Abstract
As indicated by epidemiological studies, regular and moderate wine consumption, particularly red wine, has been associated with health benefits. Clinical studies and work performed with animal models indicate that wine may protect against cardiovascular disease, atherosclerosis, hypertension, certain types of cancer, type 2 diabetes, neurological disorders, and metabolic syndrome. The mechanism of action has been attributed to antioxidant, lipid regulating, and anti-inflammatory effects. A variety of wine constituents have been studied in various disease models. Both the alcoholic and polyphenolic components of wine are believed to contribute to these beneficial effects. As wine is a complex mixture, it is likely that a multitude of chemical constituents, as well as their metabolites, work synergistically to impact human health. In sum, although wine drinking may be contraindicated in certain individuals, in healthy people, regular consumption of moderate amounts of wine may protect against certain chronic health conditions.
It has been estimated that the medicinal use of wine dates back to 2200 bc, making it the oldest known medicine (Robinson 2006). Historically, wine has been used as an antiseptic, a painkiller, and to treat dermatological conditions and digestive disorders (Feher et al. 2005, Robinson 2006). In the early 1990s, media coverage of the French Paradox popularized the health benefits of red wine in the United States and spurred research efforts to examine and explain new connections between wine and health.
The French Paradox is based on epidemiological studies that report a comparatively lower incidence of coronary heart disease in France despite high levels of saturated fat in the traditional French diet. A moderate daily consumption of red wine has been proposed to contribute to this effect (Renaud and Gueguen 1998). Additional epidemiological studies from diverse populations have revealed that individuals who habitually consume moderate amounts of wine experience a 20 to 30% reduction in all-cause mortality, particularly cardiovascular mortality, when compared with individuals who abstain or who drink alcohol to excess (German and Walzem 2000, Ruf 2003). Critics of these studies argue that the average moderate wine drinker is more likely to exercise, to be health conscious, and to be of a higher educational and socioeconomic class (Lindberg and Amsterdam 2008). Despite these potential confounding factors, there is a growing body of evidence from studies performed in animals and humans that support a connection between regular moderate wine drinking and improved health.
There is also a large body of evidence that supports the health benefits derived from grapes, grape juice, and grape seed extract (GSE). These products have been used to treat a variety of conditions, including cancer, cardiovascular disease, ischemic stroke, neurodegenerative disorders, aging, hypertension, hyperlipedemia, and dental caries (Perez-Jimenez and Saura-Calixto 2008, Iriti and Faoro 2009, Kaur et al. 2009, Nassiri-Asl and Hosseinzadeh 2009, Wu 2009, Yadav et al. 2009). Although the chemical constituents of grapes and wine vary to some degree, similar therapeutic effects have been attributed to wine. Some investigators believe these benefits may actually be enhanced in wine, perhaps due to additive effects with the alcohol component of wine and/or to an increased bioavailability of wine polyphenols as a result of the fermentation process.
The mechanisms responsible for the healthful effects of wine are extremely complex. Both the alcohol and the polyphenol components have been extensively studied and there is controversy over which component is more important (Rimm et al. 1996, Hansen et al. 2005). It has been well documented that a moderate intake of alcoholic beverages produces positive effects on antioxidants, lipids, and platelets (reviewed in Lindberg and Amsterdam 2008). Other studies provide evidence that wine demonstrates beneficial properties that are independent from the presence of alcohol, which has been attributed to the polyphenol content of wine (reviewed in Ruf 2003, Halpern 2008). Red wine has been shown to confer a greater degree of health benefits than white wine. Wine polyphenols, which mainly originate from the skins and seeds of grapes, are present in a greater variety and concentration in red wine than in white wine.
Red wine polyphenols are a complex mixture of flavonoids (such as anthocyanins and flavan-3-ols) and nonflavonoids (such as resveratrol, cinnamates, and gallic acid). Flavan-3-ols are the most abundant, with polymeric procyanidins (condensed tannins) composing up to 50% of the total phenolic constituents (Waterhouse 2002). Examples of compounds found in grapes with known health benefits include melatonin, catechins, ellagic acid, lutein, quercetin, and resveratrol (Leifert and Abeywardena 2008, Pezzuto 2008). These compounds act as potent antioxidants, reduce harmful low-density lipoprotein (LDL) cholesterol oxidation, modulate cell signaling pathways, and reduce platelet aggregation. Chemical interactions between these and potentially hundreds, if not thousands, of other wine constituents, interact to produce a pleiotropic array of therapeutic effects.
Resveratrol has been extensively studied as a critical constituent that contributes to the health benefits of red wine. Resveratrol, which alters lipid metabolism, inhibits LDL oxidation, and inhibits platelet aggregation, has exhibited both cardioprotective and chemopreventive effects in animal studies (Guerrero et al. 2009). It also inhibits the growth of some tumor types and exhibits anti-inflammatory, antibacterial, antifungal, antiviral, neuroprotective, antiproliferative, and antiangiogenic activities (Nassiri-Asl and Hosseinzadeh 2009).
A class of red wine polyphenols that has been identified as especially protective is the procyanidins. Red wines from southwestern France and Sardinia, Italy, have between two and four times as much procyanidins as other red wines. These regional wines have been suggested to contribute to the longer lifespan noted in these populations (Corder et al. 2006). However, it should be noted that procyanidins have a low bioavailability.
Antioxidant Effects
The antioxidant effects associated with moderate wine drinking may be one of the factors responsible for the French Paradox. A high fat diet is known to cause high levels of oxidative damage to plasma lipoproteins, which is counteracted by antioxidants present in wine. Oxidative stress is also associated with chronic diseases, including atherosclerosis, heart failure, cancer, and neurological degeneration, and is believed to accelerate the aging process. Red wine has been shown to protect against each of these conditions by increasing plasma antioxidant capacity, suppressing reactive oxygen species generation, increasing serum oxygen radical absorbance capacity, and decreasing oxidative DNA damage. The oxidation of LDL cholesterol is strongly associated with cardiovascular disease. It has been demonstrated that wine flavonoids protect against LDL oxidation (Aviram and Fuhrman 2002, Ursini and Sevanian 2002). Wine procyanidins have been shown to be especially active in preventing lipid oxidation of foods while in the digestive tract, indicating that red wine consumption with a meal affords the most protection (Ursini and Sevanian 2002).
The balance between alcohol and polyphenols in a wine may be critical in determining its antioxidant potential (van Golde et al. 1999). It is known that alcohol has pro-oxidant effects. Studies performed with dealcoholized wine, grapes, and GSE have shown strong antioxidant effects, indicating that the polyphenol content contributes critically to the antioxidant abilities of wine (Young et al. 2000, Abu-Amsha Caccetta et al. 2001, Bagchi et al. 2002, Durak et al. 2002, O’Byrne et al. 2002, Park et al. 2003, 2009, Vigna et al. 2003, Ko et al. 2005, Zern et al. 2005, Castilla et al. 2006). The antioxidant effects of red wine and of its major polyphenols have been demonstrated with in vitro systems, in cell culture, and in human subjects (Soleas et al. 1997, Fernandez-Pachon et al. 2006, Modun et al. 2008). Important antioxidant components include caffeic acid, catechin, chlorogenic acid, epicatechin, ferulic acid, myricetin, protocatechuic acid, quercetin, and resveratrol (Chopra et al. 2000, Boveris et al. 2002, Afaq et al. 2003). In five samples of red wines from Spain, total antioxidant activity correlated with polyphenol content (Lopez-Velez et al. 2003). In humans, wine polyphenols taken at physiologically relevant concentrations interacted synergistically to produce antioxidant effects (Pignatelli et al. 2006).
An examination of a selection of studies performed in healthy humans (Table 1) reveals that the quantity and pattern of wine consumption are critical determinants of antioxidant outcomes. For example, when only one dose of wine was given, benefits were only transient (i.e., not observed after 3 hr). When greater than 200 mL red wine was given daily for up to three weeks, a positive effect was seen in the majority of studies. In studies of four weeks or more, daily consumption of greater than 200 mL red or white wine improved antioxidant parameters, although there was an indication that the effects were not as great in the case of low-alcohol content wines.
Effect of wine consumption on antioxidant parameters in healthy humans.
Lipid Effects
Regular moderate wine consumption is associated with beneficial changes in lipid homeostasis. Wine increases high-density lipoprotein (HDL) cholesterol, which is important for ridding the body of excess cholesterol. Wine also decreases LDL cholesterol levels, which are associated with a high fat diet. High LDL cholesterol levels are associated with an increased risk of atherosclerosis, obesity, and type 2 diabetes (Njajou et al. 2009). Wine consumption with a meal is believed to be ideal because it allows cholesterol to be cleared before it is deposited in undesired locations in the body.
In a selection of studies measuring lipid effects of wine in healthy humans (Table 2), a single dose of wine was ineffective at modulating lipid levels. Studies performed for two weeks or more indicate that greater than 200 mL red wine consumption was beneficial. All of the studies with more than one dose indicated that the alcohol component of wine is critical for the beneficial lipid effects, which is supported by the established concept that alcohol raises HDL levels. However, this contradicts observations that grapes, grape juice, and grape extracts positively modulate cholesterol homeostasis (Preuss et al. 2000, Zern et al. 2005, Castilla et al. 2006, Davalos et al. 2006, Sano et al. 2007, Jimenez et al. 2008). Overall, red wine was more effective than white wine, suggesting that wine polyphenols did play a role.
Effect of wine consumption on lipid parameters in healthy humans.
Although the data presented in Table 2 do not describe a wine-associated decrease in triglyceride levels, there is some evidence that GSE or red wine consumption (150 mL for 3 weeks) may combat obesity by decreasing appetite, especially in females (Vogels et al. 2004, Djurovic et al. 2007). One study found that a diet with 10% of energy derived from white wine or grape juice for 3 months reduced percent body fat, waist circumference, blood pressure, blood glucose, insulin, triglycerides, and cholesterol, and body weight in obese subjects (Flechtner-Mors et al. 2004).
Immune Function/Inflammation
Chronic inflammation is a critical component in many human diseases and conditions, including obesity, cardiovascular diseases, neurodegenerative diseases, diabetes, aging, and types of cancer. The ethanol and polyphenol components of wine are capable of modulating immune responses (reviewed in Magrone et al. 2008). Changes in inflammatory biomarkers in human subjects suggest that red wine is capable of protecting against various immune-related disorders by both stimulating the innate and adaptive immune responses as well as reducing inflammation. Examples of these changes include suppression of inflammatory cytokine release (such as nuclear factor-kappaB) and induction of anti-inflammatory cytokine release and other protective molecules (i.e., interleukins 1α, 6, 10, 12, and interferon-gamma). Nitric oxide (NO), which protects against infections, has been shown to be released from peripheral blood mononuclear cells in response to red wine polyphenols. Inflammatory biomarkers that are reduced by wine drinking include C-reactive protein (CRP), monocyte, and endothelial adhesion molecules (ICAM-1, vascular CAM-1, E-selectin, LFA-1, Mac-1, VLA-4, MCP-1). Wine is also associated with a reduction in fibrinogen, plasma viscosity, and white blood cell count (Estruch et al. 2004, Imhof et al. 2004). In human and animal studies, grape juice and grape extract also supported immune function and exhibited anti-inflammatory effects, supporting a role for wine polyphenols (Zern et al. 2005, Castilla et al. 2006, 2008, Percival 2009).
Analysis of a selection of studies performed in healthy humans (Table 3) shows that positive effects on immune function require greater than two weeks of consumption at levels of at least two glasses of wine (300 mL) daily for men (less for women). Red wine appears to have greater positive effects than white wine. The importance of the alcohol content is not clear from these studies. However, an epidemiological study performed at multiple European sites found that moderate daily consumption of either wine or beer were both associated with lower levels of systemic inflammatory markers compared to nondrinking and heavy drinking individuals, indicating a role of alcohol (Imhof et al. 2004).
Effect of wine consumption on immune parameters in healthy humans.
Cardiovascular Effects
Cardiovascular diseases are the leading cause of death worldwide in both men and women. Moderate wine consumption (one to two glasses daily) has been associated with decreased cardiovascular mortality and decreased risk of heart disease in epidemiological studies and meta-analyses (de Gaetano et al. 2003). These benefits have been attributed to increased antioxidant capacities, changes in lipid profiles, and anti-inflammatory effects (reviewed in Cordova et al. 2005, Dohadwala and Vita 2009). Other contributing effects include decreased platelet aggregation, improved endothelial function, and increased fibrinolysis. Regular red wine consumption may especially benefit those at risk for atherosclerosis, hypertension, and hypercholesterolemia (Wang et al. 2002, Coimbra et al. 2005, Jimenez et al. 2008). Human studies have demonstrated that white wine, red wine, and GSE each significantly increased adiponectin levels, indicating a decreased risk of myocardial infarction (Sano et al. 2007, Joosten et al. 2008, Imhof et al. 2009).
Two meta-analyses performed in 2002 identified a dose-response relation between wine intake and vascular risk resulting in a J-shaped curve, suggesting that moderate drinkers may benefit while abstainers and heavy drinkers are at higher risk. The first analysis, which included 13 studies involving 209,418 people, found that the relative risk of vascular disease associated with one glass of wine (150 mL) daily was 0.68 (95% CI: 0.59–0.77) compared with nondrinkers (Di Castelnuovo et al. 2002). The second meta-analysis included 19 studies and also found a negative association of moderate wine consumption with the risk of cardiovascular events, with a significant risk reduction at two drinks (300 mL) per day (de Gaetano et al. 2002). A meta-analysis performed in 1999 found that consumption of one to four drinks per day was associated with a slightly reduced risk of mortality and coronary heart disease (Cleophas 1999). However, this study did not find an increased benefit of wine over beer or spirits.
There is conflicting evidence as to whether the alcohol or the polyphenol content of red wine is responsible for its cardioprotective effects. Moderate consumption of alcohol elevates HDL cholesterol, lowers fibrinogen plasma levels, and may prevent platelet aggregation. Red wine polyphenols exhibit antioxidant, vasorelaxant, and antithrombotic properties (Opie and Lecour 2007). Red wine polyphenols that have been implicated in protection against myocardial ischemic reperfusion injury in animal models include resveratrol and proanthocyanidins (Das et al. 1999, Rakotovao et al. 2004, Opie and Lecour 2007). There is evidence that white wine may also be cardioprotective due to alcohol and antioxidant (caffeic acid, tyrosol, and hydroxytyrosol) components (Bertelli 2007). Overall, numerous studies support the finding that wine, especially red wine, is cardioprotective.
Coagulation and platelet function.
Several studies have concluded the alcohol component of wine is largely responsible for its antiplatelet activities (Pace-Asciak et al. 1996, Pellegrini et al. 1996). Alcohol has anticoagulant properties that limit blood clotting by making platelets less prone to stick together and reducing the levels of fibrin protein that binds them together. However, more recent studies implicate wine polyphenols as the key mediator (reviewed in Ruf 2004). Clinical trials demonstrating that grapes and grape juice decrease platelet aggregation support the polyphenol argument (Folts 1998, Keevil et al. 2000). That is contradicted by findings that 300 mL of white wine daily for two weeks exhibited a higher antiplatelet activity than red wine with the same alcohol content (Pignatelli et al. 2002). However, the most likely case is that the benefits of alcohol and polyphenols are additive, which is supported by findings that alcohol, red wine, and polyphenolic grape extract each inhibited platelet adhesion in human blood (de Lange et al. 2004).
There is evidence that the effects of wine on blood coagulation may only be transient, indicating that moderate chronic consumption is critical for beneficial outcomes (Lavy et al. 1994, Kikura et al. 2004). This could explain conflicting data regarding the effect of wine on levels of fibrinogen, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), plasma protein C, CRP, von Willebrand factor, antithrombin III, plasminogen, factors VII and VIII, as well as measurements of bleeding time, platelet counts, platelet aggregation, prothrombin time, partial thromboplastin time, activated cephalin time, and thrombin-antithrombin complexes (Lavy et al. 1994, Pellegrini et al. 1996, van Golde et al. 2003, Mezzano 2004, Coimbra et al. 2005, Hansen et al. 2005). There are indications that inconsistencies in diet (i.e., high fat vs. low fat) between studies may also confound the results (Mezzano 2004). Another complication is that the assay techniques (i.e., using fibrinogen vs. collagen to stimulate platelet aggregation) apparently affect the outcome (de Lange et al. 2004, Mezzano 2004). It is not clear if this is relevant for in vivo situations.
Endothelial function.
Endothelial dysfunction is an indicator of poor prognosis in most forms of cardiovascular disease. Endothelial cells play a major role in regulating the balance between the synthesis and interaction of proteins that promote clot formation and fibrinolytic proteins that facilitate fibrinolysis (clot lysis). The endothelium regulates vascular tone by releasing NO (vasorelaxant) or endothelins (vasoconstrictors). Constricted blood vessels raise blood pressure and are more prone to clot formation. In animal models, wine polyphenols caused endothelium-dependent vasorelaxation associated with NO stimulating activity (Caimi et al. 2003b). Red wine polyphenols that promote endothelium-dependent NO production include catechin, quercetin, procyanidins, and resveratrol (Gresele et al. 2008). Wine polyphenols are believed to also have a longer-term effect by increasing endothelial NO synthase (eNOS) expression (Dell’Agli et al. 2004). Wine polyphenol content was found to correlate with inhibition of synthesis of endothelin-1 (Corder et al. 2006). A short-term supplementation of red wine caused a significant increase in circulating endothelial progenitor cells in mice (Balestrieri et al. 2008).
A favorable action of red wine, dealcoholized wine extract, or purple grape juice on endothelial function has been observed. However, ethanol alone has been shown to cause vasodilatation, making the discrimination between ethanol and polyphenol effects controversial. Short-term ingestion of red wine or purple grape juice improved endothelial function in patients with coronary artery disease (Stein et al. 1999, Whelan et al. 2004). Such benefits were not observed when more than five glasses of wine were consumed at once (binge drinking), a level at which alcohol may become toxic (Hijmering et al. 2007). Another study found dealcoholized red wine to be more effective than regular red wine (Agewall et al. 2000), but there are data that contradict these results (Boban et al. 2006, Naissides et al. 2006b).
Red wine consumption has been demonstrated to enhance endothelium-independent vasodilatation in hypercholesterolemic patients (Coimbra et al. 2005). Red wine counteracted the reduction of endothelial function caused by a high fat diet when moderate amounts were consumed over the long term (Cuevas et al. 2000), but not the short term (Djousse et al. 1999). Consumption of red wine and green olive oil with a meal was found to improve the postprandial endothelial function in a synergistic manner, which may involve an elevated plasma antioxidant capacity (Karatzi et al. 2008). Another study did not find a benefit of drinking one glass of red wine with a meal (Napoli et al. 2004), indicating that long-term consumption may be necessary for optimal results. Overall, regular, moderate red wine consumption has been demonstrated to improve endothelial function.
Fibrinolysis.
Both ethanol and polyphenols present in wine have been shown to modulate fibrinolysis (Booyse et al. 2007). Either 30 g alcohol or the equivalent amount of red wine (~300 mL) daily for four weeks reduced fibrinogen levels in healthy humans (Pellegrini et al. 1996). Similar effects were found when 300 mL (males) or 200 mL (females) of red wine (but not red grape extract) were consumed daily for four weeks (Hansen et al. 2005). Endothelial cell-mediated upregulation of t-PA and urokinase plasminogen activator (u-PA) activity and downregulation of PAI-1 (the major inhibitor/regulator of fibrinolysis) may be involved (Pasten and Grenett 2006). There are indications that long-term moderate red wine consumption is required for positive effects and that exercise may enhance these benefits (Johansen et al. 1999).
Atherosclerosis.
Studies performed with in vitro systems, in animals, and in human subjects have shown that red wine polyphenols interfere with the initiation, progression, and rupture of atherosclerotic plaques by exhibiting antioxidant, antiplatelet, and antithrombotic activities (reviewed in Aviram and Fuhrman 2002, Szmitko and Verma 2005, Lagrue-Lak-Hal and Andriantsitohaina 2006). Red wine polyphenols lower blood pressure, reduce inflammation, improve endothelial function, decrease the expression of adhesion molecules, and inhibit smooth muscle cell proliferation and migration (Dell’Agli et al. 2004). These processes all interfere with atherosclerotic plaque development, vascular thrombosis, and occlusion.
Red wines have exhibited positive effects on biomarkers of atherosclerosis in healthy humans, including a decrease in the LDL/HDL ratio, fibrinogen levels, lipoprotein (a), clotting factors, CRP, and oxidized LDL levels (Sharpe et al. 1995, Avellone et al. 2006). Also, increases in HDL cholesterol, TGFbeta, t-PA, PAI-1, membrane fluidity, and total plasma antioxidant capacity were reported. Human studies have demonstrated that short-term interventions with moderate amounts of ethanol, dealcoholized red wine, or low polyphenol sparkling wine reduced the risk of atherosclerosis, as measured by biomarkers (Vazquez-Agell et al. 2007, Imhof et al. 2008). These data indicate that the alcohol and polyphenol wine components are both important and have additive effects There is a report that one dose of 400 mL of red wine, but not dealcoholized red wine, increased coronary flow reserve in humans (Kiviniemi et al. 2007). However, another study cautioned that one month of white wine consumption caused a significant increase in pro-atherogenic homocysteine levels (Rajdl et al. 2007).
Hypertension.
Red wine polyphenols have vasorelaxing effects, which are associated with lower blood pressure (Carollo et al. 2007). Red wine, dealcoholized red wine, and grape juice consumption have lowered blood pressure in patients with coronary artery disease or hypertension (Foppa et al. 2002, Park et al. 2004, Karatzi et al. 2005, Jimenez et al. 2008). Benefits appear to be greater when red wine (and to a lesser extent white wine) is consumed during a meal (Papamichael et al. 2008). These data suggest that polyphenols, rather than alcohol, are responsible for the health benefits. The presence of garlic, onions, fish, and olive oil in the Mediterranean diet (associated with a decreased risk of hypertension) provide additional hypotensive compounds that likely act in a synergistic manner with those present in wine (de Lorgeril et al. 2008).
The effects of wine drinking in normotensive individuals are conflicting. Studies with humans subjects have found that moderate red wine consumption over the course of a month either did not change or increased both systolic blood pressure and heart rate, which was attributed to the alcohol content (Hansen et al. 2005, Zilkens et al. 2005). Another study found that one drink of red wine had vasorelaxing effects, whereas two drinks had the opposite effect (Spaak et al. 2008). Moderate to heavy alcohol consumption has been associated with increased blood pressure.
Cancer
Despite the fact that alcohol is a known carcinogen, there is evidence that moderate wine consumption may decrease the risk of several cancers, including colon, basal cell carcinoma, ovarian, and prostate (Bianchini and Vainio 2003). Consumption of approximately one glass of wine daily was associated with a decreased risk of developing Barrett’s esophagus, a precursor to esophageal adenocarcinoma, when compared to heavy drinkers or nondrinkers (Kubo et al. 2009). A meta-analysis found that modest wine consumption had an inverse association for developing lung cancer, for both average wine consumption of less than one drink per day (RR, 0.77; 95% CI, 0.59–1.00) and one drink or greater per day (RR, 0.78; 95% CI, 0.60–1.02) (Chao 2007). A study of female non-Hodgkin’s lymphoma patients found a significantly better five-year overall survival (75% vs. 69%) and five-year disease free survival (70% vs. 67%) in occasional wine drinkers versus abstainers (Han et al. 2010). Compared to nondrinkers, women who drank wine for at least 25 years prior were 33% less likely to die and 26% less likely to experience a relapse or develop a secondary cancer over the five-year period following diagnosis. No advantage of beer or alcohol consumption was found. However, heavy drinking and alcoholism, along with smoking, are leading causes of upper aero-digestive cancers. There is a large body of evidence from epidemiological as well as animal studies that chronic alcohol intake is associated with increased breast cancer risk (Dumitrescu and Shields 2005). There is limited evidence of an increased risk of cancer of the oral cavity and pharynx in populations with frequent wine consumption (Altieri et al. 2004).
In vitro and animal studies indicate that red wine polyphenols inhibit angiogenesis by reducing the proliferation and migration of endothelial and vascular smooth muscle cells and the expression of proangiogenic factors (vascular endothelial growth factor [VEGF] and matrix metalloproteinase-2) (Oak et al. 2005). Evidence that wine polyphenols contribute to the chemopreventive effects of wine come from studies performed with grape seed proanthocyanidin extract (GSPE). GSPE exhibited toxicity toward human breast, lung, and gastric adenocarcinoma cells, but not normal cells (Bagchi et al. 2002, Katiyar 2008). It protected against tobacco toxicity in oral cells, chemotherapy toxicity in liver cells, and ultraviolet toxicity in skin cells. Modulation of oxidative stress, growth factors, and inflammatory molecules were involved (Katiyar 2008).
A high percentage of the literature on the cancer-preventing effects of wine is focused on one compound in particular: resveratrol. Our laboratory was the first to demonstrate the cancer chemopreventive activity of this compound (Jang et al. 1997). Since then, an exhaustive amount of research has been performed on health benefits associated with resveratrol. Although it is only possible to briefly discuss the topic here, many comprehensive reviews have been written on the subject (Bianchini and Vainio 2003, Aggarwal et al. 2004, Aggarwal and Shishodia 2006, Pezzuto 2008, Guerrero et al. 2009, Pezzuto et al. 2009).
Resveratrol suppresses proliferation of a wide variety of tumor cells, including lymphoid, myeloid, breast, prostate, stomach, colon, pancreas, thyroid, skin, head and neck, ovarian, and cervical. Resveratrol has been effective at preventing the formation of skin, oral, colorectal, esophageal, hepatoma, neuroblastoma, glioma, laryngeal, and gastric tumors in animal models. There is conflicting data in animal models regarding inhibition of lung, intestinal, and breast tumorigenesis. Resveratrol has received a great deal of attention because it blocks the multistep process of carcinogenesis at various stages: carcinogen activation, tumor initiation, tumor promotion, and tumor progression (Jang et al. 1997). It has been demonstrated to inhibit carcinogenesis by acting as an antioxidant, anti-inflammatory agent, antimutagen, antimetastatic agent, antiangiogenic agent, antidifferentiation agent, antiproliferative agent, and pro-apoptotic agent. It modulates signal transduction, the immune response, transcription factors, growth factors, cytokines, caspases, interleukins, prostaglandin synthesis, and cell cycle-regulating proteins.
Type 2 Diabetes
Type 2 diabetes is characterized by decreased disposal of glucose in peripheral tissues, insulin resistance, overproduction of glucose by the liver, and defects in pancreatic beta-cells. Markers of vascular risk associated with type 2 diabetes include endothelial dysfunction, oxidative stress (especially after meals), inflammation, and insulin resistance. There is evidence that moderate and regular red wine consumption may prevent the onset of type 2 diabetes as well as associated complications (reviewed in Caimi et al. 2003a).
The antioxidant properties of red wine polyphenols may be responsible for the positive responses. The importance of polyphenols is supported by evidence that grapes and GSE provide therapeutic effects in type 2 diabetic patients (Zunino 2009). Resveratrol, quercetin, catechins, and anthocyanins have been shown to inhibit hyperglycemia, improve beta-cell function, and protect against beta-cell loss. In obese Type 2 diabetic subjects, GSE significantly improved inflammation and glycemic status and decreased oxidative stress and total cholesterol levels (Kar et al. 2009). Analyses of epidemiological studies concluded that moderate regular alcohol consumption is associated with an ~30% reduced risk of type 2 diabetes (Howard et al. 2004, Koppes et al. 2005), indicating that the benefits afforded by the alcohol and polyphenol contents of red wine are probably additive. In postmenopausal women, 250 mL white wine consumption daily for six weeks improved insulin sensitivity compared to white grape juice (Joosten et al. 2008).
Among patients with type 2 diabetes who had previously abstained from alcohol, initiation of 150 mL wine consumption daily for three months significantly reduced fasting plasma glucose, but not postprandial glucose (Shai et al. 2007). In a study of type 2 diabetes patients that had a previous myocardial infarction, moderate red wine consumption during meals for one year significantly reduced oxidative stress and pro-inflammatory cytokines (CRP, tumor necrosis factor-alpha, IL-6 and IL-18) and improved cardiac function (Marfella et al. 2006). Another study in type 2 diabetics found that 150 mL muscadine grape wine (especially high in polyphenols) or the dealcoholized version with meals for 28 days lowered levels of blood glucose, insulin, and glycated hemoglobin, and improved antioxidant status and membrane fluidity compared with treatment with muscadine grape juice (Banini et al. 2006). Decreases in sodium, chloride, alanine aminotransferase, and aspartate aminotransferase values indicated a protection against hypertension and liver dysfunction. Daily red wine consumption (118 mL) for 6 months was renoprotective in type 2 diabetes mellitus patients with nephropathy; benefits were not observed with white wine (Nakamura et al. 2009). However, 190 mL red wine for 10 weeks in overweight women did not alter diabetes-associated risk factors, including insulin sensitivity, body weight and composition, blood lipids, and blood pressure (Cordain et al. 2000).
Metabolic Syndrome
Metabolic syndrome is defined by the presence of metabolic risk factors associated with high risk of developing type 2 diabetes and cardiovascular disease. These risk factors include abdominal obesity, high plasma triacylglycerols, low plasma HDL, high blood pressure and high fasting plasma glucose. Several reviews have presented evidence that moderate wine consumption may prevent metabolic syndrome and its related medical complications (Leighton et al. 2006, Liu et al. 2008). A mechanism that may be important is the ability of red wine components to enhance the function of endothelial NO synthase (eNOS), which may not function properly in metabolic syndrome patients (Leighton et al. 2006).
Other Conditions
There are preliminary data that wine provides health benefits in other areas. For example, red and white wine exhibited antibacterial activity against oral streptococci (Daglia et al. 2007). Moderate wine drinkers were identified to be at a lower risk of developing age-related macular degeneration than nondrinkers (Obisesan et al. 1998). There is evidence that grape procyanidins protect against radiation injury in radiation-contacted humans (Liu and Zhong 2008). Moderate wine consumption has been shown to benefit patients with renal disease by preventing oxidative stress and endothelial dysfunction (Rodrigo and Rivera 2002, Caimi et al. 2004, Presti et al. 2007). Drinking less than four glasses daily was associated with a retention in bone density and reduced risk of developing osteoporosis in elderly women, although detrimental effects on bone mass were observed with higher intakes (Ganry et al. 2000). A retrospective study in healthy centenarians found that moderate wine drinkers (≤500 mL daily) have lower markers of liver damage compared to those who abstained (Pinzani et al. 2005).
Neurologic Effects
Epidemiological and animal studies have demonstrated that moderate red wine intake may reduce the risk of developing neurological disorders, such as dementia, stroke, and Alzheimer’s disease (reviewed in Letenneur 2004, Pinder and Sandler 2004). Epidemiological studies in women have shown that moderate levels of alcohol intake (approximately one drink per day) may be associated with better cognition and reduced risk of significant cognitive decline, compared to those who abstained (Espeland et al. 2005, Stampfer et al. 2005). Similar results were reported in elderly populations (Ganguli et al. 2005, Peters et al. 2008). There are conflicting data as to whether wine polyphenols provide additional protection beyond that of alcohol (Mehlig et al. 2008), although neuroprotective effects have also been observed with grape juice supplementation in human studies (Joseph et al. 2009). It is likely that the antioxidants present in wine prevent oxidative damage in the brain that is associated with the process of aging. The discovery that some wines contain hydroxytyrosol, a dopamine metabolite and potent antioxidant, suggest that wine constituents may modulate dopamine signaling in the brain (de la Torre et al. 2006). Resveratrol has also been shown to provide neuroprotection by reducing oxidative stress in neuronal cells and regulating signaling pathways involved in memory and learning processes (Tredici et al. 1999).
Red wine is commonly alleged to initiate migraine attacks in susceptible individuals (Littlewood et al. 1988, Sandler et al. 1995). This adverse effect may be caused by a modulation of serotonin levels induced by wine consumption or by specific wine constituents, such as histamine or phenylethylamine (Jarisch and Wantke 1996).
Pulmonary Effects
There are epidemiologic, clinical, and experimental data supporting positive effects of light-to-moderate wine consumption on lung function, chronic obstructive pulmonary disease progression, and the risk of developing lung cancer, acute respiratory distress syndrome, and high altitude pulmonary edema (Schafer and Bauersachs 2002, Kamholz 2006). Proposed mechanisms for pulmonary protection include suppression of endothelin-1 expression, inhibition of inflammatory cytokine release, and antioxidative properties (Culpitt et al. 2003).
Wine-induced asthmatic symptoms are well documented and have been attributed to natural sulfite levels in all wines as well as sulfur dioxide, which may be used as a wine preservative (Dahl et al. 1986). There is evidence that the cause and incidence of wine-induced asthma may vary between individuals, involving several mechanisms that are codependent, and that sulfites are usually not responsible (Vally et al. 1999, 2007). Histamine in wine may induce coughing and wheezing with a decrease in lung function in patients suffering from histamine intolerance (Wantke et al. 1996). Adverse reactions to wine (facial flushing, asthma, and oral allergic swelling and burning) in some cases has been determined to have been caused by a sensitivity to the venom of Hymenoptera insects (wasps, bees, ants), which may contaminate wines during vinification (Armentia 2008). A recent study in asthmatic patients with wine sensitivity reported mast cell activation as a possible mechanism for wine-induced asthma, which did not correlate with wine sulfite levels (Misso et al. 2009).
Gastrointestinal Effects
A recent survey of 9,733 older adults found that moderate alcohol consumption is associated with a lower infection rate of Helicobacter pylori, with a stronger association in wine than beer drinkers (Gao et al. 2010). Wine constituents have exhibited antibiotic activity against H. pylori isolates and protected against associated gastric damage in mice (Daroch et al. 2001, Mahady et al. 2003, Ruggiero et al. 2007, Martini et al. 2009).
White wine has been demonstrated to induce gastroesophageal reflux (GER) in healthy people and GER patients (Vandenbroucke 1991, Grande et al. 1997, Pehl et al. 2000, 2006, Levanon et al. 2002), which may be due to an inhibition of postprandial gastric contractions and/or disturbed esophageal clearance due to an increase in simultaneous contractions and failed peristalsis. Repeated reflux events have been noted to occur. Individuals at risk for acid reflux are advised to limit wine ingestion to ≤300 mL daily.
Toxic Effects
Although the positive health effects of wine are many, the evidence is clear that these benefits are the highest for those who drink red wine in moderation (two drinks per day for men and one drink per day for women) over extended periods of time. Three or more drinks per day may increase the risk of neurodegeneration, depressive disorders, obesity, weakening of bones, hypertriglyceridemia, heart disease, hypertension, stroke, breast cancer, suicide, and injuries (Saremi and Arora 2008). Wine consumption in any amount is contraindicated for pregnant women, children, patients with liver disease, and in combination with certain medications (Feher et al. 2005). Regular wine consumption should be used with caution in individuals predisposed to alcoholism, organic diseases, cirrhosis of the liver, migraine headaches, and allergies.
Red wine has been shown to decrease the bioavailability of cyclosporine, an immunosuppressant (Tsunoda et al. 2001). In some people, red wine prematurely increased the concentration of extended-release felodipine, a calcium channel blocker (Bailey et al. 2003). A high dosage of resveratrol was found to decrease the bioavailability of nifedipine (an antihypertensive drug) or lovastatin (an antilipemic drug) and to increase the bioavailability of niacin (an antilipemic drug) (Puja et al. 2007). Based on the vasodilating properties of wine, it could theoretically interact with antihypertensive agents. Hypertensive subjects taking vitamin C concomitantly with grape seed polyphenols experienced an increased systolic blood pressure (Ward et al. 2005). Although it would be expected that the antiplatelet effects of wine would cause an interaction with the anticoagulant warfarin, that has not been the case in human studies (Karlson et al. 1986, Greenblatt et al. 2006). In one study, drinking two glasses of red or white wine in the evening did not significantly increase the risk of suppression of coagulation function the next day (Mezzano 2004).
There are many reports of contaminants in wines that pose potential health risks, including pesticide and fungicide residues, acetic acid, bacteria, lead, fungi, and mycotoxins such as ochratoxin A (Brereton et al. 1997, Cabras and Angioni 2000, Battilani et al. 2006, Chulze et al. 2006, Flamini and Panighel 2006, Hocking et al. 2007, Mateo et al. 2007, Bartowsky and Henschke 2008, Cesnik et al. 2008). Different countries have different regulations for acceptable levels of these contaminants. Arginine metabolism in wine malolactic bacteria may increase the concentration of the carcinogen ethyl carbamate in wine (Li et al. 2006). Long-term consumption of red wine may provide potentially toxic levels of chromium, lead, nickel, and vanadium; whether this poses a health risk is under investigation (Hague et al. 2008).
Conclusions
There is ample evidence supporting the health benefits associated with regular and moderate consumption of wine, particularly polyphenol-rich red wine. The practice has been associated with a decreased risk of cardiovascular conditions, type 2 diabetes, and many types of cancer. The alcohol component increases HDL cholesterol levels, inhibits platelet aggregation, and reduces systemic inflammation. Polyphenols present in wine independently provide antioxidant protection, decrease platelet aggregation, and increase endothelial function. Wine polyphenols also act through a variety of mechanisms to prevent and attenuate inflammatory responses, thereby serving as possible cardioprotective, neuroprotective, and chemopreventive agents.
Wines differ in alcohol and phytochemical content and composition. The question “which wine is the healthiest?” naturally presents itself. It appears that a very tannic, procyanidin rich wine would provide the most benefit. Overall, there appear to be more health benefits associated with red than white wine. However, not all red wines have the same polyphenol content, which could be the most important factor. There is evidence certain polyphenols, such as resveratrol, provide an abundance of health benefits. Yet, resveratrol itself actually has a low bioavailability, indicating that it is the metabolites of resveratrol that are the real key players (Liu and Zhong 2008). Similar results were found for anthocyanins, flavonols, and catechin (Donovan et al. 1999, Bub et al. 2001, de Vries et al. 2001, Frank et al. 2003). Not only does this mean that the actual resveratrol content of wine may not be as important as originally thought, but it also suggests that yet unidentified compounds may be even more important. Of course, these compounds are present in a complex mixture and almost certainly antagonize and synergize in vivo. The complexity increases when considering each person may metabolize wine differently. Even if it were possible to determine that one particular wine type was the “healthiest,” each vintage is impacted by soil type, geographical region, climate, insecticides, and seasonal variations. Therefore, essentially no two bottles of wine have the exact same chemical composition. The storage procedures and duration of wine aging after it is purchased may also alter its chemical profile.
It must be emphasized that the benefits associated with red wine are dependent upon regular and moderate consumption (Walzem 2008). Although general recommendations are one drink (150 mL) daily for women and two drinks (300 mL) daily for men, individual ideals may vary based on age, gender, genetics, body type, and drug/supplement use. The pattern of wine consumption is also important. Moderate regular drinking gives many health benefits that are lost when drinking is only periodic and heavy, even though the weekly average amount may be the same.
The healthful effects of wine may be enhanced by a healthy diet. The excellent health associated with the Mediterranean diet, which combines moderate wine consumption with a diet rich in fruits, vegetables and whole grains, suggests that wine polyphenols have synergistic effects with compounds found in other types of food (Caimi et al. 2003b). Adding wine to the diet of already healthy individuals may add additional benefits. In nonsmoking, physically active adults of a normal weight that ate a healthy diet, moderate alcohol intake was associated with a lower risk for myocardial infarction and type 2 diabetes than those who abstained (Mukamal et al. 2006, Joosten et al. 2010). However, most medical professionals as well as the American Heart Association agree that heavy drinkers or alcohol abstainers should not be encouraged to drink wine for health reasons. Wine consumption should not replace a healthy lifestyle and necessary pharmacotherapy. Yet, light-to-moderate wine drinkers, without medical complications, may be assured that their wine consumption is a healthy habit.
Lastly, it is obvious that wines could be designed so that, in principal, health benefits could be enhanced. Grapevines exposed to certain environmental conditions, including vineyard elevation and fungal infection produce greater levels of stilbenes (Bavaresco 2003). It is also possible to trigger stilbene production using ultraviolet rays or heavy metals. Vinification procedures that have the most effect on wine phenolics include pomace contact, aging, and grape skin and seed maceration. Nonetheless, these approaches may not appeal to the consumer, since many factors are related to the use of wine beyond the potential of enhancing health benefits.
Acknowledgments
Acknowledgments: Work in the laboratory of the authors is supported by program project P01 CA48112 awarded by the National Cancer Institute.
This review was presented in part by J.M. Pezzuto at the 2010 International Cool Climate Symposium, 20–22 June 2010, Seattle, WA.
Abbreviations
- CRP
- C-reactive protein
- eNOS
- endothelial NO synthase
- GER
- gastroesophageal reflux
- GSE
- grape seed extract
- GSPE
- grape seed proanthocyanidin extract
- HDL
- high-density lipoprotein
- LDL
- low-density lipoprotein
- NO
- nitric oxide
- PAI-1
- plasminogen activator inhibitor-1
- t-PA
- tissue plasminogen activator
- u-PA
- urokinase plasminogen activator
- VEGF
- vascular endothelial growth factor
- VLDL
- very low-density lipoprotein
- Received February 1, 2011.
- Revision received June 1, 2011.
- Accepted June 1, 2011.
- Published online December 1969
- © 2011 by the American Society for Enology and Viticulture
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Vol 62 Issue 4
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