Resveratrol

Abstract

Resveratrol is a polyphenolic compound found in many products commonly consumed in the American diet. The reported benefits of resveratrol are broad and include antiaging effects, antioxidant effects, anticancer effects, neuroprotective effects, and an array of cardiovascular benefits such as improved cholesterol profiles, reduced atherosclerosis, improved glucose homeostasis, decreased blood pressure, and reduced ischemia– reperfusion injury. The current article discusses the literature relating the dosing, safety, and effectiveness of resveratrol for extended life span and improved cardiovascular health. Additionally, recommendations for use in clinical practice are discussed.

Introduction

Resveratrol is a polyphenolic compound found in many products commonly consumed in the American diet, including grapes, cranberries, blueberries, and peanuts. The reported benefits of resveratrol are broad and include antiaging, antioxidant, anticancer, and neuroprotective effects. Additionally, it has been reported to have an array of cardiovascular benefits such as improved cholesterol profiles, reduced atherosclerosis, improved glucose homeostasis, decreased blood pressure, and reduced ischemia–reperfusion injury. Since resveratrol was discovered in 2003, a large number of animal studies have described promising benefits from its use.^1,2 The current article discusses the literature regarding the compound’s potential effects on life span and cardiovascular health.

Resveratrol and Extended Life Span

Caloric restriction (CR) is currently the only intervention known to increase maximum life span. ³ CR is defined as a 30% to 60% decrease in calories from a diet eaten “ad libitum” or “at one’s pleasure.” The other caveat to CR is that the decrease in calories must occur without malnutrition. CR has been shown to increase life span regardless of the age of onset, although the extension is less when CR is initiated in adulthood. ⁴ A majority of the longevity research of CR has occurred in lower species studies, including drosophila, mice, and rats. However, there are currently several ongoing studies investigating the effect of CR on higher species such as humans and nonhuman primates.^5-7

Caloric restriction (CR) is currently the only intervention known to increase maximum life span.”

While the research regarding CR is promising, the feasibility of the intervention is not. Compliance to a lifelong CR regimen is a major barrier, as the change requires an enormous patient commitment. A vast amount of interest lies in the development or identification of a compound to mimic the effects of CR without the restraint on food intake. Resveratrol was found to be such a compound and extensive research has occurred or is underway to determine its therapeutic targets and human application.

A large review identified several common molecular targets of CR and resveratrol. ⁸ Among others, the list included the following: increased AMP (adenosine monophosphate)–activated protein kinase, increased endothelial nitric oxide synthase, reduced interleukin-6, reduced tumor-necrosis factor-α, and increased silent information regulator-1 (SIRT1). The various similar targets suggest the mechanism responsible for beneficial response may depend on several pathways.

Resveratrol has been shown to extend the life span of yeast, worms, flies, and fish. ⁹ The compound was found to increase average life span by up to 56% in the aforementioned species. In mice, resveratrol extended the life span of a cohort fed high-fat diets to match the life span of a lean, untreated counterpart. ⁹ Interestingly, the same result was not described in mice fed a normal diet. Several subsequent studies confirmed this result. These findings may indicate that rather than slowing the aging process, resveratrol may decrease the obesity-related consequences on health and longevity. Importantly, this series of investigations started resveratrol administration in mice aged 12 months old (considered middle aged). It is well documented that CR initiated in adulthood extends life span in mice to a lesser degree than initiation at a younger age. ³ Further research is warranted to determine whether the age of initiation makes a significant difference for resveratrol. To date, resveratrol has not been shown to increase the life span in a mammalian model on a standard diet. ³

Resveratrol and Improved Cardiovascular Health

The term French paradox describes the phenomenon that despite similarities in risk factors, France has a significantly lower mortality rate due to coronary artery disease than other countries of similar socioeconomic standing. One study determined that the only nutritional difference between France and other developed countries with a significant correlation to cardiovascular mortality was wine consumption. ¹⁰ On further investigation, resveratrol, found in the skin of the grapes used to make red wine, was hypothesized to be responsible for the cardiovascular benefits of wine consumption.

The described cardiovascular benefits of resveratrol are wide-ranging. Metabolically, resveratrol protected against the development of diet-induced insulin resistance in rodents fed a high-calorie diet and in human diabetic patients. ⁸ Resveratrol has also been shown to decrease weight gain in several overfed animal models. ¹¹ Resveratrol has vasodilatory effects, thought to be mediated through increased nitric oxide bioavailability and reduction of vasoconstricting endothelin-I, angiotensin-II, and angiotensin-II type 1 receptor. ⁸ Resveratrol also appears to mitigate atherosclerosis. Treatment with resveratrol resulted in lower circulating low-density lipoprotein and higher high-density lipoprotein and decreased oxidation of both particles. ¹¹ In addition to reducing oxidative damage, resveratrol suppresses the expression of many pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and more).

In the acute myocardial infarction setting, resveratrol has been shown to improve cardiac output, increase coronary blood flow, reduce the size of the infracted area, and decrease the amount of cardiac muscle cell death in rats. ¹¹ However, the clinical utility of resveratrol in the acute setting may not be feasible. In the chronic ischemia model, resveratrol increased pro-angiogenic vascular endothelial growth factor (VEGF) and collateral vessel flow in swine. ¹¹ In the same study, supplementation with daily resveratrol decreased swine body mass, serum cholesterol, and c-reactive protein levels. Interestingly, when resveratrol is given in combination with exogenous VEGF, worsening blood flow was observed. ¹¹ The anti-/pro-angiogenic effects of resveratrol in combination of exogenous/endogenous VEGF need to be studied further.

Resveratrol Dosing and Side Effects

Resveratrol dosing in animal studies varied widely and ranged from several hundred milligrams to several grams per day. ¹² Short-term human studies have assessed resveratrol supplements as small as 30 mg per day and as large as 5 g per day. The optimal dose may be specific to the benefits desired and different for use in humans compared with animals. According the Natural Medicines Comprehensive Database, there are currently 371 supplements containing resveratrol available on the market. ¹³ The manufactured doses range from 20 to 500 mg per tablet/capsule. Long-term supplementation of resveratrol doses, greater than that obtained through dietary intake, has not been studied in humans.

It is difficult to estimate resveratrol intake from the diet because wine consumption (the main source of resveratrol in the human diet) is patient specific. One study found that the average intake in the human diet is likely less than 4 mg per day. ¹⁴ Epidemiologic studies have shown beneficial effects on the cardiovascular system from moderate wine consumption. ¹⁵ However, consuming large amounts of alcohol has detrimental effects on the cardiovascular system ¹⁶ and even intake of modest amounts of alcohol can increase the risk of breast cancer in women. ¹⁷ Therefore, specific recommendations regarding resveratrol intake through wine consumption should be individualized, and if pursued, the importance of moderate intake should be stressed.

Resveratrol is generally well-tolerated in animal studies. Several human studies suggest that oral doses of up to 1 g per day are well tolerated. ¹¹ Gastrointestinal discomfort and diarrhea were experienced in a short-term human study at doses greater than 2.5 g per day. ¹² Resveratrol has been shown to downregulate the insulin-like growth factor cascade, which may increase the risk of several cancers. ² Valid long-term data regarding the toxicity of resveratrol in humans are not available.

Conclusions and Clinical Recommendations

Resveratrol is a naturally occurring polyphenol with promising findings in animal studies for the prevention and treatment of heart disease and the extension of life span. There are a limited number of well-designed clinical trials available to assess efficacy, safety, and toxicity in humans. Until further evidence is obtained, a recommendation for chronic resveratrol administration in humans at doses greater than those achieved from the diet (approximately 4 mg or less) is not warranted. Additionally, specific patient counseling should be provided when recommending dietary resveratrol intake through the consumption of wine.