By
Chris D. Meletis, ND and Jeffrey Reinhardt, MSc
Resveratrol is the best known health promoting molecule in red wine1 and has been studied by scientists investigating its effects on genes as well as the heart, breast, prostate, uterus, and immune system. In addition, recent studies show that resveratrol sustains healthy nerves and important brain functions including cognitive processes.2-4
In various epidemiological studies and clinical trials, consumption of resveratrol, quercetin and other red wine components have been associated with a reduced risk of heart disease and improved cardiovascular health. In vitro and animal studies also have shown that red wine components can influence various factors associated with breast, prostate and lung health, and can reduce the free radical damage that occurs during influenza virus infection. In fact, quercetin, red wine polyphenols and resveratrol provide important synergistic benefits for the heart.
Heart Health
Resveratrol is a plant protective phytoalexin produced by grapes, mulberries, peanuts and soy beans, and is found in honeybee hives, red wines such as Pinot Noir, Itadori tea and various medicinal herbs such as Japanese Knotweed (Polygonum cuspidatum). This compound occurs in two conformational forms – cis and trans-resveratrol. Trans-resveratrol is the preferred functional form. The most effective trans-resveratrol is one that is exceptionally high quality, extracted from Polygonum cuspidatum in a process that results in very low levels (1 percent or less) of undesirable cis- isomers. It is further enzymatically hydrolyzed to remove the glycosides (naturally-occurring sugar molecules), since the aglycone (sugar-free) form of trans-resveratrol is more efficiently absorbed. Accelerated stability studies performed with our trans-resveratrol demonstrate excellent stability over its projected two-year shelf life.
| Resveratrol and Life Extension Despite centuries of explorations, the search for plants or other remedies that effectively and reliably extend life span has produced no miraculous “fountain of youth” discoveries. Over the last 20 years, medical scientists in the U.S. and in France, Japan and China confirmed that a low calorie, nutritionally balanced diet not only contributes significantly to sustained good health but also increases longevity in mice, rats, primates, yeast, round worms and fruit flies. These observations led scientists to search for “longevity genes.” Once triggered by environmental cues, the longevity genes “switch on” and induce defensive changes at the cellular level, such as slowing metabolism and enhancing cellular respiration to help the body adapt to a more beneficial survival program. Researchers have found a family of genes, called sirtuins, produced by almost all life forms—from single celled organisms, to plants and mammals—during times of stress, such as famine (or caloric restriction). Sirtuins (silent information regulator proteins) are known to act as guardian genes that protect cells and enhance cellular survival. The human sirtuin, SIRT-1, for example, has been shown to suppress the p53 enzyme system normally involved in suppressing tumor growth and instigating cell death (apoptosis). By suppressing p53 activity, SIRT-1 prevents the cycle of premature aging and apoptosis normally induced when cellular DNA is damaged or stressed, thus giving cells enough time to repair any damage and prevent unnecessary cell death. A second sirtuin found in yeast, SIR2, has also been shown to become activated when placed under stress. SIR2 has been shown to increase DNA stability and speed cellular repairs, while increasing total cell lifespan. Essentially, sirtuins buy cells time to repair damage.1-2 Caloric restriction triggers the activation of sirtuins, one of the mechanisms by which caloric restriction extends lifespan. Therefore, researchers wondered if there was another way to activate sirtuins in order to extend longevity. Researchers discovered that of a number of plant compounds tested, the most potent activator of sirtuins was resveratrol. Yeast treated with resveratrol lived for an average of 38 generations, as compared to only 19 generations for untreated yeast.3 The combination of resveratrol and Sirt1 stimulates a number of stress-modifying and life-extending processes including apoptosis, immune defense mechanisms, neuronal protection and metabolic optimization in liver, muscle and fat cells. Resveratrol has other actions, including stimulation of ATP production in mitochondria of mice and modulation of insulin growth factor 1 (IGF-1), improves insulin sensitivity, mitigates against obesity and minimizes the development of fatty livers in mice fed a high-fat diet. In one animal study, researchers found that mice given resveratrol significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. The animals also experienced improved mitochondrial function. Diminished mitochondrial function and aerobic capacity are associated with reduced longevity. Another interesting finding of the study was that resveratrol protected mice against diet-induced obesity and insulin resistance.4 References
1. Sinclair DA, Guarente L. Unlocking the secrets of longevity genes. Scientific American. 2006 March; 294(3): 48-57.
2. Seung-Hoi K, Montming M. In vino veritas: a tale of two Sirt1s. Cell. 2006 Dec. 15; 127: 1091-1093.
3. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24.
4. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006 Dec 15;127(6):1109-22. |
Trans-resveratrol is thought to improve heart health in a number of ways. Laboratory experiments in vitro and studies in animals have shown that trans-resveratrol can stop blood platelets from sticking together (platelet aggregation). In one study, scientists investigated the effects of resveratrol and red wine on aggregation of platelets isolated from healthy male volunteers.
The researchers induced platelet aggregation in blood from healthy subjects and determined that trans-resveratrol significantly inhibited the sticking together of blood platelets. Researchers also induced platelet aggregation in rabbits with high cholesterol and found that when trans-resveratrol was given to the rabbits, the platelets did not stick together.5 Since sticky platelets are tied to increased risk of heart attack, stroke and blood clots throughout the body, this is a significant finding in regards to life-threatening risk factors.
According to the researchers, “These results suggest that trans-resveratrol can inhibit platelet aggregation both in vitro and in vivo, which conceivably could be one of the mechanisms by which this red wine polyphenol exerts its cardioprotective effects.”
Another of trans-resveratrol’s interesting cardiovascular implications is its ability to enhance angiogenesis, the development of new blood vessels, in order to help feed the heart during periods of oxygen deprivation (ischemia). The formation of new blood vessels caused by trans-resveratrol restores the blood supply to the ischemic area, preventing heart cell death and abnormal changes to the heart.6
In a study of 24 pre- and 20 postmenopausal women, researchers randomly assigned the subjects to receive either a placebo or grape powder rich in trans-resveratrol, quercetin and other polyphenols for four weeks. After a 3-week washout period, the subjects given the grape powder were switched to a placebo and the subjects receiving the placebo then received the grape powder. In both the pre-and postmenopausal women, concentrations of plasma triglycerides, another cardiac risk factor, dropped by 15 and 6 percent respectively after supplementation with the grape polyphenols. In addition, plasma LDL cholesterol and apolipoproteins B and E levels were lower after supplementation with the grape powder. In addition, whole-body oxidative stress was significantly reduced after supplementation with the grape powder. When subjects were taking the grape powder, the levels of plasma tumor necrosis factor-alpha, which plays a major role in the inflammation process, were lower.7 These results led the researchers to conclude that grape polyphenols, through alterations in lipoprotein metabolism, oxidative stress, and inflammatory markers, “beneficially affected key risk factors for coronary heart disease in both pre- and postmenopausal women.”
In another study, red grape polyphenol extract containing quercetin, trans-resveratrol and other polyphenols improved blood flow in the arteries of male patients with coronary heart disease.8
Anti-Inflammatory Actions
Not only are trans-resveratrol, quercetin and other red wine polyphenols powerful antioxidants, they also exert a strong anti-inflammatory effect. They appear to accomplish this by inhibiting nuclear factor-kappa beta (NF-kappaB), a protein with a pivotal role in controlling cell signaling in the body under certain physiological and pathological conditions. Among other functions, NF-kappaB controls the expression of genes encoding the pro-inflammatory cytokines (proteins produced by white blood cells), chemokines (cytokines that assist in destroying invading micro-organisms) and immune receptors, all of which play critical roles in controlling most inflammatory processes. NF-kappaB is so important in controlling inflammation that over the last decade researchers have spent a great deal of time identifying compounds that interfere with the NF-kappaB pathway in the hopes of finding agents useful in inflammatory diseases such as arthritis, asthma and autoimmune conditions. Recently, researchers have discovered that trans-resveratrol, quercetin and other polyphenols found in red wine may inhibit the NF-kappaB pathway.9
These same red wine compounds inhibit expression of another important marker of inflammation and a risk factor for heart disease—C-reactive protein (CRP). Recent research has found that quercetin and trans-resveratrol can, in a dose-dependent manner, suppress the expression of CRP that occurs after the activation of inflammatory cytokines.10
Conclusion
Trans-resveratrol is a multifunctional modulator of numerous, complex cellular signaling pathways, which regulate vital cellular processes such as cell growth, apoptosis or programmed cell death, ischemic heart disease and thrombosis, insulin resistance and diet-induced obesity, improved mitochondrial functions plus the activation of the Sirtuin family of longevity genes (see sidebar). In addition to being a powerful antioxidant, trans-resveratrol acts like a molecular master key, “opening” or up regulating important genes and functionally related sequences of DNA or “families” of genes that directly control both the lifespan and metabolic efficiency. Trans-resveratrol also stimulates the production of ATP in the mitochondria of muscles.9, 15
As a key regulatory molecule, trans-resveratrol improves cellular energy production and up regulates the expression of many different genes, leading to metabolic homeostasis as a prerequisite for a long and healthy life.
References
1. Bhat, KPL, Kosmeder, JW II, Pezzuto, JM. Biological effects of resveratrol. Antioxid Redox Signal. 2001 Dec; 3(6): 1041-1064
2. Dore S. Unique properties of polyphenol stibenes in the brain: more than direct antioxidant actions; gene/protein regulatory activity. Neurosignals. 2005; 14 (1-2): 61-70.
3. Anekonda TS. Resveratrol – a boon for treating Alzeimers disease. Brain Res Rev. 2006 Sep; 52(2): 316-326
4. Zhuang H., Kim YS, Koehler RC, Dore S., Potential mechanism by which resveratrol, a red wine constituent, protects neurons. Ann NY Acad Sci. 2003 May; 993: 276-86; discussion 287-88.
5. Wang Z, Huang Y, Zou J, Cao K, Xu Y, Wu JM. Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. Int J Mol Med. 2002 Jan;9(1):77-9.
6. Maulik N. Reactive oxygen species drives myocardial angiogenesis? Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):2161-8.
7. Zern TL, Wood RJ, Greene C, West KL, Liu Y, Aggarwal D, Shachter NS, Fernandez ML. Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. J Nutr. 2005 Aug;135(8):1911-7.
8. Lekakis J, Rallidis LS, Andreadou I, Vamvakou G, Kazantzoglou G, Magiatis P, Skaltsounis AL, Kremastinos DT. Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur J Cardiovasc Prev Rehabil. 2005 Dec;12(6):596-600.
9. Nam NH. Naturally occurring NF-kappaB inhibitors. Mini Rev Med Chem. 2006 Aug;6(8):945-51.
10. Kaur G, Rao LV, Agrawal A, Pendurthi UR. Effect of wine phenolics on cytokine-induced C-reactive protein expression. J Thromb Haemost. 2007 Jun;5(6):1309-17.