The Debate as to the Health Benefits of Wine Continues in 2011 Part 3

Breast Cancer

The relationship of breast cancer and alcohol has drawn more commentary in the press this year than any other subject dealing with health and drinking. After the Harvard-led Nurses’ Health Study was published in 2011, panic swept over the country as the study indicated that drinking as little as three glasses of wine or other drinks increased the risk of breast cancer in women compared to abstainers. Published in the Journal of American Medical Association (November 1, 2011), this prospective study reviewed the lifetime exposure to alcohol from 1976 to the present in 106,000 women ages 30 to 55 over the 28-year study period. 7,690 women developed breast cancer during the followup. Women who drank as few as three to six drinks a week increased their risk of breast cancer by a modest 15 percent. The risk increased significantly for heavy drinkers with a 51% increased risk of developing breast cancer compared to abstainers during the study period in women who consumed 19 or more drinks per week. The results indicate that there is a dose-response effect that is independent of beverage type. Alcohol intake between the ages of 18 and 40 was linked with higher breast cancer risk later in life regardless of what drinking habits were after the age of 40 indicating that the cumulative amount a woman consumed during all of adulthood was the best predictor of risk. Binge drinking (6 or more drinks at one sitting) led to a 33% increased risk of breast cancer independent of total alcohol intake over time. Summary: The seemingly alarming number if a 15% increased risk in light drinkers, need to be clarified. The overall average risk for women nondrinkers for breast cancer over a lifetime is 12% (currently more than 230,000 women a year develop breast cancer in the United States). The 15% increased risk found in this study for light drinkers translates to a 13.8% risk for women. The authors of the study admit that this increased risk was quite small. This was an observational study and cause and effect cannot be linked for certain. Only a controlled clinical trial of the relationship between alcohol and breast cancer could account completely for all confounders. The study’s lead author, Wendy Chen, M.D., said, “What I generally tell women is to keep alcohol consumption at a few servings per week.

Discussion

Steven A. Narod, M.D., director of familial breast cancer research at the Women’s College Research Institute in Toronto, Canada, offered an authoritative take on drinking and breast cancer risk in an editorial accompanying the Nurses’ Health Study research. He pointed out the following. The risk of breast cancer for women in their 50s is 2.4% according to the National Cancer Institute. Using the data from the Nurses’ Health Study Research, the 10-year risk rises to 2.8% for women who are light drinkers (less than 1 drink a day), to 3.5% for those who have 1 drink a day (moderate drinkers), and to 4.1% for those that have 2 drinks or more a day. Viewed in these terms, the increased 10 year risk of breast cancer in postmenopausal women is very modest. He remarked, “Some women with other risk factors like a family history of breast cancer or a genetic marker like the BRCA gene may find it prudent to stop drinking. But there is no data to give assurance that giving up alcohol will reduce breast cancer risk. For women without high risk factors who are moderate drinkers, I don’t think they need to stop.”

It is thought that the higher risk of breast cancer with more than 2 drinks a day is due to an increase in the amount of estrogen and related hormones that circulate in the blood. Alcohol increases the estradiol blood levels in both pre- and post-menopausal women and may increase the expression of estrogen receptors in breast cells stimulating them to proliferate. This effect appears to be independent of beverage type. The lifetime exposure to reproductive hormones is one of a number of factors that affect the risk of developing breast cancer and is related to number of children, breast feeding, oral contraceptives and hormone replacement drugs, and time of onset of menstruation and menopause. Since breast cancer is a multi-risk factor disease, other factors are important as well and will vary depending on the individual woman. These include age, family history, obesity (particularly weight gain at and after menopause), lack of exercise, smoking, exposure to ionizing radiation (mammograms use low-dose radiation and are thought to be safe), and mutations in the BRCA genes. It is obviously important for women to consult with their physicians to understand what their risk factors and how to manage them.

The rub is that the decrease risk of heart disease with moderate drinking is significantly greater than the rise in risk of breast cancer. Heart disease is the No. 1 cause of death in females of all ages according to the Centers for Disease C ontrol and Prevention. Women have a 39.2% chance of developing cardiovascular disease in a lifetime. Moderate drinking reduces this risk by 40% to 60% depending on the study. If you consider 40%, the lifetime risk decreases to 23.5%. According to the American Heart Association, one out of every 30 deaths in women is due to breast cancer and one out of every three deaths is attributable to heart disease. Each year 88,000 females age 45 to 64 have a heart attack and 50% will die within 8 years. 63 percent of women who die from a heart attack have no previous symptoms. It has been shown that all the well-known risk factors for heart disease put together (obesity, family history, high blood pressure, high cholesterol, etc.) are not as effective a predictor of heart attack as an EBCT heart scan, which shows the amount of calcium accumulated in the coronary arteries. Doctors refer to EBCT as “the mammogram for the heart.” At $255, the test is inexpensive and is something to consider if there is any significant risk factor for heart disease.

The International Scientific Forum on Alcohol Research emphasized that in the Nurses’ Health Study strong effects for the amount of alcohol and the frequency of consumption were not found. Also, the effects of folate intake on the association between alcohol and cancer were not reported although the same investigators had previously shown that folate is a potential moderator of the effects of alcohol on breast cancer risk. The Forum goes on to discuss the dilemma that women face regarding alcohol intake, which may increase slightly the risk of breast cancer but markedly decrease the risk of cardiovascular disease. Forum members and the authors agree, “An individual will need to weigh the modest risks of light to moderate alcohol use on breast cancer development against the beneficial effects on cardiovascular disease to make the best personal choice regarding alcohol consumption.”

The mention of folate by the Forum is worth discussing further in the context of breast cancer risk. Linda Prost, a nutritionist who lives and practices in Eugene, Oregon, and is the author of “Live in the Balance: The Ground- Breaking East-West Nutrition Program,” wrote about the beneficial effects of folate in the Register-Guard (December 19, 2011). She points out that back in 2005, a report in the British Medical Journal found that Australian women who were moderate to heavy drinkers (2 to 4 or more alcoholic drinks a day) and had low folate intake, had a significantly increased risk of breast cancer compared to light drinkers or abstainers. When moderate or heavy drinkers took 400 micrograms of folate the risk was offset. Other studies have shown that taking extra folate counteracts the risk of breast cancer in women who drink moderately. Diet supplementation with 400 micrograms of folate per day also has been shown to offset the increased risk of colorectal cancer in those men and women who drink two or more alcoholic beverages a day. Ina addition, studies have also shown that increased intake of folate decreases the risk of oral cancer.

Prost notes that excellent sources of folate include liver (the French are known to consume large amounts of foie gras and duck liver pate which are rich sources of folate and may help explain the French Paradox), turnip greens, spinach, asparagus, peanuts, and hummus. Folate can also be taken as a supplement, and folate (Lmethylfolate) which is the naturally occurring form found in foods, is a better choice than folic acid. She finishes her report by saying, “If you plan to sip more than a few glasses of libation a week over the holidays, or ever, consider serving up extra chicken livers or duck pate, sauteed greens, asparagus, peanuts and bean dishes. Supplementing with folate is also a good idea. You may be able to protect yourself from breast and colon cancer, reduce your risk of heart disease, and celebrate the holidays all at once.”

The effect of alcohol consumption on women who carry a BRCA gene mutation is unclear. BRCA genes function as tumor suppressors, but mutations of these genes, which are hereditary, may be harmful. The mutations can be detected with genetic screening. A case-control study published in the medical journal Breast (December 2010) of 1925 matched pairs of predominantly pre-menopausal women who carried a BRCA1 or BRCA2 mutation found that alcohol consumption did not appear to increase breast cancer risk in women carrying a BRCA gene mutation. Compared to non drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of cancer among BRCA1 carriers.

The same researchers from the Universities of Montreal, Ottawa and Toronto, Canada, will publish another study in early 2012 in The Breast Journal. Prepublication information was obtained by winespectator.com. This study found that women with the BRCA1 mutation showed a 62% lower risk of breast cancer than the general population if they drank wine, while women with the BRCA2 mutation showed a 58% greater risk. The researchers attributed the difference to the polyphenol resveratrol found in wine. Resveratrol can bind to estrogen receptors and assist in the regulation of activity of BRCA1-mutated genes, but BRCA2 mutated genes appear to be unreceptive to resveratrol. This theory is speculative as there may be other substances in wine that are decreasing the risk in women with the BRCA1 mutation.

A research report published online in The FASEB Journal (October 2011) is relevant. This study showed that resveratrol stops breast cancer cells from growing in vitro by blocking the growth effects of estrogen. A team of American and Italian scientists suggest for the first time that resveratrol is able to counteract the malignant progression by inhibiting the proliferation of hormone resistant breast cancer cells. The authors of the study conclude that resveratrol may prove to be a pharmacological tool to be used in cases when breast cancer becomes resistant to hormonal therapy by therapeutic agents such as tamoxifen. However, they are quick to point out that it does not mean people should start using red wine or resveratrol supplements as a treatment for breast cancer. Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal said, “What it does mean, however, is that scientists haven’t finished distilling the secrets of good health that have been hidden in natural products such as red wine.”

It is of note that Americans consume 8.96 liters of wine per capita, while those in France, Portugal and Italy consume 42-45 liters per capita, yet there are no studies from Europe that link alcohol to breast cancer. Could red wine be protective? A new study to be published in an upcoming issue of theJournal of Women’s Health found that drinking red wine in moderation appears to counter the risks of breast cancer risk associated with alcohol. Researchers at Cedars-Sinai Medical Center and the University of Southern California gave 8 ounces of red wine daily in the evening to 36 women and 8 ounces of white wine to another 36. After a month, the type of wine served was reversed. Blood was collected twice during the women’s menstrual cycle to measure hormone levels. The researchers found more favorable lower estrogen and higher testosterone levels when women drank red wine, while white wine did not have the same effect..

The data in this study suggested that substances in the skin and seeds of red grapes act like a class of drugs called aromatase inhibitors (AIs) which have hormone modulating effects and may explain why red wine does not appear to raise breast cancer risk. In other words, red wine acts like a nutritional AI and may work like some of the hormone treatments currently used for cancer. The findings do not mean that white wine raises breast cancer risk. The authors of the study went so far as to suggest that women who drink white wine should consider switching to red wine, but the research does not suggest that women increase their red wine consumption beyond moderation. Obviously, a much larger study is needed to confirm whether red wine can reduce breast cancer risk.

Elaine Schattner, writing in The Atlantic online (January 2012), concludes her commentary on the above research with the following pertinent statement. “The underlying problem is that it’s hard to prove cause and effect in the context of widespread alcohol use to varying degrees among women in North America today. You can’t ethically test the premise that a likely carcinogen is harmful by giving it prospectively to some women and not to others. The correlation is clear enough, but women who drink alcohol tend to be heavier than those who don’t. In some communities women who have access to alcohol may also be more affluent, more educated, or more sedentary; these and other potential co-factors aren’t easy to dismiss.”

Finally, it should be mentioned that lung cancer kills more women than breast cancer. Lung cancer is more lethal and a bigger killer of women than all the other cancers combined. The disease receives little notoriety and has a stigma attached due to its association with smoking. The fact is that most new lung cancers in women are in those who have never smoked or quit many years ago.

Other Cancers

Alcohol (ethanol) has been known to be a carcinogen at several sites in the human body since the 1980s. For most cancers, there is a dose-response curve in that the risk increases with the more alcohol people consume on a regular basis. Years of research have linked alcohol to cancers of the mouth, throat, larynx, esophagus, stomach, colon, pancreas, liver and lung. The highest association of alcohol and cancer is with cancers of the mouth, throat, larynx and esophagus. Many drinkers also smoke and this compounds the risk for these cancers. Generally, the risks of these cancers is related to heavy drinking. The quantity of alcohol matters most for men’s cancer risk. The frequency of drinking is more meaningful for women’s risk. There is no firm evidence that wine is a healthier drink from the standpoint of cancer risk although at least one study from Spain published in 2004 found that the slight association between consuming white wine and lung cancer disappeared in people who drank red wine and red wine actually had a protective effect.

It is estimated that 90% of the cancer deaths in men world wide could be avoided if drinking was limited to two alcoholic drinks a day and 50% of the cancer deaths in women could be avoided if drinking was limited to no more than one. It is unclear how long it takes for the increased risk associated with heavy drinking to resolve once drinkers cut back.

Arthur L. Klatsky, M.D., a noted alcohol researcher at the Kaiser Permanente Medical Care Program in Oakland, California, presented a talk at this years Sixth International Wine and Heart Health Summit in Newberg, Oregon, titled, “Alcoholic Beverages and the Risk of Cancer: A Balanced View.” He made the following points:

* Epidemiological evidence shows a strong association of chronic heavy alcohol consumption with cancers of the oral cavity, pharynx, larynx and esophagus. The synergy between alcohol and tobacco is strong. The relationship of moderate drinking is unclear.
* There is a clear association of heavy drinking with liver cancer.
* There is a fairly consistent association of heavier alcohol drinking with female breast cancer, but there is considerable debate about the presence and level of a risk threshold.
* The least consistent alcohol-cancer relationship is the link to the risk of colorectal cancer. Dietary folate deficiency may be an intermediary.
* The data on many other cancer types is inconclusive.
* There is a lower risk to alcohol drinkers for hematologic cancers, especially non-Hodgkins lymphoma and kidney cancer.
* The choice of alcoholic beverage is not shown to be a major factor in alcohol-cancer relationships (but see report above to be published in the Journal of Women’s Health).

Klatsky points out that there are no randomized controlled trials of the association between alcohol and cancer so a definite cause and effect relationship is difficult to confirm. Results from current cohort and case-control analyses are diminished by residual confounding and problematic statistical modeling as well as underestimation of drinking amount by study participants.

A study published in the American Journal of Epidemiology (November 11, 2011) linked alcohol consumption to four types of cancer: breast, colorectal, lung and prostate. This National Health Interview Survey conducted by epidemiologists from the National Institute on Alcohol Abuse and Alcoholism along with Harvard alcohol researcher Kenneth Mukamal had 323,000 American participants. 1 drink a day led to a lower risk of cancer than nondrinkers (13% less). Those who had 2-3 drinks a day had the same risk for the cancers as nondrinkers. People who had more than 3 drinks a day had a 27% higher risk of developing the four cancers (men) or 41% higher risk (women). Summary: The research confirms previous studies that link heavy drinking to an increased risk of certain cancers. This study did not eliminate all confounders such as lifestyle choices and did not distinguish between types of alcohol which is unfortunate.

At the American College of Chest Physicians meeting, October 2011, a large study from the Kaiser Permanente health system in Oakland, California, was reported that found that those who drank 3 or more drinks per day regularly, even if they had never smoked cigarettes, had a 30%-40% increased risk of lung cancer with the strongest risk being among beer drinkers.

A study published last year in Alcoholism: Clinical & Experimental Research (December 2011), headed by a United States team from the National Institute on Alcohol Abuse and Alcoholism, found that when ethanol is metabolized in the body, the byproducts can lead to DNA damage that may lead to cancerous changes in cells. Researchers used human cells engineered to produce an enzyme found in liver and breast tissue. The cells were exposed to a concentration of alcohol similar to blood alcohol levels attained after having a few drinks. The results indicated that ethanol was being converted to acetaldehyde, causing DNA damage and switching on the cell’s DNA repair genes. Summary: The study is consistent with a suspect role for acetaldehyde in alcohol related liver and breast cancer, but more studies on animals and humans are necessary to prove such a role.

Research by the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort looked at alcohol consumption and gastric cancer risk. Published in the American Journal of Clinical Nutrition (November 2011), the study found that heavy alcohol consumption (equal to or greater than 6 drinks a day) was association with and increased gastric cancer risk. The association was found for beer, but not wine or spirits. Lower alcohol consumption (less than 6 drinks a day) was not associated with gastric cancer risk. Summary: Heavy but not light or moderate primarily beer drinking is association with gastric cancer risk. This was a convenience sample so the transferability of the study results to the general population can be questioned.

In Nutrition and Cancer (October 2011), cancer risk and alcohol consumption were studied by reviewing a large number of epidemiological studies. Heavy alcohol consumption (equal to or greater than 4 drinks a day) resulted in a 5 fold increase risk of oral and pharyngeal cancer, and squamous cell cancer of the esophagus. The risk for laryngeal cancer was 2.5 fold. The risk for colorectal cancer was increased by 50% and the risk for breast cancer was increased by 30%. At low doses of alcohol drinking (equal to or less than 1 drink a day) the risk for oral and pharyngeal cancer was increased 20% and the risk of esophageal squamous cell cancer was increased 30%. At this level of drinking there was no increased risk of laryngeal, colorectal or pancreatic cancer. Moderate alcohol intake, especially wine, was inversely associated with distal colorectal cancer and no risk of endometrial cancer. If alcohol consumption was less than 3 drinks a week, there was no increased risk of breast cancer and at 3 to 6 drinks a week, there was a small increased risk. Summary: Heavy drinking is associated with a significant increased risk of colorectal, breast, pancreatic, oral, pharyngeal, laryngeal, and esophageal cancers.

A large Chinese population analysis of all studies involving alcohol consumption and cancer was published in PLoSOne (April 2011). Cohort studies indicated that alcohol consumption was not associated with gastric, esophageal and lung cancers. Case-control studies did show an increased risk of gastric, liver, nasopharyngeal and oral cancers and alcohol consumption was protective for female breast cancer and gallbladder cancer. No significant correlations were found with lung, colorectal, pancreatic and prostate cancers. Summary: The combined results of case-control and cohort studies reviewed revealed that alcohol consumption was associated with a higher risk of esophageal and gastric cancers.

A large prospective cohort study in eight European countries regarding the alcohol attributable burden of incidence of cancer was reported in the British Medical Journal (April 2011). Participants included 109,118 men and 254,870 women, mainly aged 37-70. If causality is assumed, for both men and women, the incidence of total cancer was attributable to former and current alcohol consumption in the eight European countries. For selected cancers the figures were 44% (21 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (-3 to 38%) for liver, 17% (10 to 25%) and 4% (-1 to 10%) for colorectal cancer for men and women, respectively, and 5% (2 to 8%) for female breast cancer. For all cancers causally related to alcohol consumption, the proportions were 32% in men and 5% in women, with a substantial part (40-98%) being attributable to current alcohol consumption above the recommended limit of two drinks a day in men and one drink a day in women. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit. Summary: In western Europe, many cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits.

A new study published online by the Journal of the American Medical Association(January 26, 2012) assessed the prevalence of oral human papillomavirus (HPV) infection in the United States. The study showed that 7% of American teens and adults carry HPV in their mouths and that oral sex practices are a key method of transmission. This high incidence or oral HPV may explain the increasing rates of mouth and throat cancer over the last 25 years. The number of cases of HPV-related oropharyngeal cancers has increased from 0.8 per 100,000 people in 1988 to 2.6 per 100,000 people in 2004 (according to the Ohio State University Comprehensive Cancer Center). A study published in Journal of Clinical Oncology (October 2011) found that 70% of new cases of oral cancers are related to HPV infection, making it more causative than tobacco. HPV is also the leading cause of cervical cancer in women. HPV vaccines approved by the FDA are not a cure and can't effectively prevent all strains of HPV infection in those who are sexually active. It is uncertain if the HPV vaccine protects against oropharyngeal cancers. Polyphenols, specifically epicatechin-based antioxidant compounds from cocao have shown to have strong antiviral properties. Resveratrol has been shown to inhibit herpes simplex virus types 1 and 2, varicella-zoster virus, certain inluenza viruses and human cytomegalovirus. Preliminary studies in mice indicate reservatrol can inhibit oral cancer in mice (see report describe below under Reservatrol).

Resveratrol

The bloom is partially off the rose regarding the hype over resveratrol which has been the darling of the media as a panacea for longer life and many other beneficial health effects. Resveratrol was first reported in red wine in 1992 and early on it was thought to explain the French Paradox. Subsequent studies found that resveratrol could extend lifespan in cell culture and animal models and inhibit the development of cancer, diabetes and other life-threatening illnesses. Some recent studies have disputed some of the early research and tempered some of the optimism (see page 13). There have been a limited number of human trials to date with a substantial body of research on lab animals. Human studies have shown good safety but poor bioavailabity. Resveratrol is found not only in grapes, but in grape juice, peanuts and berries including blueberries and cranberries. Resveratrol is but one of many polyphenol flavonoids which are also found in spices and dried herbs, cocoa, some seeds (flaxseed), chestnuts and hazelnuts, and some vegetables including olives and globe artichoke leaves. Resveratrol is found primarily in the skin of red grapes with the amount varying depending on the grape and its geographic origin. The chart below shows published resveratrol content of red wines from various wine-producing regions. There are no significant differences in the polyphenolic composition of wine between wine made from organically grown and conventionally grown grapes. Resveratrol levels in wine can be increased by extending maceration times and by malolactic fermentation and can be decreased by fining and filtration.

Resveratrol is the most researched of the class of compounds known as polyphenols. At the recent 6th International Wine and Heart Health Summit in Newberg, Oregon, Balz Frei, PhD, Director and Endowed Distinguished Professor in the Department of Biochemistry & Biophysics at Oregon State University, presented a paper titled, “Flavonoids; From Antioxidant Capacity to Cardiovascular Functions.” This is highly relevant to any discussion of resveratrol and other polyphenols in wine and will be summarized here.

Flavonoids consist of 5,000 plant compounds with a common chemical structure called polyphenol (polyphenols have multiple aromatic rings, that is, six connected carbon atoms who share electrons - see chemical tattoo of resveratrol above). They are found in fruits, vegetables, and beverages such as wine, tea, cocoa and fruit juices. There are seven subclasses of flavonoids: (1) isoflavones (soy products), (2) flavanones (for example naringenin in citrus), (3) flavanols (catechins and condensed tannins or proanthocyanidins in tea, cocoa, red wine and several fruits), (4) flavonols (quercetin in fruits and vegetables), (5) anthocyanidins (in berries and grapes including resveratrol), (6) flavons and (7) flavanonols. Flavonoids are poorly absorbed in the digestive tract, rapidly eliminated and have a low bioavailability with their metabolites having often less activity. This has required that studies on flavonoids use high unphysiological amounts and these studies have shown powerful antioxidant activity in vitro but limited effect in vivo. Their beneficial effects have often been attributed to antioxidant actions.

Dr. Frei makes the following important points:

* There is minimal or no direct antioxidant activity of flavonoids compared to other important antioxidants like Vitamin C and E.
* Instead, flavonoids modulate cell-signaling pathways, that is, cell growth, cell proliferation, and removal of damaged cells (apoptosis).
* The concentration need to affect cell-signaling mechanisms is much lower than that need to affect cellular antioxidant activity.
* Flavonoids may selectively inhibit cell-signaling enzymes called kinases which initiate chronic disease.
* The modulation of cell-signaling by flavonoids could help prevent cardiovascular disease by (1) decreasing inflammation by lowering c-reactive protein and inhibiting atherosclerosis secondary to inflammation of arterial walls, (2) decreasing vascular endothelial cell adhesion so that inflammatory white blood cells are not allowed to adhere, and (3) increasing vascular endothelial nitric oxide which maintains normal blood vessel relaxation (dilation). Decreasing endothelial-dependent vasodilation is closely related to the risk of cardiovascular disease.
* Proanthocyanadins are able to suppress endothelin-1 factor which is important in the development of coronary artery disease.
* Flavonoids decrease platelet aggregation which is one of the first steps in forming a blood clot.
* Flavonoids can cross the blood-brain barrier and exert a multiplicity of neuroprotective actions in the brain including (1) protecting neurons against injury from neurotoxins, (2) suppressing neurological inflammation which has a crucial role in Alzheimer’s and Parkinson’s diseases, (3) promoting memory, learning, and cognitive function, and (4) reversing the course of neuronal and behavioral aging.

Also at the International Wine and Heart Health Conference, Roger Corder, PhD and MRPharmS from London’s School of Medicine & Dentistry presented a talk on “the Importance of Dietary Polyphenols for Optimal Vascular Health.” He noted that the total polyphenol concentration in red wine is between 1 and 3.5 g/L with some wine from Tannat and Sagrantino grapes exceeding 5 g/L. Polyphenol concentration is related to grape variety and the length of maceration of the pips and skins. Other factors are oak aging, vineyard management, ripeness and terroir. The polyphenols contribute to color, flavor and mouth feel of red wines. The importance of the different polyphenols in red wine is the subject of much debate. Corder has shown that the oligomeric procyanidins (OPC - a type of flavonol) have greatest effect on vascular endothelial function at the concentration found in red wine. Resveratrol and quercetin lack biological activity on the vascular endothelium in amounts found in red wine. He plans future clinical trials on OPC-rich products to determine if they could have a future pharmacological role in the prevention and treatment of cardiovascular disease.

I have referenced a number of studies involving resveratrol in previous pages of this issue, but I will summarize additional important research published or presented in 2011 on resveratrol and other polyphenols.

Dr. Andrew Waterhouse, Professor of Enology at University of California at Davis reported on papers presented at the 5th International Conference on Polyphenols & Health in Spain in 2011. His comments were published in Wines & Vines (December 2011). One significant study found that the consumption of wine polyphenols when eating meat results in lower lipid oxidation in the stomach and lower levels of toxic aldehydes circulating in the blood. Summary: Drinking red wine with meat has favorable health implications. Note: Dr. Waterhouse points out that since about 2000, the U.S. wine industry has pursued a policy of not funding health related research, and the U.S. government has always avoided supporting any research that might show benefits to alcohol consumption. The reality of this was reflected in the large number of studies reported at the Conference on olive oil, chocolate and juices including grape juices, which all benefit from strong industry funding.

Research presented by the Dutch at the American Heart Association High Blood Pressure Research Meeting in Florida was published in Health Day News (September 2011). 61 people who averaged over 61 years of age with borderline high blood pressure were given daily beverages containing red wine polyphenol or a placebo. No difference in blood pressure was found in the two groups after 4 weeks. Summary: Polyphenols may be beneficial in reducing heart disease, but it does not seem to be through the mechanism of lowering blood pressure.

A study of red wine polyphenols was reported in Food Research International (online July 29, 2011). The researchers studied in vitro the effects of red wine polyphenols on oxidation stability of human plasma fatty acids, particularly those most involved in inflammatory responses. Wine polyphenols conferred increased resistance to perioxidation of omega-3 more than omega-6 fatty acids. Summary: Red wine polyphenols may protect omega-3 fatty acids from breaking down in the body. This may be one of the mechanisms to explain the cardiovascular benefits of red wine consumption.

A double-blind randomized placebo-controlled intervention study on 28 male smokers supplemented with 200 mg a day of monomeric and oligomeric flavanols (MOFs) from grape seeds was published in PLoSOne (December 2011). All subsequent measured vascular effects at 4 and 8 weeks after instituting supplementation were integrated into a global, so-called vascular health index which revealed a significant improvement of overall vascular health compared to placebo. Summary: This integrative multi-biomarker approach unveiled the pleiotropic vascular health benefit of an 8 week supplementation with 200 mg/d of MOF in humans.

A review published this past year did not find that resveratrol could prolong survival or life span of mice. Published in Heart Failure Reviews (July 2011), resveratrol was found to induce expression of several longevity genes including Sirt1, Sirt3, Sirt 4, Fox01, Foxo3a, and PBEF and prevent aging related cardiovascular decline function including cholesterol level and inflammatory response but was unable to affect the actual survival of laboratory mice. Summary:Resveratrol possesses diverse biochemical and physiological properties, including estrogenic, anti-platelet and anti-inflammatory properties as well as a wide range of health benefits ranging from chemoprevention to cardioprotection. Its life-prolonging ability is controversial and this review disputes its ability to affect actual survival or life span of mice.

A study published in Nutrition, Metabolism & Cardiovascular Disease (November 2011) is the first of its kind investigating whether resveratrol can improve flow-mediated dilation (FMD) in a clinical trial setting. This randomized, double-blind, placebo-controlled crossover human intervention trial used obese subjects with high blood pressure. They were give 3 doses (30-90-270 mg) and a placebo using 3 doses a week and the FMD was measured. With increasing doses of resveratrol, there was a proportional increase in the blood plasma resveratrol concentration and FMD was increased for each of the doses. FMD is the loss of endothelial-dependent vascular smooth muscle relaxation and when impaired is a cardiovascular disease risk factor. Summary: Oral resveratrol improved endothelial-dependent vasodilation by increasing FMD. There was significant improvement in FMD even at the lowest dose. This effect may contribute to the purported cardiovascular health benefits of grapes and red wine. It is not clear that the amount of resveratrol in a normal diet will have the same effect. Dietary supplements may be the answer.

A comprehensive review of human clinical trials of resveratrol and health was published in Molecular Nutrition & Food Research (April 2011). Summary:"The emerging data from human clinical trials confirms what the past decade of in vitro and laboratory animal models have suggested: resveratrol has considerable potential to improve health and prevent chronic disease in humans. We believe the evidence is sufficiently strong to conclude that a single dose of resveratrol is able to induce beneficial physiologic responses, and that either weeks or months of resveratrol supplementation produces physiologic changes that are predictive of improved health, especially in clinical populations with compromised health. However, it is not yet certain if long term resveratrol supplementation will maintain these physiologic benefits to ultimately impact the incidence of chronic disease or extend lifespan, and the small number of human clinical trials remains dwarfed by the thousands of basic science experiments. Nonetheless, we believe it is possible that healthy individuals may still benefit from resveratrol’s potential to delay or prevent age and lifestyle induced decrements in health, though considerable research is need on this front."

Robert Sclafani, a professor of biochemistry and molecular genetics at the University of Colorado School of Medicine and Rajesh Agarwal, a professor in the Department of Pharmaceutical Studies at the School of Medicine have recently found that resveratrol is successful in preventing oral cancer in mice. Their hope is to test the effects of resveratrol in humans with oral cancer. High quantities of concentrated resveratrol could be given to patients with oral cancer as a mouth wash or gel. To date, there are no known side effects of resveratrol. This preliminary report was published online at aurorasentinel.com. Summary:Resveratrol is extremely effective in preventing the appearance of oral cancer in mice.

Two interesting studies published in Food Chemistry (October and December 2011) looked at which type of cooperage produces wines with the highest polyphenol content. Aging wine in oak barrels changes the sensory characteristics of the wine plus the antioxidant capacity of the wine which is primarily due to polyphenols. The first study on toasting found that wine aged in non-toasted oak barrels had significantly higher antioxidant and total polyphenol levels than wines aged in oak barrels that had been toasted. A second study looked at the origin of the barrel wood and the species of the plant. Aging wine in different species of wood did have influence on the antioxidant capacity of wine due to varying polyphenol composition of different wood species. Theoretically, some woods such as chestnut which are higher in polyphenols could produce healthier wines. Summary: The antioxidant capacity and polyphenolic composition of different woods used in cooperage can result in different polyphenolic composition of the resultant wine.

I will conclude this section on resveratrol with a few comments on resveratrol supplements which have caught the fancy of many consumers. A word of caution is needed since resveratrol supplements are not regulated by the FDA and the pills vary widely in their purity and actual potency. Many producers are using deceptive marketing to tout the value of resveratrol supplements, yet they have no proven health benefit and long-term effects are yet unknown. The supplements must be made in an oxygen-free environment (single-pill foil wraps) to obtain the active compound and they must be in the trans-resveratrol form. Resveratrol can slow down the speed at which the liver metabolizes certain drugs such as statins and calcium channel blockers and this could affect dosing of these drugs, but otherwise it is thought that the supplements are probably safe if used in moderate doses (100 to 500 mg a day). Many researchers feel it makes more sense to drink red wine and eat foods that contain high amounts of resveratrol naturally than take unproven supplements.

Binge Drinking

A study by the Centers for Disease Control and Prevention (CDC) adults was released in January 2012 as part of a new report highlighting the dangers of binge drinking. The study was titled, "Excessive Alcohol Use: Addressing a leading risk for death, chronic disease and injury." About one in six adults 18 and older (about 33 million adults total) and one in four adults between the ages of 18 and 34 report binge drinking one or more times within the last 30 days using the definition of four or more drinks within a short period of time or occasion for women and five or more drinks within a short period of time or occasion for men. "Occasion" was not strictly defined in the survey and this is one of the weaknesses of the report. An "occasion" could mean an evening, a day or a weekend and its time period was left up to the interpretation of the survey respondents. Binge drinkers engage in this activity on average about four times a month or roughly once a week. Seniors who reported binge drinking (only about 4% of people 65 years of age and over binge drink) did so more frequently, about five times a month, than even younger people which was a surprise to the leaders of the CDC. Also surprising was the finding that binge drinkers reported consuming eight or more drinks on average during at least the largest episodes of binge drinking within the past 30 days. College-age adults average 9 alcoholic beverages when they binge drink. That level of drinking puts the individual binge drinker at an increased risk for a host of problems including long-term issues of cancer, heart disease and liver failure, not to mention sexually transmitted diseases that may result from unprotected sex that is frequently associated with binge drinking. Binge drinking was more common in men, white non-Hispanics, people who have been to college, those with incomes of $75,000 or more, active-duty military personnel, college students, and residents of the upper midwest with Wisconsin topping the list. Also, the study found that binge drinkers engage in this activity on average about four times a month or roughly once a week. Health officials estimate that about 50% of the alcohol consumed in the United States by adults each year is drank during binge drinking episodes. The CDC study also found that of the 80,000 deaths that alcohol is responsible for in this country every year, half of them are due to binge drinking. 14 colleges and universities have teamed in The Learning Collaborative on High-Risk Drinking, which will examine ways to thwart binge drinking, which affects an estimated 40 percent of college students nationally. For information, visit www.nchip.org/alcohol.

UCLA researchers have discovered a compound that counteracts the effects of alcohol. The report was published in the Journal of Neuroscience (January 2012). In vitro experiments on rats involved giving them a strong dose of alcohol and then some rats were also given Dihydromyricetin (DHM) which is from the ancient Hovenia Dulcis tree, an ancient herbal treatment. Rats that received the DHM sobered up faster, showed a higher tolerance for alcohol in general, and showed fewer side effects usually associated with hangovers. The research was aimed at finding a treatment for alcohol use disorders, but the hangover resistance was a surprising finding. Rats that were allowed to drink alcohol gradually start consuming more of it, but if they drank DHM-laced alcohol, they did not show a desire to increase consumption. Summary: DHM shows promise as a treatment for alcohol use disorders since no alcohol addiction occurs when alcohol is drank with DHM. DHM may also prove useful in treating hangovers. Human trials are needed to confirm the results.

Anti-Alcohol Forces

The position statement released by the Cancer Council of Australia (CCA) on May 1, 2011 surprised the scientific community. This report was well detailed by Margaret Raber online at winespectator.com (May 13, 2011). The position statement claimed that 5 percent of all cancers in that country were due to long-term alcohol use, arguing that alcohol increased the risk of developing certain cancers such as upper aerodigestive tract cancers and colorectal cancers in men and breast cancers in women. The report claimed that 7 percent of male colorectal cancer cases in men and 22 percent of female breast cancer cases were due to alcohol consumption. The basis for this claim came from data for the United Kingdom, gleaned from the World Cancer Research Fund and the American Institute for Cancer Research. They also stated that alcohol could increase body weight which further increased the risk for cancer. The CCA recommended that people stop drinking alcohol completely or at least stay within the nationally recommended maximums. The CCA went on to say that the current research on the relationship between alcohol and heart health is flawed. The report claimed that 7 percent of male colorectal cancer cases and 22 percent of female breast cancer cases were due to alcohol.

Soon after the report was released, the Winemaker’s Federation of Australia responded, emphasizing, “There is currently no research to show a positive relationship between moderate alcohol consumption and cancer risk.” Researchers questioned some of the facts contained in the report, including the high rate of risk of breast cancer related to alcohol. Dr. Richard Corder, PhD & MRPharmS, a noted polyphenol researcher from London’s School of Medicine and Dentistry commented, “The paper is alarmist, perhaps because too many Australians drink in excess, and so perhaps the message is actually one of moderation to avoid adverse consequences.” It is true, that Australians have a notorious reputation for copious social drinking with at least 13.4 percent of Australians drinking at a high risk level of 7 or more drinks per day for men and 5 or more for women (as of the latest National Health Survey statistics in 1995). The typical Australian starts drinking alcohol at the age of 15.5 and binge drinking is a serious problem during the teen years.

In August, 2011, the federally funded Alcohol Education & Rehabilitation Foundation in Australia recommended favored warnings for alcoholic beverages that included: “Drinking alcohol increases your risk of developing cancers,” and “Drinking alcohol damages the young developing brain.” A helpline was set up for people who were concerned about alcohol intake. The Australian Medical Association urged the government to require tough mandatory health warnings on alcoholic beverages. Australia’s alcohol industry launched its own voluntary program to label its products with health warnings aimed primarily at teenagers and pregnant women. DrinkWise Australia, headed up the alcohol industry’s program and has released three principal messages that include, “Kids and Alcohol Don’t Mix,” “Its Safest Not to Drink While Pregnant,” and “Is Your Drinking Harming Yourself or Others.”

The Alcohol Policy Coalition of Australia (APC), a group of Australian health organizations, released a position paper in September 2011 titled, “Myth Busted: Red Wine No Magic Remedy for Heart Disease,” and published a document entitled Cancer, Cardiovascular Disease and Alcohol Consumption. Kathy Bell, CEO of the Heart Foundation and a member of the coalition said, “After reviewing all the scientific evidence it appears any positive effects of alcohol in reducing the risk of cardiovascular disease have been hugely overestimated. In particular, red wine has no special, protective qualities when it relates to cardiovascular diseases. The Heart Foundation does not recommend red wine or other types of alcohol to prevent or treat cardiovascular disease. To reduce your lifetime risk of alcohol related harm, you should drink no more than two standard drinks on any day.”

The International Scientific Forum on Alcohol Research responded to the APC’s publication in Critique 058. Members of the forum said, “They were disturbed that the coalition statement was limited almost exclusively to the effects of abusive drinking, was based primarily on extremely limited sources of information, and indicated a strong bias against alcohol.” Forum members contended that the Australian report misrepresented the extensive scientific data available on alcohol and health. The full critique can be read at http://www.bu.edu/ alcohol-forum/critique-058-a-misguided-statement-on-alcohol-and-health-from-a-coalition-in-australia-28- september-2011/.

The APC in turn responded to Critique 058 and the argument rages on. The APC’s response can be viewed at http://www.bu.edu/alcohol-forum/a-response-from-the-alcohol-policy-coalition-of-australia-to-critique-058- %E2%80%9Ca-misguided-statement-on-alcohol-and-health-from-a-coalition-in-australia%E2%80%9D/.

There continues to be significant anti-alcohol sentiment throughout the world. For example, Professor Jennie Connor of the Dunedin School of Medicine in New Zealand, stated to couriermail.com.au, “I feel strongly that there is no scientific justification for the promotion of alcohol as health-enhancing for any subgroup of the population. The potential for harm is great, and the potential for good is unknown." Nicolay Sorenson of Alcohol Concern in the UK told decanter.com, “There is no such thing as risk-free drinking. Every unit of alcohol you drink has a toxic effect as soon as it enters your body.”

Postscript

A very conservative, but appropriate view of the alcohol and health discussion is taken by Arthur L. Klatsky, M.D., whose name has appeared throughout this review. He feels confident in making the following generalizations. The increased risk of alcohol related accidents in young men (a 30-year-old for example) outweighs the possible heart related benefits of moderate alcohol consumption. Young women are at low risk for cardiovascular disease so the risk of moderate drinking exceed the benefits. The cardiovascular benefits of moderate consumption increases with age so that a 60-year-old man who drinks one drink a day can expect that the protection afforded against heart disease is likely to outweigh potential harm. A 60-year-old woman is more likely to die from heart disease than breast cancer, so the benefits of light to moderate consumption outweigh the risks, even though women are often afraid of breast cancer. In other words, mature adults benefit potentially most from moderate alcohol consumption.

The health benefits from red wine are only obtainable through regular and moderate consumption. Individual ideals will vary considerably depending on a number of factors, but the most widely accepted recommendation is one glass of red wine a day for women and up to two glasses of red wine daily for men, assuming no medical contraindications. Consult your physician before altering your alcohol consumption habits.

The words of Hermann Smith-Johannson, a Scandinavian cross-country skier who died at the age of 103, are a fitting conclusion to this discussion. “The secret to a long life is to stay busy, get plenty of exercise, and don’t drink too much. Then again, don’t drink too little.