Resveratrol - Uncovering the Health Benefits of Red Wine

Resveratrol: the Antiaging Compound in Red Wine

Resveratrol is an important phytonutrient and antioxidant that naturally occurs in the skin of red grapes, peanuts, and some berries,^[1] and is touted as the health-promoting compound found in red wine. In the last few years, resveratrol research has exploded. Well over 1,000 research papers have been written to examine the health benefits of this plant compound in the past two years alone. The potent antioxidant and antiaging effects of resveratrol have made it a prime candidate for use as a dietary supplement, as well as a popular agent for topical use. Resveratrol has demonstrated beneficial effects on a vast array of targets, and there is good evidence regarding effects on the circulatory, endocrine, skeletal, and nervous systems, and some preliminary benefits on reproductive health and pregnancy. Resveratrol is also being extensively investigated for its ability to prevent and treat cancer. In this article, we will critically examine the research to assess the current evidence base for the use of resveratrol as an antiaging compound, as well as its effects in preventing the two most common diseases of aging: cardiovascular disease and cancer. Lastly, we will evaluate preliminary evidence for the use of resveratrol to improve fertility outcomes in women with PCOS or obesity, as well as in older women who are trying to conceive.

Early interest in researching resveratrol was sparked by the French paradox, that is, the observation that people in certain parts of France had a relatively low incidence of coronary heart disease despite a high dietary intake of saturated fat. What was it, scientists asked, that prevented inflammation and vascular damage, and prolonged the lives of the French? In the early 1990s, resveratrol was suggested as the missing link, and epidemiological studies emerged suggesting that a moderate intake of wine, red wine in particular, reduced the risk of cardiovascular disease and mortality.^[2] In vitro lab-based studies supported this hypothesis, showing that resveratrol could in fact inhibit processes involved in the development of atherosclerosis, or arterial plaques, including the aggregation of platelets within blood vessels and oxidative damage to LDL cholesterol. A plausible mechanism for cardioprotection was born. Since then, a steadily increasing number of both in vitro and in vivo studies have been conducted, seeking to uncover the mechanism whereby resveratrol can slow the aging process.^[2]

Through such studies, it has been discovered that resveratrol possesses a number of key properties allowing it to prevent age-related changes in the body. For instance, resveratrol possesses strong antioxidant abilities,^{[2, 3]} protecting cells from the harmful effects of reactive oxygen species. Resveratrol protects the DNA within the cells by enhancing telomerase activity,^[4] an enzyme which protects the ends of DNA strands, called telomeres, from the process of gradual shortening that typically occurs as part of the aging process; this process exposes the DNA strands to damage over time and inhibits appropriate genetic expression by the cell. Resveratrol also protects the mitochondria,^[4] the energy-powerhouse of the cell. Its dramatic anti-inflammatory action ^[5] and ability to affect the expression of certain longevity genes ^{[4, 6]} are also crucial to its protective, antiaging mechanism of action.

Due to this vast array of biological activity, resveratrol is able to affect many different tissues and organ systems. In a mouse model fed the human equivalent of 30 mg of resveratrol per day, several protective changes in the heart, brain and skeletal muscle were observed over time.^[7] Neuroprotective effects have also been demonstrated,^[3] along with beneficial effects on memory and cognition.^{[3, 8, 9]} Resveratrol has been shown to act as a selective estrogen receptor modulator.^[10] In a rat model of menopause, it has been shown to prevent bone loss in a degree comparable with hormone replacement therapy (HRT),^[10] while avoiding adverse effects on the cardiovascular system and the uterus (unlike HRT).^{[8, 10]}

Although it has not yet been shown to extend lifespan, resveratrol shows promising results in preventing age-related changes at the cellular level, such as those associated with genetic expression and DNA protection. Due to such effects, resveratrol may be able to prevent or delay the progression of certain age-related diseases, such as Alzheimer’s disease, osteoporosis, cardiovascular disease, and even cancer.^[11] Further studies conducted in human subjects are warranted to determine the most effective dose, form, and duration of resveratrol use. We will now turn our attention to the role of resveratrol on specific conditions including fertility, cardiovascular health, and cancer.

Resveratrol and Fertility

So far, we have described the basis for resveratrol as an antiaging compound. As is well known, fertility declines with age, and it seems that this process can be sped up by the presence of oxidative damage. Therefore, as it relates to fertility, resveratrol may have a role in preserving fertility, protecting immature egg cells or oocytes, and potentially extending the fertile years. The decline in female fertility begins in a woman’s early 30s. In fact, a woman’s chronological age is often cited as the single most important factor in predicting the reproductive potential of a couple. A woman’s age will impact both the quantity of oocytes (immature eggs waiting to be released) as well as the quality of the eggs.^[4] While assisted reproductive technologies (ART) such as in vitro fertilization (IVF) can often increase the number of eggs available to fertilize through induction of “superovulation,” few interventions exist which can favorably impact the quality of the eggs.^[4] As such, poor egg quality often hinders a couple’s ability to conceive.

Each woman is born already possessing all of her egg cells; they are located in each of her ovaries, and are arrested in middevelopment at birth. For 10 to 15 years until puberty, these immature eggs will remain quiescent, until a hormonal cascade signals their growth, ovulation, or atresia (normal breakdown process). During this prolonged wait period, the immature eggs are susceptible to damage caused by free-radical accumulation.^[4] Damage to mitochondria, telomerase, and mutations in the DNA affect egg quality and a woman’s chances of conceiving, as they hinder the ability of the egg to survive and grow.^[4] As described earlier, resveratrol plays a role in protecting cells from oxidative damage by activating antiaging genes, protecting mitochondrial function, and enhancing telomerase activity.^[4] Several animal studies have highlighted the potential ability of resveratrol to favorably impact both egg quality and quantity.

A 2013 study was carried out in mice to assess whether resveratrol could protect oocytes from damage caused by free radicals. Given the plausible mechanism, the researchers wondered whether resveratrol could maintain oocyte quality over time, thus prolonging the reproductive years.^[4] The results were very impressive and provided evidence of a fertility-sparing effect of resveratrol in the female mouse. Mice who had been given resveratrol maintained a larger follicle pool than their age-matched controls.

Furthermore, telomerase activity, and gene expression in the ovaries of the mice receiving resveratrol resembled that of younger mice, indicating resveratrol was able to slow was able to slow the aging process in the ovaries and preserve oocyte quality.^[4] A second animal study showed similar results, with resveratrol-treated animals maintaining a greater number of oocytes in the follicular pool.^[12] Thus, both of these studies demonstrated that treatment with resveratrol is able to favorably impact both the quality and the quantity of oocytes and extend reproductive life span in rodents.^{[4, 12]} It should be noted that although these results seem very promising, there is a need to confirm these effects in humans, as the applicability to extending the human reproductive period remains to be determined.^[4]

A second common condition affecting fertility is polycystic ovary syndrome (PCOS). A newly published study assessed whether resveratrol could pact the follicles of women suffering from PCOS or obesity-related infertility who were undergoing IVF. In women with obesity and/or PCOS, elevated levels of oxidative stress are proposed as a major contributing factor to infertility. For instance, these women have elevated levels of oxidized LDL cholesterol (i.e. damaged LDL), which circulates through the body and subsequently damages various cells and tissues. In the ovary, high levels of oxidized LDL damage developing follicles, which can reduce the chances of ovulation. In fact, in these women, levels of oxidized LDL were approximately double and were found to correlate negatively with the success of IVF outcomes.^[13] The study went on to evaluate whether resveratrol could protect the granulosa cells (the cells which surround and nourish the oocyte) from the damaging effects of oxidized LDL. In the presence of oxidized LDL, the follicle was less likely to survive. However, when the granulosa cells were exposed to resveratrol, markers of oxidative stress were significantly reduced, and the cells were better able to survive.^[13] As a whole, the study highlights a potential role for resveratrol in reducing oxidative stress in the ovary, thereby improving fertility outcomes for women who suffer from infertility related to PCOS or obesity.^[13] Future human trials may help to more fully understand the extent of benefits and possible transgenerational effects of the use of resveratrol to improve fertility outcomes.^[13]

Resveratrol and Metabolic Syndrome: Cardiovascular Risk Factors

Metabolic syndrome is defined as a constellation of risk factors that independently and collectively contribute to the development of cardiovascular disease, diabetes, and early mortality.^[14] This cluster of conditions known as metabolic syndrome includes: central obesity, hypertension, elevated fasting blood sugar, and poor cholesterol profiles. Even the presence of borderline abnormalities of these factors is considered a criteria for metabolic syndrome. Metabolic syndrome currently affects approximately 25% of the North American population. Inflammation and oxidative stress are classically associated with these conditions. Given its demonstrated anti-inflammatory and antioxidant properties, resveratrol is a candidate of prime interest as a dietary intervention for this epidemic.

Based on the observation of the French paradox, the role of resveratrol as a cardioprotective agent seems highly plausible. Moreover, the accumulating body of evidence is highly suggestive that resveratrol is not only able to quench free radicals and fight inflammation, but that it can also inhibit fat accumulation in the liver,^[14] improve endothelial function (blood-vessel function),^[2] benefit cholesterol profiles,^[6] and improve insulin resistance (prediabetes).^[15] In numerous animal trials, resveratrol has been shown to significantly decrease inflammation and improve parameters of vascular health.^{[2, 16]} Resveratrol improved aortic elasticity, maintained health of the vascular endothelium (blood vessel lining),^[16] improved insulin sensitivity, and protected liver cells.^[2]

A study of individuals with type 2 diabetes mellitus was designed to determine the impact of using resveratrol along with oral diabetic medication. While both groups in the study continued to take their hypoglycemic medication, only one group was given resveratrol, at a dose of 250 mg/d. This study demonstrated a statistically significant benefit of resveratrol on several markers of cardiovascular health. Most notably, there were significant improvements in insulin sensitivity, along with reductions in systolic blood pressure and total cholesterol levels.^[15] This study highlights a novel role for resveratrol in reducing cardiovascular risk alongside oral hypoglycaemic agents in type 2 diabetes. Similarly, the benefits of resveratrol supplementation on blood pressure and insulin resistance were replicated in a second study of obese men with impaired glucose tolerance, using a dose of 150 mg/d.^[2] In addition, this study noted decreases in inflammatory markers as well as decreased fat accumulation in the liver after one month of resveratrol use.^[2]

Additional benefits have been documented in studies of patients with angina, where supplementation with 20 mg resveratrol for 60 days resulted in a significant decrease in C-reactive protein (CRP), a marker of inflammation, and improved quality of life;^[17] as well as in smokers, where supplementation with 500 mg resveratrol was shown to significantly increase total antioxidant status, decrease CRP, and improve the cholesterol profile.^[18] Not all of the human studies, however, have been in agreement. In a study of obese subjects with normal glucose control, 500 mg resveratrol failed to show any further benefit on insulin sensitivity or body composition,^[19] calling into question the use of resveratrol in humans with good glycemic (blood-sugar) control. In addition, another study that was conducted to examine the effects of resveratrol supplementation when combined with exercise yielded unexpected results.^[20] A group of previously inactive but otherwise healthy older men were instructed to engage in high-intensity exercise for a period of eight weeks. Half of the study participants were supplemented with resveratrol and the other half received a placebo. By the end of the study, the group of men who did not receive resveratrol showed marked improvements in numerous parameters of cardiovascular health, including reductions in blood pressure and favorable changes to blood-lipid profiles. In the group who did receive resveratrol, these benefits were not observed.^[20] A possible explanation for these unexpected results is that, in the last two studies mentioned, resveratrol was administered to otherwise healthy individuals. It would be hard to show further benefits to blood glucose, for instance, if the subjects already have normal glucose. Therefore it is argued that results from unhealthy populations cannot be generalized to healthy individuals without risk of misleading results.^[21]

Overall, it should be remembered that the vast majority of evidence points towards a potent cardioprotective and antidiabetic role of resveratrol in humans.^{[2, 15, 17, 18]} Low doses of resveratrol (10–30 mg/d) have been shown to favorably impact the action of the heart, while a dose of 90 mg/d has been shown to exert anti-inflammatory action in humans.^[2] For its antidiabetic or insulin-sensitizing action, a higher dose of resveratrol has been studied (150–250mg/d).^{[2, 15]}

Resveratrol and Cancer

We have now examined the role of resveratrol in aging, fertility, and cardiovascular health. In the final section of this article, we will examine how resveratrol acts to prevent the onset of cancer and potentially delay its progression. Resveratrol is showing great promise in the area of cancer treatment and prevention. Numerous in vitro, animal, and human studies have been carried out to date, and have demonstrated a beneficial effect of resveratrol against several types of cancer, including breast, skin, lung, leukemia, bladder and colorectal cancers.^{[2, 22, 23, 24]} The evidence suggests that not only is resveratrol a chemopreventive agent, protecting the cells from the DNA damage associated with aging, but that it can also inhibit the progression of cancer and may even enhance treatment outcomes when combined with certain conventional chemotherapeutic agents. Resveratrol is shown to affect all three discrete stages of carcinogenesis: initiation, promotion, and progression.^{[2, 24]} The mechanism for its anticancer effect is attributed to its anti-inflammatory activity, and its direct ability to modulate signal transduction pathways within the cell, thus affecting the following: cell division and growth; apoptosis (inducing normal cell death); angiogenesis (inhibiting development of new blood vessels that feed tumor cells); and metastasis (inhibiting distant spread of cancer cells).^[24] In addition, resveratrol is able to block a hormone called insulin-like growth factor (IGF-1), which induces obesity-related cancers such as breast and prostate cancer.^[23] Because the cause of cancer is multifactorial, effective anticancer agents need to act through several anticancer mechanisms, as seen with resveratrol.

Some of the best evidence for the role of resveratrol in cancer treatment and prevention comes from the area of colorectal cancer. Colorectal cancer is the third most commonly diagnosed cancer in men, and the second most common in women.^[23] Despite a slow progression and screening measures in place, colorectal cancer continues to have a poor prognosis for many. General dietary and lifestyle recommendations to reduce the risk of developing colorectal cancer include limiting the intake of red meat and processed meat products, avoiding high temperatures when cooking meat, avoiding alcohol and cigarette smoke, maintaining a healthy weight, and incorporating regular physical activity.^[23] Along with these dietary and lifestyle interventions, colorectal cancer is an ideal condition to target with specific chemopreventive agents, given its long precancerous stage.^[23]

In an in vitro study of colon cancer cells from humans, resveratrol was shown to induce tumor cell death (apoptosis) and consistently reduce the number of viable cancerous cells.^[25] Importantly, when combined with the chemotherapeutic agent 5-fluorouracil (5-FU), resveratrol and 5-FU demonstrated a synergistic effect on the suppression of tumor growth and on inducing apoptosis of colon cancer cells.^[25] This unique finding demonstrates the role of resveratrol not only as a protective agent against cancer progression, but also as a chemosensitizer: an agent that allows cancer drugs to work with increased efficacy. Another study in patients with colorectal cancer found that supplementation of 500 mg/d or 1000 mg/d for eight days before surgical treatment was able to reduce tumor cell proliferation as reflected by Ki-67 staining.^[26]

The results of the current study, taken together with the numerous other studies done on a wide array of cancer cell lines, have consistently highlighted the role of resveratrol in inhibiting cancer-cell proliferation and tumorigenesis. The potential use of this antioxidant both in cancer prevention and in the treatment of active cancer, along with chemotherapeutic agents, is an exciting field of ongoing research.^[24]

Conclusion

In conclusion, this article has reviewed the major health benefits of resveratrol, the antioxidant compound found in the skin of red grapes and red wine. Its effects include antioxidant, anti-inflammatory, antiaging, anticarcinogenic, hepatoprotective, and cardioprotective activities. Over the past several decades, resveratrol has received increasing attention in the scientific literature, in large part due to observation of the French paradox. It is now well-established that resveratrol is able to slow cellular aging by a variety of complex mechanisms, including antioxidant and DNA protective effects. Several preliminary studies in animals and humans have highlighted the potential use of resveratrol in couples who are trying to conceive. Preliminary data suggest that resveratrol may have a protective role on developing follicles that are exposed to increased amounts of oxidative stress, either due to the natural aging process, or due to obesity or PCOS. As for its effect on metabolic health, resveratrol has been shown to reduce inflammatory and oxidative damage in the cardiovascular system, protect against nonalcoholic fatty liver disease, and improve lipid profiles. The effect of resveratrol on glycemic control and in combination with exercise has been called into question; however, the bulk of the evidence indicates benefit when used in populations with clinical disease. Resveratrol acts as chemopreventive and anticancer agent via induction of antitumor genes, by regulation of the cell cycle, and by reducing oxidative damage and inflammation. Resveratrol continues to be a compound of high scientific interest and many clinical trials investigating its numerous benefits are currently underway.