Sunday, 16 June 2013
Scientific research of Resveratrol
Resveratrol (3,5,4′-trihydroxystilbene) was first isolated from the roots of white hellebore (Veratrum grandiflorum O. Loes) in 1940 and later, in 1963, from the roots of Polygonum cuspidatum, a plant used in traditional Chinese and Japanese medicine. Initially characterized as a phytoalexin, resvera- trol, a polyphenol present in black grapes and its derivatives, attracted little interest until 1992, when it was postulated to account for some of the cardioprotective effects of red wine. Since then, dozens of reports have shown that resveratrol can prevent or slow down the progression of a wide variety of illnesses, including cancer, cardiovascular disease, and ischemic injuries, as well as enhance stress resistance and extend the life span of various organisms from yeast to vertebrates. Recent reports indicate that resveratrol treatment alone has a range of beneficial effects in mice, but does not increase the longevity of ad libitum-fed animals when started midlife in contrast to high-fat diet–fed mice.
The mechanism by which resveratrol exerts such a range of beneficial effects across species and disease models is not yet clear, although at the beginning it was proposed that the antioxidant properties of this drug may explain the majority of its beneficial effects. Attempts to show its favor- able effects in vitro have met with almost universal success, and have led to the identification of multiple direct targets for this compound. However, results from pharmacokinetic studies indicate that circulating resveratrol is rapidly metabolized, and cast doubt on the physiological relevance of the high concentrations typically used for in vitro experiments. Further experiments are needed to show whether resveratrol or its metabolites accumulate sufficiently in tissues to recapitulate in vitro observations, or whether alternative higher-affinity targets, such as quinone reductase 2, have the key roles in its protective effects. In vivo results have, therefore, become increasinglyimportant in the attempts to understand how effective resveratrol is in the treatment of different diseases. It is also unclear what conclusion should be drawn from the studies described so far. The benefits of resveratrol, as we noted above, can be explained by its antioxidant properties or better if this substance acts through a specific genetic pathway that has evolved to increase disease and stress resistance. With regard to the latter proposal, there is already an ample evidence for the existence of health-promoting pathways that are activated by caloric restriction. It has been known since the 1930s that a severe lowering of caloric intake dramatically slows down the rate of aging in mam- mals and delays the onset of numerous diseases of aging, including cancer, cardiovascular disease, diabetes, and neurodegeneration. The hypothesis that resveratrol might use the same pathways acti- vated by caloric restriction in mammals is attractive because it appears to do so in lower organisms; however, proving this hypothesis will require a better understanding of these processes.
In reference to antioxidant action of resveratrol, it is widely accepted that resveratrol exerts anti- oxidant effects, but it is not yet clear if this is primarily a direct scavenging effect or the result of the activation of pathways that up-regulate cells’ natural antioxidant defenses. Reactive oxygen species (ROS) have been shown to have a role in the initiation and progression of cancer by directly damag- ing DNA and other macromolecules. In addition to its possible modulation of antioxidant enzymes involved in the phase II response, resveratrol has an intrinsic antioxidant capacity that could be related to its chemopreventive effects. In vivo, resveratrol has been shown to increase plasma antiox- idant capacity and decrease lipid peroxidation; however, it is difficult to assess whether these effects are direct or the result of up-regulation of endogenous antioxidant enzymes. In addition, clinical trials of antioxidant molecules have yielded disappointing results, suggesting that phytochemicals could possess other properties that are more relevant to cancer prevention.
Oxidation of low-density lipoprotein (LDL) particles is strongly associated with the risk of coronary heart disease and myo- cardial infarction. Resveratrol prevents LDL oxidation in vitro by chelating copper, as well as by directly scavenging free radicals (although other components of red wine are superior free radical scavengers) [30]. Treatment of normal rats with resveratrol does not affect lipid peroxidation, as reflected by the presence of thiobarbituric acid-reactive substances. However, resveratrol can be detected in LDL particles from humans after consumption of red wine, which is rich in this compound, and the pure compound prevents increases in lipid peroxidation induced by tumors or ultraviolet irradiation, in addition to blocking gentamicin-induced nephrotoxicity. In stroke-prone, spontaneously hypertensive rats, resveratrol significantly reduces markers of oxida- tive stress such as glycated albumin in serum, and 8-hydroxyguanosine in urine. Furthermore, in guinea pigs, resveratrol induces the activities of QR1 and catalase in cardiac tissue, and decreases the concentration of ROS generated by menadione. These results indicate that resveratrol can suppress pathological increases in the peroxidation of lipids and other macromolecules in vivo, but whether the mechanism is direct, indirect, or both is not yet clear.
Another mechanism by which resveratrol could combat tumor formation is induction of cell cycle arrest and apoptosis. The antiproliferative and proapoptotic effects of resveratrol in tumor cell lines have been extensively documented in vitro and are supported by down-regulation of cell cycle proteins and increases in apoptosis in tumor models in vivo. Although resveratrol has been found to target leukemic cells preferentially in vitro in some studies, the specificity of these effects remains unclear because other researchers have found that resveratrol inhibits growth and induces apoptosis in normal hematopoietic cells at similar doses. Some level of specificity could arise from the appar- ent increased susceptibility of cycling cells to the effects of resveratrol. A more precise mechanism by which resveratrol could act is sensitization of tumor cells to other inducers of apoptosis. Resveratrol has been shown to sensitize several tumor lines, but not normal human fibroblasts, to TRAIL (tumor necrosis factor–related apoptosis-inducing ligand)-induced apoptosis. It remains to be seen whether the proapoptotic effects of resveratrol in vivo are related to these in vitro observa- tions, or secondary to other effects, such as inhibition of angiogenesis.
The last protective mechanism related with resveratrol is its role as activator of SIRT1. Resveratrol increases the affinity of SIRT1 for its acetylated substrates, possibly inducing a conformationalchange of SIRT1. The rat brain has receptors for polyphenols such as resveratrol. This indicates that this substance and its derivatives can pass the blood-brain barrier, and several studies suggest that it may have a protective effect in some neurodegenerative processes, as we will describe below in greater extent. Hence, the axis SIRT1/PGC-1 activated by resveratrol is a signaling pathway involved in several cellular contexts and each of the actors involved may promote a separate slowdown in the neurodegenerative process. This neuroprotective action is very likely because the central factor of this signal, PGC-1, promotes mitochondrial activity, while neurodegenerative diseases are linked to mitochondrial failures. It is strongly suggested that the activation of the axis SIRT1/PGC-1 by resveratrol could be a key feature of the mechanisms of neuroprotection by this polyphenol and could lead to new therapeutic prospects.
The mechanism by which resveratrol exerts such a range of beneficial effects across species and disease models is not yet clear, although at the beginning it was proposed that the antioxidant properties of this drug may explain the majority of its beneficial effects. Attempts to show its favor- able effects in vitro have met with almost universal success, and have led to the identification of multiple direct targets for this compound. However, results from pharmacokinetic studies indicate that circulating resveratrol is rapidly metabolized, and cast doubt on the physiological relevance of the high concentrations typically used for in vitro experiments. Further experiments are needed to show whether resveratrol or its metabolites accumulate sufficiently in tissues to recapitulate in vitro observations, or whether alternative higher-affinity targets, such as quinone reductase 2, have the key roles in its protective effects. In vivo results have, therefore, become increasinglyimportant in the attempts to understand how effective resveratrol is in the treatment of different diseases. It is also unclear what conclusion should be drawn from the studies described so far. The benefits of resveratrol, as we noted above, can be explained by its antioxidant properties or better if this substance acts through a specific genetic pathway that has evolved to increase disease and stress resistance. With regard to the latter proposal, there is already an ample evidence for the existence of health-promoting pathways that are activated by caloric restriction. It has been known since the 1930s that a severe lowering of caloric intake dramatically slows down the rate of aging in mam- mals and delays the onset of numerous diseases of aging, including cancer, cardiovascular disease, diabetes, and neurodegeneration. The hypothesis that resveratrol might use the same pathways acti- vated by caloric restriction in mammals is attractive because it appears to do so in lower organisms; however, proving this hypothesis will require a better understanding of these processes.
In reference to antioxidant action of resveratrol, it is widely accepted that resveratrol exerts anti- oxidant effects, but it is not yet clear if this is primarily a direct scavenging effect or the result of the activation of pathways that up-regulate cells’ natural antioxidant defenses. Reactive oxygen species (ROS) have been shown to have a role in the initiation and progression of cancer by directly damag- ing DNA and other macromolecules. In addition to its possible modulation of antioxidant enzymes involved in the phase II response, resveratrol has an intrinsic antioxidant capacity that could be related to its chemopreventive effects. In vivo, resveratrol has been shown to increase plasma antiox- idant capacity and decrease lipid peroxidation; however, it is difficult to assess whether these effects are direct or the result of up-regulation of endogenous antioxidant enzymes. In addition, clinical trials of antioxidant molecules have yielded disappointing results, suggesting that phytochemicals could possess other properties that are more relevant to cancer prevention.
Oxidation of low-density lipoprotein (LDL) particles is strongly associated with the risk of coronary heart disease and myo- cardial infarction. Resveratrol prevents LDL oxidation in vitro by chelating copper, as well as by directly scavenging free radicals (although other components of red wine are superior free radical scavengers) [30]. Treatment of normal rats with resveratrol does not affect lipid peroxidation, as reflected by the presence of thiobarbituric acid-reactive substances. However, resveratrol can be detected in LDL particles from humans after consumption of red wine, which is rich in this compound, and the pure compound prevents increases in lipid peroxidation induced by tumors or ultraviolet irradiation, in addition to blocking gentamicin-induced nephrotoxicity. In stroke-prone, spontaneously hypertensive rats, resveratrol significantly reduces markers of oxida- tive stress such as glycated albumin in serum, and 8-hydroxyguanosine in urine. Furthermore, in guinea pigs, resveratrol induces the activities of QR1 and catalase in cardiac tissue, and decreases the concentration of ROS generated by menadione. These results indicate that resveratrol can suppress pathological increases in the peroxidation of lipids and other macromolecules in vivo, but whether the mechanism is direct, indirect, or both is not yet clear.
Another mechanism by which resveratrol could combat tumor formation is induction of cell cycle arrest and apoptosis. The antiproliferative and proapoptotic effects of resveratrol in tumor cell lines have been extensively documented in vitro and are supported by down-regulation of cell cycle proteins and increases in apoptosis in tumor models in vivo. Although resveratrol has been found to target leukemic cells preferentially in vitro in some studies, the specificity of these effects remains unclear because other researchers have found that resveratrol inhibits growth and induces apoptosis in normal hematopoietic cells at similar doses. Some level of specificity could arise from the appar- ent increased susceptibility of cycling cells to the effects of resveratrol. A more precise mechanism by which resveratrol could act is sensitization of tumor cells to other inducers of apoptosis. Resveratrol has been shown to sensitize several tumor lines, but not normal human fibroblasts, to TRAIL (tumor necrosis factor–related apoptosis-inducing ligand)-induced apoptosis. It remains to be seen whether the proapoptotic effects of resveratrol in vivo are related to these in vitro observa- tions, or secondary to other effects, such as inhibition of angiogenesis.
The last protective mechanism related with resveratrol is its role as activator of SIRT1. Resveratrol increases the affinity of SIRT1 for its acetylated substrates, possibly inducing a conformationalchange of SIRT1. The rat brain has receptors for polyphenols such as resveratrol. This indicates that this substance and its derivatives can pass the blood-brain barrier, and several studies suggest that it may have a protective effect in some neurodegenerative processes, as we will describe below in greater extent. Hence, the axis SIRT1/PGC-1 activated by resveratrol is a signaling pathway involved in several cellular contexts and each of the actors involved may promote a separate slowdown in the neurodegenerative process. This neuroprotective action is very likely because the central factor of this signal, PGC-1, promotes mitochondrial activity, while neurodegenerative diseases are linked to mitochondrial failures. It is strongly suggested that the activation of the axis SIRT1/PGC-1 by resveratrol could be a key feature of the mechanisms of neuroprotection by this polyphenol and could lead to new therapeutic prospects.
New Benefits of Reserve
Here’s great news that will help you slash your risk of heart attack, high blood pressure and all forms of heart disease: Researchers uncovered “hidden” benefits from the popular heart and longevity nutrient resveratrol.
Turns out resveratrol stimulates the production of adult stem cells called endothelial progenitor cells.
These stem cells are so powerful, they have the ability to seek out, repair and heal the trouble areas in the lining of your blood vessels called the endothelial cell barrier or ECB.
Since the release of a landmark study published in the New England Journal of Medicine in 2003, scientists and researchers have focused more and more on the power of these endothelial progenitor cells.
And for good reason. The study from the New England Journal of Medicine showed a “strong correlation” between the number of progenitor cells circulating in the blood and a person’s overall risk of heart disease.1
The connection is so strong, I could make the case that the number of progenitor cells will become the new “marker” of cardiovascular health, even replacing the two major forms of cholesterol, HDL and LDL.
Simply stated, the more of these progenitor cells you have, the more likely you are to avoid disease. This view is supported by the fact that patients with diabetes, high blood pressure and/or cardiovascular disease have low levels of progenitor cells.
Studies showed, “the number of endothelial progenitor cells was significantly reduced in patients with hypercholesteroemia (extremely high cholesterol levels) compared with that in control subjects.”2
In these patients with very high cholesterol, they found the ability of endothelial progenitor cells to proliferate, migrate, adhere to vessel walls and induce the regeneration of blood vessels was weakened.
Resveratrol had the opposite effect.
In many recent studies I’ve read, I find that resveratrol increases the number of these endothelial progenitor cells.3,4,5,6 Resveratrol also has the distinction of activating telomerase, the enzyme that rebuilds your telomeres.
These two critical functions are enabled by resveratrol’s ability7to “turn on” genes that promote longevity, and “turn off” genes that promote disease. By influencing the way genes are expressed, resveratrol has the ability to activate anti- aging genes called sirtuins. Sirtuins transmit signals to every cell in your body that literally cancel out the effects of aging. They bring the processes that lead cell death to a crawl, buying your body more time to repair the DNA damage that brings life to an end.
To Your Good Health, Al Sears, MD
Turns out resveratrol stimulates the production of adult stem cells called endothelial progenitor cells.
These stem cells are so powerful, they have the ability to seek out, repair and heal the trouble areas in the lining of your blood vessels called the endothelial cell barrier or ECB.
Since the release of a landmark study published in the New England Journal of Medicine in 2003, scientists and researchers have focused more and more on the power of these endothelial progenitor cells.
And for good reason. The study from the New England Journal of Medicine showed a “strong correlation” between the number of progenitor cells circulating in the blood and a person’s overall risk of heart disease.1
The connection is so strong, I could make the case that the number of progenitor cells will become the new “marker” of cardiovascular health, even replacing the two major forms of cholesterol, HDL and LDL.
Simply stated, the more of these progenitor cells you have, the more likely you are to avoid disease. This view is supported by the fact that patients with diabetes, high blood pressure and/or cardiovascular disease have low levels of progenitor cells.
Studies showed, “the number of endothelial progenitor cells was significantly reduced in patients with hypercholesteroemia (extremely high cholesterol levels) compared with that in control subjects.”2
In these patients with very high cholesterol, they found the ability of endothelial progenitor cells to proliferate, migrate, adhere to vessel walls and induce the regeneration of blood vessels was weakened.
Resveratrol had the opposite effect.
In many recent studies I’ve read, I find that resveratrol increases the number of these endothelial progenitor cells.3,4,5,6 Resveratrol also has the distinction of activating telomerase, the enzyme that rebuilds your telomeres.
These two critical functions are enabled by resveratrol’s ability7to “turn on” genes that promote longevity, and “turn off” genes that promote disease. By influencing the way genes are expressed, resveratrol has the ability to activate anti- aging genes called sirtuins. Sirtuins transmit signals to every cell in your body that literally cancel out the effects of aging. They bring the processes that lead cell death to a crawl, buying your body more time to repair the DNA damage that brings life to an end.
To Your Good Health, Al Sears, MD
Why Reserve? Réserve CAP‐e Test Results
Please keep in mind, the purpose of the CAP‐e test is to determine if antioxidants are capable of entering into and protecting live cells from oxidative damage. Since a protective effect was seen and an IC50 was reached, we were able to generate a CAP‐e number and state there is extremely significant biological antioxidant penetration and protection by the product.
On a complex product like this, with antioxidant compounds with very different solubility properties, it was agreed that testing in both aqueous and non‐aqueous solvent would provide the best appreciation of the antioxidant protection provided to living cells. By doing both extraction methods, you get a broader understanding of the biological activity and antioxidant protection than by doing only one solvent.
We understand that one of the many antioxidant ingredients is Resveratrol. This compound has some, but limited solubility in water. It therefore contributes only a little bit to the water extract CAP‐e. In contrast, it is likely contributing much more to the ethanol CAP‐e. Other ingredients have other solubility properties.
On a complex product like this, with antioxidant compounds with very different solubility properties, it was agreed that testing in both aqueous and non‐aqueous solvent would provide the best appreciation of the antioxidant protection provided to living cells. By doing both extraction methods, you get a broader understanding of the biological activity and antioxidant protection than by doing only one solvent.
We understand that one of the many antioxidant ingredients is Resveratrol. This compound has some, but limited solubility in water. It therefore contributes only a little bit to the water extract CAP‐e. In contrast, it is likely contributing much more to the ethanol CAP‐e. Other ingredients have other solubility properties.
Thursday, 13 June 2013
Media and Anti Aging Research - Resveratrol
Dr Sinclair from Harvard interviewed on abc news and 60 minutes on anti-aging.
Dr Oz recommends Resveratrol for longer life!
on abc: Dr Oz shares that Resveratrol turns on Sirtuin in the body, and talks about stem cell technology on the Oprah Winfrey Show.
Dr David Sinclair's research on Resveratrol
Groundbreaking antiaging research from Dr Sinclair of Harvard Medical! Wanna live longer and look younger? Take Reserve!
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