Resveratrol & Related Phenolic Compounds

Resveratrol has been called the “miracle molecule” and the “polyphenol most likely to succeed.” It has attracted attention because of a number of scientific studies suggesting that the potential health benefits of red wine are due in part to the phenolic compounds found in the skin and seeds of grapes. Although there are many studies that suggest the phenols in wine give it superior health benefits over other alcoholic beverages, this has not been completely proven.

Phenols are found in all plants and are known as phtoalexins or phytochemicals, compounds that have biological activity in the human body. Without getting too technical, there are two categories of phenolic compounds: non-flavonoids and flavonoids. There are three classes of flavonoids: flavanols, flavonols, and anthocyanins. Resveratrol is the best known phenolic compound of the hundreds found in wine, an anthocyanin occurring primarily in the skin of red grapes where it is produced in response to stresses such as fungal infection.

The levels of resveratrol vary among different grape varieties and vineyards locations. The highest levels of resveratrol are in wines from cooler climates (resveratrol disappears in strong sun). Pinot Noir produces wine with the highest resveratrol counts regardless of where it is grown. Techniques of maceration play a huge role as well (see Washington State University Voice of the Vine Newsletter January 25, 2012).

Much of the scientific research on resveratrol has centered on mice and in vitro (outside the living organism) studies with little work on human subjects. Resveratrol has been demonstrated to lower cholesterol, reduce inflammation, decrease pain, and increase life expectancy of lower forms of life in the lab. It has been shown to be protective against several cancers and therapeutic in some. It has also shown promise in the prophylaxis of heart disease and diabetes mellitus. Despite the optimism, and excitement in the press, the actions of beneficial wine compounds such as resveratrol are complex and poorly understood at this time.

In 2012, Dipak Das, a University of Connecticut professor and researcher who published studies exalting the health benefits of red wine was accused by the university of falsifying data in at least 23 publications over the years, and eventually was dismissed from the university. Much of this research centered on resveratrol and its cardiovascular system benefits. His research represented a very small number of studies among the thousands published to date on resveratrol.

Resveratrol2012, the 2nd International Conference of Resveratrol and Health was held December 5-7, 2012, at the University of Leicester in England (www.resveratrol2012.edu). Of the 65 presentations, 8 focused on the clinical effects of resveratrol. The 2012 recommendations for the use of resveratrol by the conference’s scientific working group are as follows:

1. There are not yet unequivocal scientific data to support the recommendation of resveratrol for disease prevention in humans or for human lifespan extension. Although clinical trials with encouraging results have been completed in the past two years or are currently underway, there is not yet sufficient evidence to unequivocally support a therapeutic effect of resveratrol for the treatment of any specific condition. Preliminary clinical evidence has demonstrated potential benefits with regard to changes in biomarkers and or physiologic parameters that are consistent with health promotion, particularly in the area of endothelial vasodilator function. In many cases, resveratrol has the same effects in humans as have been shown previously in experimental animals.
2. No adverse effects were observed in humans receiving resveratrol as a single agent in short-term studies. Some side effects of resveratrol have been reported at doses at and above 1 gram per day whereas other studies observed no side effects up to 1.5 grams per day. The potential for adverse drug-resveratrol interactions, based in indirect evidence, needs to be evaluated further in clinical trials. In rats, resveratrol is well tolerated with no toxic effects in the range of 700-1000 mg per kg body weight per day.
3. A relevant or optimal dose for resveratrol has to be established in human studies.
4. There is sufficient evidence to suggest that resveratrol enhances vascular health and reduces hypertension, heart failure and ischemic heart disease in experimental animal models including pigs. There are promising results on the prevention of colon and prostate cancer in animals. There is sufficient evidence that resveratrol improves insulin sensitivity, reduces serum glucose levels in multiple animal models, protects against high fat diet-induced obesity, and improves diabetic kidney disease in rodents.

The conference’s scientific working group overall conclusions:

1. To date, published evidence from human trials is not sufficiently strong to justify the recommendation of chronic resveratrol consumption by humans for any given indication.
2. New animal data and recent short-term clinical trials are promising and indicate the need for further longterm human clinical trials.
3. The use of resveratrol is not an alternative to maintaining a healthy lifestyle.

Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases Cell 148 (3) February 2012 A well done study on mice from Boston. Resveratrol has been shown to have health benefits but its mechanism of action remains controversial. The study showed that the metabolic effects of resveratrol result from competitive inhibition of cAMP-dependent phosphodiesterases (PDEs), triggering a cascade of events which in turn increases the activity of important energy-sensing metabolic regulators AMPK, PGC-1a and SIRT 1. Inhibiting PDE4 with rolipram reproduces all metabolic benefits of resveratrol including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose intolerance in mice. Administration of PDE4 inhibitors rolipram and resveratrol may also protect against and ameliorate the symptoms of metabolic diseases associated with aging. The biologic mechanisms demonstrated in this study could lead to new approaches for the prevention or treatment of chronic diseases in humans, especially those related to vascular and metabolic diseases and mortality. The levels of resveratrol in wine or foods are not likely high enough to produce significant health benefits or problems. Inhibitors of PDE4 offer the benefits of resveratrol without the potential toxicities arising from resveratrol’s interactions with other proteins. One PDE4 inhibitor, roflumilast, has been approved by the FDA for the treatment of chronic obstructive pulmonary disease.

Piceatannol, Natural Polyphenolic Stilbene Inhibits Adipogenesis via Modulation of Mitotic Clonal Expansion and Insulin Receptor-dependent Insulin Signaling in Early Phase of Differentiation J of Bio Chem 287 January 2012 Piceatannol is an analog and metabolite of resveratrol that is similar to resveratrol, but it is harder for the body to digest so it stays in the body longer and has strong antioxidant, anti-inflammatory and anti-tumor activities. Piceatannol was found to be an effective fat blocker (converting fat cells into fatty tissue or adipogenesis) in the lab. The anti-adipogenic function of piceatannol is through inhibition of mitotic clonal expansion and insulin receptor activity in the early phase of adipogenesis. Berries, grapes, passion fruit and red wine are high in piceatannol. This study was a lab simulation and more animal and human studies are needed to explore the potential for piceatannol as a modulator of the development of adipose tissue.

Endothelium-dependent Vasodilator and Antioxidant Properties of a Novel Enzymatic Extract of Grape Pomace from Wine Industrial Waste Food Chemistry 135 December 2012 A rat model study showed that grape seed, grape skin extract and grape pomace extracts may possess significant health benefits. Enzymatic extract of grape pomace from wine making possessed antioxidant and protective vascular properties and there is potential for this extract to be a healthy and functional food.

Resveratrol Modulates Murine Collagen-induced Arthritis by Inhibiting Th17 and B-cell Function Annals of Rheum Dis 71 (1) 2012. This study showed that resveratrol can prevent and treat experimentally induced inflammatory arthritis in mice. The mechanism of action is speculative. Curcumin and resveratrol are natural compounds with strong anti-inflammatory effects and could play a role in the treatment of chronic diseases like rheumatoid arthritis.

The Effect of Resveratrol on Longevity Across Species: A Meta-analysis Biology Letters 8 (5) June 21, 2012 A meta-analysis by researchers at New Zealand’s University of Otago of 19 studies that looked at whether resveratrol extended life in various lower life forms. The effect of prolonging life was pronounced only in yeast turquoise killifish and nematodes. Mice and fruit flies longevity was unaffected. Researchers said that the take home message from the research is that people need to consider all the evidence regarding claims of resveratrol life-extending properties especially in the light of the fact that there is no proof in humans that resveratrol supplements can prolong life.

The Lifespan Extension Effects of Resveratrol are Consergved in the Honey Bee and May be Driven by a Mechanism Related to Caloric Restriction Aging 4 (7) July 2012 Researchers in Norway and Arizona found the behavior of honey bees was altered when they were fed diets supplemented with resveratrol. Resveratrol treatments lengthened the lifespan of wild-type honey bees by 33% to 38% and altered their gustation (they regulated their intake of sugar better) and compared to controls, ingested fewer quantities of food. It is not known if the results will translate to humans.

Resveratrol Supplementation Does Not Improve Metabolic Function in Nonobese Women with Normal Glucose Tolerance Cell Metabolism 16 (5) October 2012 A study of healthy, non-obese post-menopausal women in their 50s and 60s who took resveratrol supplements for 12 weeks showed no change in factors linked to developing diabetes and heart disease. Resveratrol supplementation increased plasma resveratrol concentration, but did not change resting metabolic rate, LDL, HDL, and total cholesterol. To get the equivalent amount of resveratrol from wine used in this study, women in the resveratrol group would have had to drink 8 liters of red wine a day. This suggests that resveratrol supplements do not benefit healthy people. Sales of resveratrol supplements are now about $30 million a year. The researchers emphasized that resveratrol may be involved in health-boosting benefits of red wine even though resveratrol in pill form does not appear to benefit healthy people. Exercise, proper diet, and managing stress are more important than a pill.

Dietary Factors and Lung Function in the General Population: Wine and Resveratrol Intake Eur Respir J 39 March 2012 This research was conducted in the Netherlands and assessed the impact of wine and resveratrol on lung function. The dose of resveratrol in the study was at a level expected from moderate wine consumption. Resveratrol intake is associated with a higher forced vital capacity (FVC) levels and white wine intake with higher forced expiratory volume and lower risk of airway obstruction. Genetic factors were not related. The International Scientific Forum on Alcohol Research criticized this study in that resveratrol may not be the key factor and there are probably many compounds in wine that are responsible. The study did not prove resveratrol was the direct cause and effect since the researchers studied white wine as well. Many studies have shown that moderate wine intake has a favorable affect on lung function but the source of the effect is unknown.

High-dose Resveratrol Supplementation in Obese Men: An Investigator-initiated, Randomized, Placebocontrolled Clinical Trial of Substrate Metabolism, Insulin Sensitivity, and Body Composition Diabetes 28 2012 24 obese, but otherwise healthy men, were randomly assigned to one month of resveratol supplements or placebo treatment. Extensive metabolic examination before and after treatment found that insulin sensitivity, endogenous glucose production, turnover rate of glucose, blood pressure, and other metabolic factors were unchanged in those receiving resveratrol supplementation. This lack of effect disagrees with persuasive data from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.

Red Wine Could Mask Testosterone Levels Science Daily January 8, 2013 Researchers found in a test tube experiment that the polyphenol quercetin in red wine partially blocks the action of UCT2B17 which searches for testosterone and signals the kidneys to excrete it in the urine. The upshot of this is that red wine might boost athletes’ performance by increasing the level of the hormone testosterone in their bodies. Red wine could also potentially distort the findings of drug tests taken from urine samples since the wine might reduce the amount of testosterone secreted. Athletes are prohibited from taking testosterone since it can boost muscle mass and stamina and speed recovery. Green and white tea can also inhibit testosterone excretion. There are no human trials yet.

A Possible Role for Perforin and Granzyme B in Resveratrol-enhanced Radiosensitivity of Prostate Cancer Journal of Andrology 33 (4) July-August 2012 Researchers from the University of Missouri School of Medicine found that resveratrol makes prostate tumor cells more susceptible to radiation treatment at least in part due to increased apoptosis (cell death). When resveratrol was introduced into the prostate tumor cells, 97 percent of them died, a higher percentage than with treatment with radiation alone. The dosage of resveratrol was so high that humans would experience side effects. Resveratrol helps increase the activity of perforin and granzyme B, proteins needed to kill tumor cells. Previously it has been found that resveratrol made tumor cells more susceptible to chemotherapy. Animal studies and then clinical studies are planned looking at delivery methods to deliver resveratrol to the tumor site.

Influence of Red Wine Polyphenols and Ethanol on the Gut Microbiota Ecology and Biochemical Biomarkers Amer J of Clin Nutrition 95 (6) May 2, 2012 A Spanish study followed 10 healthy middle-aged men who were given one of three beverages to drink: 9 oz of Merlot, 9 oz of low-alcohol-content red wine, or about 3 oz of gin. The results indicated that the balance of intestinal bacteria shifted in the men in a similar way whether they drank Merlot or low-alcohol red wine showing a larger percent of certain beneficial bacteria typically found in the colon. Presumably this effect was due to polyphenols in wine. This suggests that possibly there are prebiotic benefits associated with the inclusion of red wine polyphenols in the diet. This was the first in vivo study to show regular moderate consumption of red wine could have a significant affect on the growth of select gut microbiota. This could be implicated in the reduction of C-reactive protein and cholesterol also observed in the study.

The Red Wine Study. 26 medical centers in the United States are participating in this study. Researchers are studying whether resveratrol can stop the progression of Alzheimer’s Disease. Doctors believe that resveratrol can activate a gene associated with aging of the brain. In the study, patients will take pills containing a concentrated form of resveratrol with a gradually increasing dose until they are taking the resveratrol equivalent of 1,000 bottles of red wine. Stay tuned.

224th National Meeting & Exposition of the American Chemical Society August 19, 2012 (reported at www.medicalxpress.com). Cal State Los Angeles researchers studied young and old lab mice which were fed a diet containing resveratrol for 8 weeks. They periodically tested their ability to navigate a steel mesh balance beam. Initially, the older mice had more difficulty maneuvering on the obstacle, but by week 4, the older mice were on a par with the young mice. This study was the first of its kind. The theoretical mechanism proposed is that resveratrol mitigates the damage done by oxygen free radicals generated by the breakdown of dopamine and activates protein signaling pathways that appear to promote cell survival. The problem is that resveratrol is poorly absorbed in the body so investigations are looking at man-made compounds that mimic the effects of resveratrol and have more bioavailability. A preliminary study of resveratrol supplement versus a blueberry diet found that the fruit was more effective at reversing age related motor deficits. Even if the effects of resveratrol in brain are minute, a small margin potentially could be enough to help older people remain steady on their feet and avoid falls.

One-year Consumption of a Grape Nutraceutical Containing Resveratrol Improves the Inflammatory and Fibrinolytic Status of Patients in Primary Prevention of Cardiovascular Disease Amer J Cardiology 110 (3) August 2012 An investigation of the effects of a dietary resveratrol-rich grape supplement on inflammatory and fibrinolytic status of subjects with high risk of cardiovascular disease. 75 patients were studied in a triple-blinded, randomized, parallel, dose-response, placebo-controlled 1-year follow up trial. The 1-year consumption of a resveratrol-rich grape supplement improved inflammatory and fibrinolytic status in patients who were on statins for primary prevention of cardiovascular disease and at high risk for cardiovascular disease. This study shows for the first time that dietary intervention with grape resveratrol could complement the standard therapy in primary prevention of cardiovascular disease. No adverse effects of the supplement were observed.

A large number of studies have shown that resveratrol inhibits cancers. A South Korea study found resveratrol stopped progression of fibrosarcoma, a connective tissue cancer. An Israel study found resveratrol inhibited the growth of colon cancer cells. An Italian study found resveratrol and related plant polyphenols inhibited skin cancer growth caused by ultraviolet radiation. A US study found resveratrol inhibited the growth of breast cancer by stopping stem-like cells that form into breast cancer tumors. Spain researchers found resveratrol inhibited the growth of breast cancer. Other studies have shown an inhibitory effect of resveratrol in multiple myeloma, lung, prostate, pancreatic and thyroid cancer. It has been noted that to achieve a minimum ability to affect gene expression of potential or already-forming cancer cells, at least 20 milligrams per day are needed. It would require 41 glasses of typical red wine to achieve this minimum effective dose of 20 milligrams.