RESVERATROL FACTS French Wine in a Bottle The Resveratrol Story
Over the past hundred-plus years, research has discovered a variety of substances contained in plants that the cells of our body require to convert food to energy. These substances also allow cells to make key structural components for maintaining the health of our eyes, skin, bone, muscle and brain.
Resveratrol is present in many plants and especially concentrated in the skin of grapes - and grapes from France naturally have a higher concentration of Reseveratrol. It is similar in structure to the catechins present in tea (especially green tea), as well as compounds present in richly colored berries and fruits (blueberries, pomegranates) that also have significant support as health-promoting agents. Plants, it is believed, synthesize these compounds to use as a weapon against invading pathogens like fungi, bacteria and viruses.
Best Sources of Resveratrol
While present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as mulberries and peanuts, resveratrol's most abundant natural sources are Vitis vinifera, labrusca, and muscadine grapes, which are used to make wines. It occurs in the vines, roots, seeds, and stalks, but its highest concentration is in the skin [1], which contains 50-100 micrograms (µg) per gram [4]. Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease [1]. For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA [2]. Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration [3].
The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process. Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted [3]. Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A fluid ounce of red wine averages 160 µg of resveratrol, compared to peanuts, which average 73 µg per ounce [6]. Since wine is the most notable dietary source, it is the object of much speculation and research.
RESVERATROL RESEARCH - Why It Expands Life
Breaking research demonstrates that Resveratrol shows similiar results that calorie restricted diets have demonstrated. In humans, consuming a low-calorie diet is associated with several possible markers of greater longevity, such as lower insulin levels and reduced body temperatures, along with less of the chromosomal damage that typically accompanies aging. Furthermore, people who consume a low-calorie diet may be less prone to diseases associated with being overweight or obese, such as metabolic syndrome, diabetes, cancer, and atherosclerosis.
Although caloric restriction may be effective in promoting longevity, the problem is that most adults find this stringent lifestyle strategy to be impractical. As a result, scientists have sought to uncover the precise mechanisms by which caloric restriction promotes longevity, in order to help people capture its life-extending benefits through more practical means.
Resveratrol Offsets Perils of a High-Calorie Diet
Remarkable new research suggests that it may be possible to achieve the life-extending benefits of caloric restriction using the readily available, plant-derived compound known as resveratrol. Resveratrol and caloric restriction appear to work via similar mechanisms to promote health and longevity in numerous animal species.
In an interview, a leading resveratrol researcher, Dr. Xi Zhao-Wilson of BioMarker Pharmaceuticals, told Natural Biology, “There has been a great deal of attention focused on resveratrol in the past few years, following a study showing that resveratrol activates molecular pathways involved in life-span extension, now demonstrated in yeast, worms, flies, fish, and mice, and which possibly bear a relationship to mechanisms under-lying caloric restriction.”
This heightened interest in resveratrol has produced several recent breakthroughs. In a landmark study, Harvard University scientists showed that resveratrol could prolong survival by regulating a gene associated with aging that is present in all life forms.
How Fat Mice Live As Long as Skinny Ones
They demonstrated that while middle-aged mice fed a high-calorie diet suffered the ravages of obesity—including metabolic changes resembling diabetes, liver and heart damage, and premature death—mice that were fed resveratrol in addition to the high-calorie diet actually exhibited beneficial changes in their physiology, resembling those of mice fed a standard diet.5
Among the life-prolonging benefits of resveratrol supplementation demonstrated in the study were:
Resveratrol significantly increased survival, reducing the risk of death from the high-calorie diet by 31%. Together, these findings offer powerful evidence that resveratrol protected the animals from the harmful effects of a high-calorie diet.
Resveratrol’s positive impacts on insulin sensitivity and survival were apparent after only six months of treatment. Resveratrol also improved the animals’ quality of life, as reflected in their physical abilities. On a test of balance and coordination, the resveratrol-fed mice on the high-calorie diet steadily improved as they aged.
The obese resveratrol-supplemented animals experienced all of these benefits without a significant reduction in body weight.
Harvard Research
“These data demonstrate that resveratrol can alleviate the negative impact of a high-calorie diet on overall health and life span,” the Harvard scientists concluded. “The ability of resveratrol to prevent the deleterious effects of excess caloric intake and modulate known longevity pathways suggests that resveratrol and molecules with similar properties might be valuable tools in the search for key regulators of energy balance, health, and longevity.”
Mechanisms by Which Resveratrol May Extend Life
Today, scientists around the world are studying resveratrol to determine how it helps fight aging and prolong life span. Current evidence suggests that resveratrol exerts antioxidant effects, boosts energy production, and favorably alters patterns of gene expression.
Oxidative stress is implicated in numerous disease processes and in aging itself. Resveratrol demonstrates powerful antioxidant capabilities, with profound implications for human health. Scientists report that resveratrol inhibits the oxidation of dangerous low-density lipoprotein (LDL) and scavenges harmful hydroxyl radicals. Resveratrol also helps preserve levels of glutathione, one of the body’s most essential antioxidants.
According to prominent resveratrol investigator Dr. Milos Sovak, “There is no question that resveratrol is one of the best free-radical scavengers and that it has many effects whose ramifications might affect not only longevity but also general health.”
Resveratrol stimulates energy production in the cellular powerhouses known as the mitochondria. Diminished mitochondrial energy production is associated with reduced longevity. By enhancing the production of life-sustaining energy, resveratrol may help protect against metabolic disease and obesity, thereby improving health and prolonging survival in animals.
Growing evidence indicates that resveratrol influences many genetic pathways, which may underlie its ability to lengthen life. In the recent Harvard study, investigators noted that a high-calorie diet produced numerous changes in gene expression. However, supplemental resveratrol opposed the effects of this high-calorie diet in 144 of 153 significantly altered genetic pathways. Moreover, resveratrol’s effects were dose dependent, with larger amounts yielding greater effects, leading the investigators to suggest that resvera-trol may offer “new approaches for treating obesity-related disorders and diseases of aging.”7
Some of the genetic pathways influenced by resveratrol are similarly affected by caloric restriction. For example, caloric restriction is associated with long-term activation of AMP-activated kinase (AMPK), a metabolic enzyme promoting insulin sensitivity and fatty-acid oxidation. Resveratrol likewise increases AMPK activity, which is associated with life-span extension.
Scientists believe that caloric restriction increases life span in part through its effects on the sirtuin genes. Present in all life forms, sirtuin genes are associated with aging and longevity. Resveratrol may confer benefits similar to those of caloric restriction by influencing the sirtuin gene known as SIRT2.5,8-10 In the Harvard study, resveratrol helped counteract changes in SIRT2 expression induced by a high-calorie diet.
“The genes and pathways [affected by resveratrol or by caloric restriction] are related to activation of sirtuins, a class of histone deacetylase enzymes (HDACs) involved in cell death and life-span regulation,” Dr. Zhao-Wilson told Life Extension. “Based on the large body of evidence, the resveratrol/sirtuin activators have become the focus of pharmaceutical drug discovery efforts now [targeting] HDACs.”
Researchers believe that compounds like resveratrol that either activate or inhibit sirtuin activity may have therapeutic potential for a broad array of human diseases, including cancer, diabetes, heart failure, and neurodegenerative conditions such as Alzheimer’s and Huntington’s disease.
Cardiovascular Effects
Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Several studies have demonstrated that resveratrol is an effective antioxidant [7-10]. It inhibits lipid peroxidation of low-density lipoprotein (LDL) [7,8], prevents the cytotoxicity of oxidized LDL [7], and protects cells against lipid peroxidation [7]. It is thought that because it contains highly hydrophilic and lipophilic properties, it can provide more effective protection than other well-known antioxidants, such as vitamins C and E [7]. On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine [2]. Reduced platelet aggregation has also been demonstrated in studies on resveratrol, further contributing to its prevention of atherosclerosis [2,9]. To date, most of the research on resveratrol's antioxidant and anti-platelet properties has been done in vitro (in an artificial environment using test-tube or tissue-culture preparations). Further studies in animals and humans are necessary to determine whether resveratrol supplementation makes sense.
Cancer-Related Effects
Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation, and as an anti-mutagen in rat models [4]. Resveratrol appears to decrease tumor promotion activity by inhibiting cyclooxygenase-1 (COX-1) [4,11,12], an enzyme that converts arachidonic acid to pro-inflammatory substances that stimulate tumor-cell growth [3]. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation [4] and inhibited ribonucleotide reductase, an enzyme needed for DNA synthesis in proliferating cells [12]. One appealing characteristic of resveratrol's anti-cancer potential is its minimal toxicity to blood-forming cells [11]. More studies using both cellular and animal models are needed before any such data would be applicable to human use.
The similarity in structure between resveratrol and diethylstilbestrol (a synthetic estrogen) has prompted investigations into resveratrol's potential as a phytoestrogen (a plant compound that produces estrogen-like effects). However, these properties also stimulate the growth of human breast cancer cells [5]. This finding seems contrary to its other anticancer activities, and is a cause for concern.
The Bottom Line
Laboratory tests have clearly demonstrated that resveratrol may help prevent cardiovascular disease and cancer. However, there are several reasons why recommending a population-wide increase would be premature.
First, little is known about the absorption and clearance of resveratrol, the identities of its metabolic products, or its effects on the liver [5]. A study in rats showed that resveratrol is absorbed in the gut and has a high affinity for the heart and liver [13,14]. Second, the research on resveratrol has focused on its short-term effects [2] and has been dominated by in vitro studies on non-human models. Third, its role as a potentiator of breast carcinomas may significantly limit its use, even for its "proven" benefits. Finally, its main dietary source is red wine. Not only is its concentration in wine extremely variable, but recommending increased consumption of red wine to boost resveratrol intake could certainly do more harm than good. In spite of any beneficial aspects, red wine and other alcoholic beverages pose health risks that include liver damage and physical addiction. The health-food industry is claiming that resveratrol is the wine component responsible for the "French Paradox." While taking resveratrol pills is certainly safer than heavy consumption of red wine, supplementing with unproven substances is generally unwise. At this point, occasional use of red wine seems far more prudent.
Multi-Tasking Resveratrol
Recent animal and cell culture studies, examining the effects of this polyphenolic compound on other organisms, have indicated that resveratrol may help to inhibit cancer growth and tissue-destructive inflammation. Laboratory studies also suggest that it may help to improve cardiovascular health and blood pressure, as well as cholesterol levels, and even to extend the lifespan of a number of species of animals, including mice.
The details as to the mechanism involved in these resveratrol-induced benefits are complex and currently under intense investigation.
Osteoporosis and HRT
Osteoporosis is a decrease in bone strength due to loss of bone mineral and structural components. It is a significant issue associated with aging in both sexes, especially in post-menopausal women.
Several years ago, bone loss was linked to a decrease in serum levels of the hormone estrogen, a post-menopausal phenomenon. The medical profession began treating post-menopausal patients, who exhibited early signs of osteoporosis, with estrogen. This hormone replacement therapy (HRT) did significantly inhibit progression of the disease.
Unfortunately, recent studies have shown this form of treatment to be associated with considerable risk, including an increase in cardiovascular disease and cancer. These results have prompted the medical profession to be more cautious in the treatment of osteoporosis with HRT as potential risks may offset the benefits.
Osteoporosis and Resveratrol
Resveratrol, according to another recent laboratory study, has the potential of helping to prevent osteoporosis without the health risks associated with HRT.
Demonstrating that this plant compound is a phytoestrogen, which can bind to and activate estrogen receptors, was the impetus to investigate the potential role resveratrol may play in bone metabolism.
Studies were carried out in cell cultures as well as animals that were susceptible to bone loss (ovariectomized rats). Collectively, the results demonstrated a number of bone-forming activities associated with resveratrol treatment.
Resveratrol turns on genes involved in bone formation and turns off genes involved in bone destruction. The result is the conversion of precursor bone cells to bone-forming cells (osteoblasts), as well as the inhibition of the production of bone-destroying cells (osteoclasts). The net result in bone is anabolic. In other words, the bone is getting stronger with an increase in bone mineral and bone structural components or proteins.
Tumor Suppressing Bonus
What sets resveratrol apart from HRT? While both promote the production of bone strength and inhibit osteoporosis, resveratrol, rather than increasing the risk of cancer, prevents tumor growth. Why the difference?
Although resveratrol, like HRT, activates a biochemical pathway to promote bone-forming cell growth and inhibit bone-destructive cell growth, it simultaneously activates a pathway that culminates in the synthesis of a tumor-suppressor protein, FOXO3A, which accumulates in the cell's nucleus.
Resveratrol's Future
The bone-forming property associated with resveratrol, without the cancer risks associated with HRT, would appear to make this compound an ideal therapeutic strategy for the prevention of osteoporosis. However, the studies to date, although very encouraging, were performed on cell cultures and animals. To be appropriate as a therapeutic for human use, future studies will have to demonstrate similar effects in clinical trials.
Nevertheless, resveratrol is a compound of significant interest, with respect to its many purported health benefits, including improved cardiovascular health, cancer prevention and anti-aging. In addition, there are virtually no reported negative side effects in studies using very large doses.
Many following this research believe that either this compound or more potent synthetic derivatives of resveratrol will be future therapeutics. The work associated with resveratrol has already led to exciting discoveries that should help promote the development of therapeutics for a variety of disease states.
Resveratrol Source
Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of the blood vessels, heart [1,2], and liver [2]. It came to scientific attention only four years ago, however, as a possible explanation for the "French Paradox" -- the low incidence of heart disease among the French people, who eat a relatively high-fat diet [3]. Today, it is touted by manufacturers and being examined by scientific researchers as an antioxidant [4], an anti-cancer agent, and a phytoestrogen [5]. It is also being advertised on the Internet as "The French Paradox in a bottle." [A] Arkopharma, of Wallingford, Connecticut, even markets a red-wine extract antioxidant product called "French Parad'ox." This article reviews the recent research on resveratrol's physiologic activity.
Resveratrol and Extended Life Span:
WHAT YOU NEED TO KNOW....
Resveratrol, a health-promoting compound found in grapes, has been shown to increase life span in several animal species.
In a recent Harvard study, mice that consumed a high-calorie diet known to shorten life lived longer when they also consumed resveratrol. These mice also had better coordination, less heart and liver damage, and better insulin sensitivity than overweight mice that were not fed resveratrol.
Scientists have proposed that resveratrol in red wine may help explain the “French paradox”—the fact that cardiovascular disease rates in France are relatively low, despite a diet traditionally high in fat. Because widespread use of pesticides has diminished the amount of resveratrol contained in grapes and red wine, supplemental resveratrol may the best way to ensure optimal intake.
Laboratory and animal studies suggest that resveratrol may have therapeutic potential for cardiovascular disease, cancer, inflammatory arthritis, Alzheimer’s disease, and other neurodegenerative conditions. Clinical trials studying resveratrol’s effects on cancer and diabetes are also under way.
Resveratrol may enhance health and support longevity via several mechanisms. These include its potent antioxidant effects, ability to enhance cellular energy production, and ability to influence patterns of gene expression in a manner similar to caloric restriction (the best-documented method of extending life span in animals).
Because resveratrol exerts protective effects through a variety of mechanisms, it may be a useful supplement for healthy adults wishing to reduce their risk of chronic disease and live a long and healthy life. Studies to date suggest that resveratrol is safe and nontoxic.
Buy Vintage Resvertrol from Natural Biology - Click Here
References
Celotti E and others. Resveratrol content of some wines obtained from dried Valpolicella grapes: Recioto and Amarone. Journal of Chromatography A 730(1-2): 47-52, 1996. Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: A molecule whose time has come? And gone? Clinical Biochemistry 30:91-113, 1997. Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? European Journal of Endocrinology 138:619-620, 1998. Jang M and others. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218-220, 1997. Gehm H and others. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proceedings of the National Academy of Sciences U.S.A. 94:557-562, 1997. Sanders TH, McMichael RW. Occurrence of resveratrol in edible peanuts. Presentation, American Oil Chemists Society, Las Vegas, Nevada, 1998. Discussed in Peanuts contain significant amount of plant compound that may prevent risk of heart disease and cancer, a news release from The Peanut Institute, Sept 8, 1998. Chanvitayapongs S, Draczynska-Lusiak B, Sun AY. Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport 8:1499-1502, 1997. Belguendouz L, Fremont L, Gozzelino MT. Interaction of transresveratrol with plasma lipoproteins. Biochemical Pharmacology 55:811-816, 1998. Rotondo S and others. Effect of trans-resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function. British Journal of Pharmacology 123:1691-1699, 1998. Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol. Lancet 341:1103-1104, 1993. Clement MV and others. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 92:996-1002, 1998. Fontecave M and others. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Letters 421:277-279, 1998. Bertelli AA and others. Evaluation of kinetic parameters of natural phytoalexin in resveratrol orally administered in wine to rats. Drugs under Experimental and Clinical Research 24:51-55, 1998. Bertelli A and others. Plasma and tissue resveratrol concentrations and pharmacological activity. Drugs under Experimental and Clinical Research 24:133-138, 1998.
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Resveratrol is present in many plants and especially concentrated in the skin of grapes - and grapes from France naturally have a higher concentration of Reseveratrol. It is similar in structure to the catechins present in tea (especially green tea), as well as compounds present in richly colored berries and fruits (blueberries, pomegranates) that also have significant support as health-promoting agents. Plants, it is believed, synthesize these compounds to use as a weapon against invading pathogens like fungi, bacteria and viruses.
Best Sources of Resveratrol
While present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as mulberries and peanuts, resveratrol's most abundant natural sources are Vitis vinifera, labrusca, and muscadine grapes, which are used to make wines. It occurs in the vines, roots, seeds, and stalks, but its highest concentration is in the skin [1], which contains 50-100 micrograms (µg) per gram [4]. Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease [1]. For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA [2]. Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration [3].
The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process. Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted [3]. Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A fluid ounce of red wine averages 160 µg of resveratrol, compared to peanuts, which average 73 µg per ounce [6]. Since wine is the most notable dietary source, it is the object of much speculation and research.
RESVERATROL RESEARCH - Why It Expands Life
Breaking research demonstrates that Resveratrol shows similiar results that calorie restricted diets have demonstrated. In humans, consuming a low-calorie diet is associated with several possible markers of greater longevity, such as lower insulin levels and reduced body temperatures, along with less of the chromosomal damage that typically accompanies aging. Furthermore, people who consume a low-calorie diet may be less prone to diseases associated with being overweight or obese, such as metabolic syndrome, diabetes, cancer, and atherosclerosis.
Although caloric restriction may be effective in promoting longevity, the problem is that most adults find this stringent lifestyle strategy to be impractical. As a result, scientists have sought to uncover the precise mechanisms by which caloric restriction promotes longevity, in order to help people capture its life-extending benefits through more practical means.
Resveratrol Offsets Perils of a High-Calorie Diet
Remarkable new research suggests that it may be possible to achieve the life-extending benefits of caloric restriction using the readily available, plant-derived compound known as resveratrol. Resveratrol and caloric restriction appear to work via similar mechanisms to promote health and longevity in numerous animal species.
In an interview, a leading resveratrol researcher, Dr. Xi Zhao-Wilson of BioMarker Pharmaceuticals, told Natural Biology, “There has been a great deal of attention focused on resveratrol in the past few years, following a study showing that resveratrol activates molecular pathways involved in life-span extension, now demonstrated in yeast, worms, flies, fish, and mice, and which possibly bear a relationship to mechanisms under-lying caloric restriction.”
This heightened interest in resveratrol has produced several recent breakthroughs. In a landmark study, Harvard University scientists showed that resveratrol could prolong survival by regulating a gene associated with aging that is present in all life forms.
How Fat Mice Live As Long as Skinny Ones
They demonstrated that while middle-aged mice fed a high-calorie diet suffered the ravages of obesity—including metabolic changes resembling diabetes, liver and heart damage, and premature death—mice that were fed resveratrol in addition to the high-calorie diet actually exhibited beneficial changes in their physiology, resembling those of mice fed a standard diet.5
Among the life-prolonging benefits of resveratrol supplementation demonstrated in the study were:
- increased insulin sensitivity
- lower blood sugar
- enhanced mitochondrial energy production
- improved motor function.
Resveratrol significantly increased survival, reducing the risk of death from the high-calorie diet by 31%. Together, these findings offer powerful evidence that resveratrol protected the animals from the harmful effects of a high-calorie diet.
Resveratrol’s positive impacts on insulin sensitivity and survival were apparent after only six months of treatment. Resveratrol also improved the animals’ quality of life, as reflected in their physical abilities. On a test of balance and coordination, the resveratrol-fed mice on the high-calorie diet steadily improved as they aged.
The obese resveratrol-supplemented animals experienced all of these benefits without a significant reduction in body weight.
Harvard Research
“These data demonstrate that resveratrol can alleviate the negative impact of a high-calorie diet on overall health and life span,” the Harvard scientists concluded. “The ability of resveratrol to prevent the deleterious effects of excess caloric intake and modulate known longevity pathways suggests that resveratrol and molecules with similar properties might be valuable tools in the search for key regulators of energy balance, health, and longevity.”
Mechanisms by Which Resveratrol May Extend Life
Today, scientists around the world are studying resveratrol to determine how it helps fight aging and prolong life span. Current evidence suggests that resveratrol exerts antioxidant effects, boosts energy production, and favorably alters patterns of gene expression.
Oxidative stress is implicated in numerous disease processes and in aging itself. Resveratrol demonstrates powerful antioxidant capabilities, with profound implications for human health. Scientists report that resveratrol inhibits the oxidation of dangerous low-density lipoprotein (LDL) and scavenges harmful hydroxyl radicals. Resveratrol also helps preserve levels of glutathione, one of the body’s most essential antioxidants.
According to prominent resveratrol investigator Dr. Milos Sovak, “There is no question that resveratrol is one of the best free-radical scavengers and that it has many effects whose ramifications might affect not only longevity but also general health.”
Resveratrol stimulates energy production in the cellular powerhouses known as the mitochondria. Diminished mitochondrial energy production is associated with reduced longevity. By enhancing the production of life-sustaining energy, resveratrol may help protect against metabolic disease and obesity, thereby improving health and prolonging survival in animals.
Growing evidence indicates that resveratrol influences many genetic pathways, which may underlie its ability to lengthen life. In the recent Harvard study, investigators noted that a high-calorie diet produced numerous changes in gene expression. However, supplemental resveratrol opposed the effects of this high-calorie diet in 144 of 153 significantly altered genetic pathways. Moreover, resveratrol’s effects were dose dependent, with larger amounts yielding greater effects, leading the investigators to suggest that resvera-trol may offer “new approaches for treating obesity-related disorders and diseases of aging.”7
Some of the genetic pathways influenced by resveratrol are similarly affected by caloric restriction. For example, caloric restriction is associated with long-term activation of AMP-activated kinase (AMPK), a metabolic enzyme promoting insulin sensitivity and fatty-acid oxidation. Resveratrol likewise increases AMPK activity, which is associated with life-span extension.
Scientists believe that caloric restriction increases life span in part through its effects on the sirtuin genes. Present in all life forms, sirtuin genes are associated with aging and longevity. Resveratrol may confer benefits similar to those of caloric restriction by influencing the sirtuin gene known as SIRT2.5,8-10 In the Harvard study, resveratrol helped counteract changes in SIRT2 expression induced by a high-calorie diet.
“The genes and pathways [affected by resveratrol or by caloric restriction] are related to activation of sirtuins, a class of histone deacetylase enzymes (HDACs) involved in cell death and life-span regulation,” Dr. Zhao-Wilson told Life Extension. “Based on the large body of evidence, the resveratrol/sirtuin activators have become the focus of pharmaceutical drug discovery efforts now [targeting] HDACs.”
Researchers believe that compounds like resveratrol that either activate or inhibit sirtuin activity may have therapeutic potential for a broad array of human diseases, including cancer, diabetes, heart failure, and neurodegenerative conditions such as Alzheimer’s and Huntington’s disease.
Cardiovascular Effects
Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Several studies have demonstrated that resveratrol is an effective antioxidant [7-10]. It inhibits lipid peroxidation of low-density lipoprotein (LDL) [7,8], prevents the cytotoxicity of oxidized LDL [7], and protects cells against lipid peroxidation [7]. It is thought that because it contains highly hydrophilic and lipophilic properties, it can provide more effective protection than other well-known antioxidants, such as vitamins C and E [7]. On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine [2]. Reduced platelet aggregation has also been demonstrated in studies on resveratrol, further contributing to its prevention of atherosclerosis [2,9]. To date, most of the research on resveratrol's antioxidant and anti-platelet properties has been done in vitro (in an artificial environment using test-tube or tissue-culture preparations). Further studies in animals and humans are necessary to determine whether resveratrol supplementation makes sense.
Cancer-Related Effects
Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation, and as an anti-mutagen in rat models [4]. Resveratrol appears to decrease tumor promotion activity by inhibiting cyclooxygenase-1 (COX-1) [4,11,12], an enzyme that converts arachidonic acid to pro-inflammatory substances that stimulate tumor-cell growth [3]. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation [4] and inhibited ribonucleotide reductase, an enzyme needed for DNA synthesis in proliferating cells [12]. One appealing characteristic of resveratrol's anti-cancer potential is its minimal toxicity to blood-forming cells [11]. More studies using both cellular and animal models are needed before any such data would be applicable to human use.
The similarity in structure between resveratrol and diethylstilbestrol (a synthetic estrogen) has prompted investigations into resveratrol's potential as a phytoestrogen (a plant compound that produces estrogen-like effects). However, these properties also stimulate the growth of human breast cancer cells [5]. This finding seems contrary to its other anticancer activities, and is a cause for concern.
The Bottom Line
Laboratory tests have clearly demonstrated that resveratrol may help prevent cardiovascular disease and cancer. However, there are several reasons why recommending a population-wide increase would be premature.
First, little is known about the absorption and clearance of resveratrol, the identities of its metabolic products, or its effects on the liver [5]. A study in rats showed that resveratrol is absorbed in the gut and has a high affinity for the heart and liver [13,14]. Second, the research on resveratrol has focused on its short-term effects [2] and has been dominated by in vitro studies on non-human models. Third, its role as a potentiator of breast carcinomas may significantly limit its use, even for its "proven" benefits. Finally, its main dietary source is red wine. Not only is its concentration in wine extremely variable, but recommending increased consumption of red wine to boost resveratrol intake could certainly do more harm than good. In spite of any beneficial aspects, red wine and other alcoholic beverages pose health risks that include liver damage and physical addiction. The health-food industry is claiming that resveratrol is the wine component responsible for the "French Paradox." While taking resveratrol pills is certainly safer than heavy consumption of red wine, supplementing with unproven substances is generally unwise. At this point, occasional use of red wine seems far more prudent.
Multi-Tasking Resveratrol
Recent animal and cell culture studies, examining the effects of this polyphenolic compound on other organisms, have indicated that resveratrol may help to inhibit cancer growth and tissue-destructive inflammation. Laboratory studies also suggest that it may help to improve cardiovascular health and blood pressure, as well as cholesterol levels, and even to extend the lifespan of a number of species of animals, including mice.
The details as to the mechanism involved in these resveratrol-induced benefits are complex and currently under intense investigation.
Osteoporosis and HRT
Osteoporosis is a decrease in bone strength due to loss of bone mineral and structural components. It is a significant issue associated with aging in both sexes, especially in post-menopausal women.
Several years ago, bone loss was linked to a decrease in serum levels of the hormone estrogen, a post-menopausal phenomenon. The medical profession began treating post-menopausal patients, who exhibited early signs of osteoporosis, with estrogen. This hormone replacement therapy (HRT) did significantly inhibit progression of the disease.
Unfortunately, recent studies have shown this form of treatment to be associated with considerable risk, including an increase in cardiovascular disease and cancer. These results have prompted the medical profession to be more cautious in the treatment of osteoporosis with HRT as potential risks may offset the benefits.
Osteoporosis and Resveratrol
Resveratrol, according to another recent laboratory study, has the potential of helping to prevent osteoporosis without the health risks associated with HRT.
Demonstrating that this plant compound is a phytoestrogen, which can bind to and activate estrogen receptors, was the impetus to investigate the potential role resveratrol may play in bone metabolism.
Studies were carried out in cell cultures as well as animals that were susceptible to bone loss (ovariectomized rats). Collectively, the results demonstrated a number of bone-forming activities associated with resveratrol treatment.
Resveratrol turns on genes involved in bone formation and turns off genes involved in bone destruction. The result is the conversion of precursor bone cells to bone-forming cells (osteoblasts), as well as the inhibition of the production of bone-destroying cells (osteoclasts). The net result in bone is anabolic. In other words, the bone is getting stronger with an increase in bone mineral and bone structural components or proteins.
Tumor Suppressing Bonus
What sets resveratrol apart from HRT? While both promote the production of bone strength and inhibit osteoporosis, resveratrol, rather than increasing the risk of cancer, prevents tumor growth. Why the difference?
Although resveratrol, like HRT, activates a biochemical pathway to promote bone-forming cell growth and inhibit bone-destructive cell growth, it simultaneously activates a pathway that culminates in the synthesis of a tumor-suppressor protein, FOXO3A, which accumulates in the cell's nucleus.
Resveratrol's Future
The bone-forming property associated with resveratrol, without the cancer risks associated with HRT, would appear to make this compound an ideal therapeutic strategy for the prevention of osteoporosis. However, the studies to date, although very encouraging, were performed on cell cultures and animals. To be appropriate as a therapeutic for human use, future studies will have to demonstrate similar effects in clinical trials.
Nevertheless, resveratrol is a compound of significant interest, with respect to its many purported health benefits, including improved cardiovascular health, cancer prevention and anti-aging. In addition, there are virtually no reported negative side effects in studies using very large doses.
Many following this research believe that either this compound or more potent synthetic derivatives of resveratrol will be future therapeutics. The work associated with resveratrol has already led to exciting discoveries that should help promote the development of therapeutics for a variety of disease states.
Resveratrol Source
Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of the blood vessels, heart [1,2], and liver [2]. It came to scientific attention only four years ago, however, as a possible explanation for the "French Paradox" -- the low incidence of heart disease among the French people, who eat a relatively high-fat diet [3]. Today, it is touted by manufacturers and being examined by scientific researchers as an antioxidant [4], an anti-cancer agent, and a phytoestrogen [5]. It is also being advertised on the Internet as "The French Paradox in a bottle." [A] Arkopharma, of Wallingford, Connecticut, even markets a red-wine extract antioxidant product called "French Parad'ox." This article reviews the recent research on resveratrol's physiologic activity.
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References
Celotti E and others. Resveratrol content of some wines obtained from dried Valpolicella grapes: Recioto and Amarone. Journal of Chromatography A 730(1-2): 47-52, 1996. Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: A molecule whose time has come? And gone? Clinical Biochemistry 30:91-113, 1997. Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? European Journal of Endocrinology 138:619-620, 1998. Jang M and others. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218-220, 1997. Gehm H and others. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proceedings of the National Academy of Sciences U.S.A. 94:557-562, 1997. Sanders TH, McMichael RW. Occurrence of resveratrol in edible peanuts. Presentation, American Oil Chemists Society, Las Vegas, Nevada, 1998. Discussed in Peanuts contain significant amount of plant compound that may prevent risk of heart disease and cancer, a news release from The Peanut Institute, Sept 8, 1998. Chanvitayapongs S, Draczynska-Lusiak B, Sun AY. Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport 8:1499-1502, 1997. Belguendouz L, Fremont L, Gozzelino MT. Interaction of transresveratrol with plasma lipoproteins. Biochemical Pharmacology 55:811-816, 1998. Rotondo S and others. Effect of trans-resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function. British Journal of Pharmacology 123:1691-1699, 1998. Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol. Lancet 341:1103-1104, 1993. Clement MV and others. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 92:996-1002, 1998. Fontecave M and others. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Letters 421:277-279, 1998. Bertelli AA and others. Evaluation of kinetic parameters of natural phytoalexin in resveratrol orally administered in wine to rats. Drugs under Experimental and Clinical Research 24:51-55, 1998. Bertelli A and others. Plasma and tissue resveratrol concentrations and pharmacological activity. Drugs under Experimental and Clinical Research 24:133-138, 1998.
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