, both red wine and grapes were recognized for their health benefits. It has been reported in various texts that the father of medicine, Hippocrates, recommended wine as a nutritional supplement. The material medica, a collection of traditional Asian medicines and therapeutic foods, described the grape as "good for muscle, bone, and longevity" in its oldest book, estimated to be published in A.D. 22-250.2
In addition to grapes and, therefore, wine, resveratrol is also present in various fruits such as cranberry, blueberry, mulberry, lingonberry, bilberry, jackfruit, as well as a number of flowers. Although early resveratrol supplements were extracted from grape skins, now commercially it is extracted from the dried roots of Polygonum cuspidatum (Japanese knotweed), found mainly in Japan and China. The extract has been used in traditional Japanese and Chinese medicine to treat fungal infections, skin irritation/inflammation, liver disease, and cardiovascular disease.3
Over the last 10-15 years, the media has highlighted resveratrol's potential health benefits for both treatment and prevention of multiple age-related diseases. This has led many supplement companies to offer resveratrol-based supplements. These have been so popular that a 2007 study found that resveratrol is taken by two-thirds of people who routinely take supplements.4
Resveratrol has numerous mechanisms of action that could translate to potential health benefits. Polyphenols in general are recognized for their antioxidant ability. It also induces the expression of a variety of antioxidant enzymes, making it difficult to fully understand precisely how each mechanism contributes to the overall oxidative stress.5 Resveratrol interacts with a large number of receptors, kinases, and other enzymes that could realistically contribute to health benefits. Many of these influence the regulation of metabolism in multiple body tissues.6
Resveratrol has been found to inhibit cyclooxygenases and could, therefore, act through similar mechanisms as aspirin.7 The cardioprotective mechanism has been postulated to stem from its ability to up-regulate endothethial nitric oxide synthase,8 which ultimately increases nitric oxide mediated vasodilatation and blood flow.9 The potential mechanisms of action are so complex that designing human studies to measure specific health outcomes has been difficult thus far.
There are no valid data on the toxicity of chronic intake of resveratrol in humans. Based on animal studies, it appears that resveratrol is generally well-tolerated. The longest chronic exposure experiment was 24 months in mice and there were no toxic effects at doses ≥ 1 g/kg body weight per day.10
In a double-blind, randomized, placebo-controlled study, healthy volunteers were given 25, 50, 100, or 150 mg of resveratrol six times per day for 2 days (maximum daily dose, 975 mg daily). Adverse effects were mild and similar between the groups.11 Another small study used daily dosing of 2.5 g or 5 g resveratrol for 28 days. Authors reported that adverse events including gastrointestinal discomfort and diarrhea were mild and reversible.12
Resveratrol concentrations in wine vary widely, even within a given variety of grape and growing region. Red wine tends to contain considerably higher amounts than white wine. It is estimated that people who consume one or two glasses of red wine per day get an average of 2-4 mg/day of resveratrol. In supplement form, resveratrol doses are much higher, but also highly variable. Common supplements recommend anywhere from 25 mg to 250 mg per day.
In the clinical studies reviewed, side effects were inconsistent and mild. High doses (> 2500 mg/day) in humans produced frequent abdominal discomfort and diarrhea in participants.
Several long-term clinical studies are underway but, to date, only small human studies of short duration have been published, and few of these were in peer-reviewed journals. Therefore, the prediction of health benefits has had to rely very heavily on data from animal studies and in vitro studies about potential mechanisms of action. Similarly, a review of the current literature on resveratrol relies heavily on animal studies. In the broad literature search for this review, the most common potential resveratrol health benefits include cardioprotective properties, anti-carcinogenic properties, and prevention of diabetes and obesity. These areas are the focus of this review.
Cardiovascular Effects. Endothelial dysfunction is defined as impairment of endothelial-dependent relaxation, and it is an early event in the development of atherosclerosis and present before structural changes in blood vessels.13 Arterial responsiveness is often measured using flow-mediated vasodilatation (FMD) of the brachial artery. One small study measured FMD 45 minutes after 30 mg, 90 mg, and 270 mg of resveratrol in 19 overweight and obese individuals with unmedicated borderline hypertension. FMD significantly increased compared to placebo at all three dosages.14
In one recent review of resveratrol effects in animal studies, nine of 11 studies demonstrated significant reduction in hypertension. On average, the dosing used in the studies was 10 mg/kg/day, which is much higher than with typical wine consumption. The effects were seen within an average of 3 weeks and maintained for 10 weeks. Five other animal studies showed preventive effects of various doses of resveratrol on myocardial infarction induced by surgery in mice/rat models.15 These studies showed significantly decreased infarct size. Long-term treatment with resveratrol also reduced infarct area after middle cerebral artery occlusion.16
Obesity and Diabetes. In 2008, Sirtris pharmaceuticals reported improved glucose tolerance in people with type 2 diabetes treated with resveratrol at a dose of 2.5-5 g/day.17 In 2010, 10 patients aged 60-80 with impaired glucose tolerance were given resveratrol 1-2 g/day for 4 weeks. Fasting glucose was unchanged, but postprandial glucose levels were lowered without an increase in insulin production.18 In a 2011 study, 4 weeks of treatment with resveratrol at a much lower dose of 5 mg daily significantly lowered blood glucose levels and delayed peak glucose following a standard meal in 19 people with type 2 diabetes compared to placebo.19 None of the human studies on clinical effects or bioavailability reported hypoglycemia as a side effect.
Multiple animal studies have found resveratrol to be effective at increasing insulin sensitivity and reducing blood glucose levels. A 2011 review summarized the findings of nine studies using obese or diabetic rats (induced by high-fat diets or genetically and chemically induced diabetes). All nine studies showed reduced insulin levels or increased insulin sensitivity in rats fed 2.5-400 mg/kg/day and covering 1-6 months of treatment.20 Ten studies looked at the effect on blood glucose levels of genetically obese mice or rats, and all but one study found significantly reduced blood glucose levels following resveratrol exposure for anywhere from 5 days to 2 months.20 Obviously it is difficult to draw direct conclusions from these studies because of the variability of dosing and duration, but the positive results indicate more long-term human trials are necessary to see if resveratrol is beneficial for obese, diabetic, or prediabetic humans.
Cancer Therapy and Prevention. Resveratrol has been widely publicized as a potential anticancer agent since it was first reported to have an inhibitory effect on the carcinogenic process in 1997.21 Since then, several animal studies have shown that oral resveratrol significantly reduces the incidence of chemically induced skin cancer in mice, and there have been many in vitro and in vivo animal studies to further evaluate its potential, particularly in the realm of colon cancer and its prevention.
Resveratrol's exact mechanism in chemoprevention appears to be multifaceted. Numerous studies have demonstrated that resveratrol inhibits cellular events associated with all three stages of carcinogenesis, namely, initiation, promotion, and progression.21,22 As previously discussed, this polyphenol can have similar effects on cyclooxygenase as aspirin and other NSAIDs. This has led to intriguing studies evaluating its effect in the prevention of colon cancer with the theoretical advantage of having a superior cardiovascular profile over NSAIDs. In a 2001 study, oral resveratrol was given to mice that were genetically predisposed to colon cancer. Oral dosing started at 5 weeks of age and continued through senescence. The mice that received the resveratrol had a 70% reduction in tumor formation when compared to the control group.23
In vitro and animal studies regarding resveratrol are numerous and promising, and indicate that it has a good safety profile. However, human trials are scarce. An interesting pilot study carried out in 2009 evaluated the effect of resveratrol on colon cancer in humans. After 14 days of resveratrol in either freeze-dried grape powder or tablets (dose range 20-80 mg depending on the type of tablet), the expression of target genes seen in active colon cancer were not inhibited. However, these same genes existing in normal mucosa showed reduced expression, possibly indicating that resveratrol could have potential in the prevention of colon cancer.24 It must be noted that this was a small, phase 1 pilot study without dietary control of resveratrol-rich foods that did not account for possible confounders such as medication ingestion.
Challenges with Metabolism and Bioavailability. The numerous and promising in vitro and animal studies are all very encouraging and the results thus far certainly merit further investigation. However, there are challenges when applying polyphenol research results in clinical practice. Resveratrol has been shown to be quickly absorbed but also very quickly metabolized. This occurs primarily via glucuronidation in the liver followed by prompt excretion by the kidneys. In 2004, Walle et al used Carbon-14 labeled resveratrol to better understand its metabolism and found that when given intravenously the plasma concentration rapidly declined over a one-hour period.25 There is some preliminary evidence suggesting that the metabolites of resveratrol may themselves be bioactive and can be found at much higher concentrations in tissues such as the colon as compared to serum after administration.26 More work remains to confirm this finding and determine its clinical significance.
Resveratrol is an exciting molecule that may have many potential health benefits. There are many intriguing results from animal and in vitro studies but more long-term and well-conducted human studies are necessary. Resveratrol seems safe with limited side effects. In most studies it seems moderate wine consumption, especially red wine, is recommended for cardioprotective effects. Although alcohol possesses cardioprotective properties, it is widely believed that these effects in red wine are related mostly to resveratrol and other polyphenols.
The studies we looked at in both humans and animals used much higher doses of resveratrol than the 2-4 mg/day found in moderate wine consumption. The doses varied widely but were generally 25 mg up to as much as 2500 mg/day. Although some of the effects seen in studies so far are promising, much more research and clinical studies are obviously needed. Many of you will be pleased that at this point we can safely recommend moderate daily red wine consumption for cardioprotective effects based on the studies we reviewed. Chronic human intake above the amount found in natural food should be considered experimental until more long-term human studies have been done.