Life Extension Magazine February 2008
Living Longer, Healthier Lives with Resveratrol
By David Nayor and Dale Kiefer
By David Nayor and Dale Kiefer
Back in 2003, longevity scientists became excited when the natural, plant-derived compound resveratrol was found to extend the life span of yeast cells by as much as 70%.1 What got scientists so interested was that the gene expression changes induced by resveratrol in yeast cells were similar to those thought to confer longer life in human beings.
Drug development companies are actively seeking to patent resveratrol-like molecules to create pharmaceuticals that would prevent and treat a wide range of age-related diseases, including diabetes, heart disease, cancer, and even Alzheimer’s. The good news for consumers is that they can obtain resveratrol compounds in low-cost dietary supplements today.
Resveratrol is a polyphenol most commonly found in red wine and grapes. It is also found in peanuts, certain berries, some pines, and the roots and stalks of Japanese knotweed.2
Resveratrol plays an important role in the plant’s natural defense system against injury, infection, and disease. Researchers became interested in exploring the health benefits of resveratrol after they observed the surprisingly low rates of heart disease found in populations that consume a diet high in saturated fat and red wine.
Today, resveratrol is attracting attention for its unique ability to mimic the gene expression effects of caloric restriction, the only intervention that has been shown in peer-reviewed studies to prolong maximum life span and/or produce anti-aging effects in a variety of organisms, including mice, rats, dogs, and monkeys. These studies suggest that resveratrol may have similar health and longevity benefits in humans.
Many people find the prospect of long-term caloric restriction too difficult and uncomfortable. A better option would be to find a means to mimic the beneficial effects of caloric restriction through a healthy, convenient dietary supplement such as resveratrol.
Resveratrol: A Caloric-Restriction Mimetic
A 2003 study at Harvard University found that resveratrol mimics the effects of caloric restriction in yeast cells, boosting their life spans by as much as 70%.3 The following year the researchers went on to demonstrate that resveratrol slows aging in two standard laboratory animals, roundworms and fruit flies.4 That made resveratrol the first compound to show anti-aging effects in widely divergent species. Then in 2006, scientists in Pisa, Italy, showed that resveratrol’s magic could be applied to more advanced animals— large doses of resveratrol extended the life span by more than 50% in a species of fish, Nothobranchius furzeri, which typically lives just nine weeks.5
In a study published in 2006 in the journal Cell, researchers in France found that resveratrol protects mice against diet-induced insulin resistance and obesity.6 Furthermore, mice given the resveratrol supplement demonstrated improved endurance levels during exercise. The researchers also studied the cell-signaling pathway in the mitochondria of these mice. Mitochondria are the power plants of cells, which are responsible for intracellular energy production. Resveratrol activated a protein in the sirtuin family (SIRT1), which then stimulated the activity of another protein involved in mitochondrial function. Other recent studies, including one conducted at the Joslin Diabetes Center, have found another member of the sirtuin family of cellular proteins that may play a major role in how fat is produced and stored, offering a new target for treatments to prevent obesity and reduce the risk of type 2 diabetes.7,8
The French researchers surmised that resveratrol helped control weight gain by enhancing energy expenditure.6 Since the study found a link between sirtuins and energy utilization, the researchers concluded that resveratrol may be helpful in the prevention and treatment of certain metabolic disorders, especially those related to mitochondrial dysfunction, such as Alzheimer’s and Parkinson’s disease—two neurodegenerative conditions that become more prevalent with aging.9
Resveratrol Supports Endothelial Health
Recent experiments have shown that the benefits of resveratrol include improvements in the health of the endothelial tissue lining blood vessels. This holds special significance for long-term cardiovascular health, as atherosclerosis is believed to begin when damage to specialized endothelial cells goes unchecked, leading to an inflammatory condition that culminates in endothelial dysfunction and possible vessel blockage.10-17
Resveratrol also benefits the circulatory system by eliciting a decrease in the oxidation of low-density lipoprotein (LDL); by fostering decreases in platelet aggregation; and by promoting relaxation of small blood vessels called arterioles.18-21 Collectively, these mechanisms benefit the overall health of the cardiovascular system by decreasing factors that contribute to the development of atherosclerosis, and by decreasing the likelihood of undesirable clotting, which, in turn, decreases the risk of stroke.22 Furthermore, new data indicate that resveratrol decreases the incidence of dangerous heart arrhythmias.23
One of the most intriguing of resveratrol’s heart-healthy mechanisms involves the upregulation of endothelial progenitor cells (adult stem cells). There is emerging recognition by medical professionals that these adult stem cells are crucial components of cardiovascular health. In fact, scientists now believe that endothelial progenitor cells may serve as a key indicator of overall circulatory function and predict that levels of these specialized stem cells may one day supplant the lipid profile as the biomarker of choice for cardiovascular disease risk.13,24,25
Research within the past five years has shown that the number and functionality of endothelial progenitor cells, which are critically involved in blood vessel repair, are directly correlated with current and future cardiovascular wellness. To put it simply; the more of these endothelial progenitor cells one has in the general circulation, the more robust one’s cardiovascular health is likely to be. Manufactured in the bone marrow, endothelial progenitor cells are low in patients with diabetes, hypertension, and/or cardiovascular disease, and their functionality decreases significantly with advancing age.26-28
Since the publication in 2003 of an article in the influential New England Journal of Medicine, scientists have increasingly focused on the activities of endothelial progenitor cells. In that landmark report, researchers from the National Institutes of Health noted that there is a “strong correlation” between the number of circulating endothelial progenitor cells and a patient’s Framingham risk factor score.13 The Framingham score is a commonly accepted method of assessing an individual’s 10-year risk of developing coronary heart disease. It takes into account risk factors such as LDL, HDL, and triglyceride levels, age, gender, history of smoking, and other factors.
Interestingly, research by Chinese investigators indicates that the influence of cholesterol levels on the development of atherosclerosis (and thus heart disease) may actually relate to the relationship between endothelial progenitor cells and cholesterol. On the heels of the New England Journal of Medicine article, Chinese researchers published a report, which concluded that high LDL may be damaging precisely because it reduces the number and functionality of endothelial progenitor cells.12
Experiments showed, “the number of endothelial progenitor cells was significantly reduced in patients with hypercholesteroemia (extremely high cholesterol levels) compared with that in control subjects.”12 In patients with high total cholesterol and LDL, the ability of endothelial progenitor cells to proliferate, migrate, adhere to vessel walls, and induce the regeneration of vessels was impaired. As cholesterol levels increased, they found, endothelial
progenitor cell levels declined. Other investigators found that endothelial progenitor cell levels are depressed among patients with elevated homocysteine.29 Resveratrol, on the other hand, has been shown in the past year to increase the number of these crucial cells in the peripheral circulation, even at doses achievable by moderate red wine intake or through dietary supplementation.11,14,30,31
Resveratrol Produces Favorable Metabolic Changes
In a landmark mouse study published in the journal Nature, resveratrol countered some effects of a high-calorie diet, improving the health of the mice and increasing their life span, even though they did not lose any weight.32 These mice shared many of the problems of humans on an equivalent diet, including obesity, insulin resistance, and heart disease.
The study compared middle-aged mice fed a standard diet with those on a high-fat (60% of daily calories) diet, with and without high-dose resveratrol supplements. Over a two-year period, the resveratrol-fed mice on the high-fat diet lived as long as the ones on a standard diet and at least 15% longer than their untreated, obese peers. How much better off were the treated mice? The resveratrol-treated mice demonstrated improved insulin sensitivity compared with their obese counterparts who did not receive resveratrol, suggesting that resveratrol conferred important benefits for longevity and diabetes prevention.32 Additionally, the resveratrol-treated animals displayed greater numbers of liver mitochondria than animals who consumed a high-fat diet that did not contain resveratrol. The study further suggested that resveratrol might lead to better health and endurance than is usually seen in obese mice. Resveratrol’s exact working mechanism is not yet known with certainty, but the researchers believe it may be activating SIRT1, a sirtuin protein that is thought to be involved with longevity.
The mouse studies also hinted that resveratrol induces basic metabolic changes akin to those produced by caloric restriction.6,32 Gene-expression analysis in livers of these aged and overweight mice indicated that resveratrol favorably modified some of the known metabolic pathways that are also affected by caloric restriction.32 Perhaps the most intriguing result of the recent mouse studies was resveratrol’s ability to increase the number of mitochondria, the key cell components that serve as energy producers.6,32
Resveratrol’s ability to restore function to mitochondria is especially exciting because it seems that restored mitochondria are more efficient than the aging mitochondria they replace, are less prone to churn out free radicals, and are more efficient at ridding the body of damaged cells that induce chronic inflammatory reactions. Caloric restriction appears to do the same thing, but is much more difficult to implement and maintain in humans.
Resveratrol’s effect on mitochondria may be enough by itself to account for much of the compound’s demonstrable effects in the mouse studies. It may account for the enhanced running abilities observed in the overweight mice treated with resveratrol. What makes the findings of these recent mouse studies so potentially significant to researchers is that humans have genes similar to those linked to resveratrol intake in the mice.6,32
Resveratrol and Cancer
In addition to its anti-aging and anti-heart disease effects, resveratrol may promote longevity through another avenue—that of fighting cancer, one of the chief causes of death in older adults.
When added to cells cultured in media, resveratrol has been found to inhibit the proliferation of a variety of human cancer cell lines, including those from breast, prostate, stomach, colon, pancreatic, and thyroid cancers.33
In 2004, a team of biochemists at the University of Virginia looked at resveratrol’s role in blocking cancer growth and progression. Resveratrol appears to reduce the activation of nuclear factor-kappab (NF-kb), a protein that has been implicated in cancer by acting like a switch to turn on inflammatory processes.34,35 Resveratrol also enhances cancer cell sensitivity to certain immune cell-induced death mechanisms.34 Nuclear factor-kappab inhibitors like resveratrol may thus have important implications for increasing the effectiveness of anticancer therapies in humans.36
Researchers from the State University of New York at Stony Brook looked at the drinking habits of 360 red and white wine drinkers with similar lifestyles. White wine consumption had no association with colorectal cancer incidence. On the other hand, regular red wine consumption was linked to a 68% reduced risk of the cancer. The researchers believe that resveratrol was most likely the component in wine that was behind the apparent benefits.37 The findings confirmed results from an earlier study conducted by the same group showing that wine consumption reduced colorectal cancer risk by 45%.38
Last year, researchers from the University of Alabama at Birmingham examined resveratrol’s potential in preventing prostate tumors. In the study, published in Carcinogenesis, the mice were given the resveratrol found in one liter of red wine per day. Mice who consumed a diet supplemented with resveratrol had a dramatic eight-fold reduced incidence of poorly differentiated prostatic adenocarcinoma, a type of prostate cancer with a poor prognosis. The mice that experienced the greatest cancer-protection effect consumed resveratrol in a powdered formula mixed with their food for seven months.39 Since it is medically inadvisable to consume one liter of red wine every day, this study points to the importance of resveratrol supplementation as part of prostate cancer defense.
An earlier study published in the Journal of Carcinogenesis found that dietary resveratrol helped prevent breast cancer in female rats. Starting at birth, rats were fed either a control diet or a diet supplemented with resveratrol. At the age of 50 days, both groups were exposed to a cancer-inducing chemical. The resveratrol-fed rats were significantly protected against breast cancer, demonstrating fewer tumors per animal and longer tumor latency (an asymptomatic period in this disease process). The researchers concluded, “our work supports the previous reports that resveratrol in the diet is effective at inhibiting…mammary cancer. We have shown that resveratrol can enhance maturation of the mammary gland as well as reduce cellular prolifer-ation and increase apoptosis (programmed cell death) in mammary epithelial cells, in a manner that is protective against mammary carcinogenesis.”40