In all animals in which it has been tested, caloric restriction—the practice of restricting calorie intake while maintaining good nutritional status—improves multiple aspects of age-related decline. Caloric restriction does this, in part, by producing changes in gene expression that are associated with long life and a slowing of the aging process.

Resveratrol is also gaining growing recognition for its promise in fighting age-related diseases ranging from dementia to diabetes. For example, the National Institutes of Health is currently sponsoring a clinical trial investigating resveratrol’s ability to fight colon cancer.

In this article, we bring our readers up to date on the latest clinical research on resveratrol, and why leading researchers believe this remarkable nutrient may hold the key to living a longer, more vibrant, disease-free life.

Resveratrol and Caloric Restriction

To date, the most reliable, best-researched way to extend life span is through the practice of caloric restriction, which involves reducing calorie intake while simultaneously maintaining good nutritional status.

In numerous studies, restricting calorie intake in laboratory animals has been shown to prolong their life span by as much as 60%.1-3 While scientists have not yet determined whether caloric restriction extends life span in humans, the preliminary evidence is very promising. 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.4 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 Life Extension, “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.5 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:

While mice on the non-supplemented high-calorie diet developed enlarged, fatty livers, resveratrol supplementation prevented these changes. Similarly, heart disease and evidence of atherosclerosis were seen in mice fed the high-calorie diet, but not in those that were also given resveratrol. 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.5

Resveratrol’s positive impacts on insulin sensitivity and survival were apparent after only six months of treatment.5 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.5 The obese resveratrol-supplemented animals experienced all of these benefits without a significant reduction in body weight.5

“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.”5

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.6 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.7

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.5

Scientists believe that caloric restriction increases life span in part through its effects on the sirtuin genes.5 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.5

“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.11

Specific Health Applications of Resveratrol

While resveratrol’s impact on cardiovascular disease has undergone the most scrutiny to date, researchers are also exploring its effects on a broad array of diseases, including cancer, arthritis, diabetes, and Alzheimer’s.16,17

Cardiovascular Benefits

In laboratories around the world, innovative studies identified the impact of resveratrol on reducing the risks of heart disease and the damage from strokes.20 Some of these discoveries include the reduction of atherosclerosis, including control of blood vessel diameter and muscle tone, inhibition of oxidative stress, anti-inflammatory effects, inhibition of LDL (low-density lipoprotein) oxidation, and a reduced “stickiness” of platelets leading to a reduction in deadly clot formation.21-25

The multiple health benefits have led even the conservative US Department of Health and Human Services to recommend moderate wine consumption because of its resveratrol content in its Healthy People 2010 initiative.26

In a unique study seeking more knowledge about the complex interaction of resveratrol and heart disease, Korean scientists demonstrated the relationship between resveratrol, inflammation, and blood lipids, immune cells, and the cells lining arterial walls.27 In this remarkable study, the researchers supplemented atherosclerosis-prone mice with either resveratrol, a prescription lipid-lowering drug called clofibrate, or a control diet. The scientists found that resveratrol-supplemented mice had consistently lower total cholesterol and LDL levels than did control animals. Both the resveratrol and the clofibrate-supplemented animals experienced consistently higher levels of beneficial HDL (high-density lipoprotein) than controls. Importantly, the resveratrol-supplemented group also saw significantly higher levels of a vital enzyme called paraoxonase, which is an HDL-associated protein capable of preventing the LDL oxidation that triggers the inflammatory cascade of atherosclerosis.28 And in a remarkable finding, the activity of the cholesterol-producing enzyme HMG-CoA-reductase (HMGR) was significantly lower in both the resveratrol and the clofibrate group—a noteworthy finding, since reducing HMGR activity is the target of the widely prescribed lipid-lowering medications called statins.

Resveratrol also diminished levels of adhesion molecules in vessels walls that are responsible for promoting plaque and clot formation. Of course, the most exciting finding from this comprehensive study was that resveratrol actually reduced the number of atherosclerotic changes and the amount of fat deposition in and around the arteries in the supplemented animals. These researchers concluded that “these results provide new insight into the anti-atherogenic and cholesterol-lowering properties of resveratrol in mice that were fed a normal diet.”

Animal studies also demonstrate resveratrol’s impressive power to prevent or reverse damage even when a cardiovascular event does occur. For example, chronic hypertension and obesity can contribute to an overgrowth of heart muscle known as cardiac hypertrophy, which in turn is a major contributor to congestive heart failure.29,30 Canadian researchers showed that resveratrol could reduce rat cardiac cell hypertrophy by blocking inflammatory signals.31 Further, Korean scientists used resveratrol to protect heart cells from free radical-induced cell death.32 And Chinese cardiologists were able to use resveratrol to prevent death of rat cardiac cells through the activation of sirtuins, preventing the subsequent remodeling of heart muscle that contributes to congestive heart failure following a heart attack.33 Similar results are now being obtained in laboratories around the world.34,35

Stroke is another devastating outcome of atherosclerosis, and one that is also ripe for prevention by resveratrol’s multiple modes of action.36 Through its activation of sirtuin molecules, resveratrol can prevent injury to brain cells subjected to stroke-like conditions in the laboratory.37,38 Chinese neuroscientists found that when resveratrol was given to live animals for seven days before an experimentally induced stroke, it reduced the amount of brain tissue injured, while limiting the actual neurological deficits the stroke produced.39 These changes were accompanied by a substantial reduction in the inflammatory markers that are among the hallmarks of brain injury in stroke. Similar results, with the additional benefit of reduction in markers of brain cell oxidation, have been reported by others.40,41 Studies with humans and human tissues have also been promising.

A dramatic finding comes from the work of Turkish cardiac surgeons who applied resveratrol to cross-sectional pieces of blood vessels obtained from 38 men undergoing cardiac bypass operations.42 The in-vitro treatment produced relaxations of the vessels of 35%—a dramatic increase in their capacity to carry blood efficiently. They went on to show that these results were directly related to the effects of resveratrol on the vital endothelial layer lining the vessels—the layer that is the most immediate site of atherosclerotic change.

In a 2005 study of 30 men with coronary heart disease, Greek cardiologists examined the effects of a resveratrol-containing red grape extract on flow-mediated dilation (FMD), a sensitive measure of endothelial function in a large artery of the arm.43 Fifteen of the men received the supplement, and 15 a placebo. An ultrasound machine determined FMD after fasting and then at 30-, 60-, and 120-minute intervals following the supplement. Men who took the supplement experienced an increase in FMD significantly above baseline values, peaking at one hour after intake of the supplement, while no change was found in the placebo recipients. Since FMD is a direct measure of arteries’ ability to respond to changes in blood flow, this study provided powerful evidence for a benefit of resveratrol-containing red grape extract on arterial performance.

Another manifestation of resveratrol’s cardiovascular benefit comes from the work of internists in Italy, who were interested in platelet aggregation (clumping), an important part of both atherosclerosis and acute clot formation in heart attacks and stroke.24 This study examined blood parameters from healthy volunteers before and after 15 days of controlled red or white wine intake. The researchers found that wine intake increased the production of the biochemical signaling molecule nitric oxide, blunting a pathological response that ultimately increases platelet aggregation. The scientists pursued the effect further, treating platelets directly with resveratrol at the concentrations they had measured in subjects’ blood. In addition to a number of beneficial effects on nitric oxide production, the researchers also identified reductions in the activity of inflammatory pathways and systems that produce destructive reactive oxygen species.

Diabetes and the Metabolic Syndrome

Type 2 diabetes is associated with development of the metabolic syndrome, which dramatically elevates risk of cardiovascular disease, the number one cause of death in the aging population.16,44 Epidemiologic studies have established beyond doubt that red wine consumption is associated with a lower incidence of metabolic syndrome and heart disease, and scientists believe the resveratrol component may explain why red wine is more effective than alcohol in general.44 According to Dr. Ling Liu of the University of Hong Kong, “[resveratrol] can act as a potent activator of … sirtuins to expand the life span and to prevent the deleterious effects of excess intake on insulin resistance and metabolic derangement.”44 In fact, resveratrol’s activation of sirtuins is so effective that many researchers are now interested in its use as a potential drug for the treatment of diabetes.45 Let’s examine in more detail a few of the landmark studies of resveratrol’s metabolic effects.

Since cellular uptake of glucose is impaired in diabetes, Canadian researchers decided to examine the effects of resveratrol on enhancing muscle cells’ ability to absorb sugar—an insulin-like function.46 In a laboratory culture of skeletal muscle, the researchers found that addition of resveratrol stimulated glucose uptake to more than 200% of baseline, similar to the action of insulin itself. They were able to trace this effect to the stimulation of sirtuins in the muscle cells. Such activity in humans has the potential to help regulate glucose levels in the blood of diabetic patients, while enhancing delivery of much-needed glucose to hungry skeletal muscles. Of interest is that a similar improvement in insulin-glucose function occurs in response to calorie restriction.

Taking resveratrol treatment a logical step further, Spanish researchers in the Basque country explored the effects of resveratrol on prevention of non-alcoholic fatty liver disease in laboratory rats.47 This is a crucial area of research because non-alcoholic fatty liver disease is linked to obesity, diabetes, and elevated triglyceride levels in blood—all independent risk factors for cardiovascular disease. The researchers fed rats either a control diet or a high-carbohydrate diet for four weeks, including resveratrol in one group of the high-carbohydrate subjects. As expected, the high-carbohydrate group developed fatty liver and associated inflammatory biochemical changes seen in humans. The resveratrol group had decreased fat deposition in their livers compared with the untreated high-carbohydrate group, and also had significant reductions in levels of inflammatory and oxidative stress markers in their blood. The supplemented animals also had higher levels of natural antioxidant enzymes that help combat the effects of oxidized fat molecules. Finally, glucose levels were decreased in the resveratrol-supplemented group.

In a remarkable set of studies, biochemists in Madras reported on a direct comparison of resveratrol with an oral glucose-lowering drug, glyclazide, in control of blood sugar levels in diabetic rats.48,49 The animals were treated with resveratrol orally for 30 days, and experienced a significant decrease in blood sugar, the target outcome. Of clinical importance, the animals also had significant reductions in levels of hemoglobin A1C, a sensitive marker of long-term sugar levels and of protein damage caused by exposure to elevated sugars. The animals were also found to have lower levels of biomarkers of inflammation and liver injury. The researchers noted that these effects are comparable with those of glyclazide, and concluded that “resveratrol may be considered as an effective therapeutic agent for the treatment of diabetes mellitus.”49

Another group of Spanish investigators studied obese rats in a model of the metabolic syndrome.50 These animals, like their human counterparts, have high plasma lipid (fat) levels, insulin resistance, and increased levels of inflammatory molecules produced in their abdominal fat—all destructive changes we know to be associated with cardiovascular disease and other metabolic syndrome consequences. Amazingly, all of these metabolic disruptions were significantly reduced when the animals received resveratrol supplementation. Interestingly, and significantly for overweight and obese humans, the supplemented animals also had reductions in their blood pressure. Encouragingly, resveratrol mimics many of the metabolic benefits of caloric restriction through its activation of sirtuins, without the deprivation associated with a reduced calorie diet.51

Neurodegenerative Diseases

According to the noted Spanish neuropharmacologist Merce Pallas, “healthy aging remains one of the ideals of modern society.”52 Nowhere are the ravages of unhealthy aging more visible than in the terribly destructive neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases—and because these diseases are linked inexorably to oxidative damage and inflammation, resveratrol researchers hold high hopes for the molecule’s potential impact in these areas. It has been suggested that, like caloric restriction, resveratrol helps to preserve and regulate energy levels in brain and nerve cells, prolonging their active lives in part through beneficial, sirtuin-activating effects on mitochondria, the cellular powerhouses.41,53-56

Direct evidence of a resveratrol-mediated neuroprotective effect in Alzheimer’s disease was published in 2009 in a report by Cornell neuroscientists who studied mice given an experimental version of human Alzheimer’s.57 The mice were given resveratrol over a 45-day period; their brains were then examined for the damaging inflammatory beta-amyloid plaques characteristic of Alzheimer’s disease. Despite finding no resveratrol directly in the brain tissue, the scientists reported reductions in plaque formation of 48% to 90% in specific and important regions of the brain! These dramatic changes were accompanied by substantial increases in brain antioxidant molecules. The researchers concluded that “onset of neurodegenerative disease may be delayed or mitigated with use of dietary chemopreventive agents that protect against beta-amyloid plaque formation and oxidative stress.”

It’s not just in chronic degenerative diseases of the brain that resveratrol holds promise—neurosurgeons in Turkey found that resveratrol actually produced better biochemical outcomes in an animal model of spinal cord injury than did methylprednisolone, the steroid commonly given in high doses to trauma victims.58 And the mitochondria-preserving characteristics of resveratrol are now being explored by other neurologists and neurosurgeons as a means of preventing the devastating neurotoxic effects of restoring blood flow to brain tissue deprived of oxygen.41

Resveratrol May Reverse Arterial Aging

“Atherosclerosis is reversible” is not a phrase we expected to hear from mainstream medical researchers until very recently—since these are the precise opening words of a remarkable editorial about resveratrol that appeared in a recent issue of the prestigious New England Journal of Medicine.67 Just as astonishingly, the editorial was written by a renowned immunologist, Linda K. Curtiss, PhD, of the Scripps Research Institute in La Jolla, California. The fact that an immunologist is writing about cardiovascular disease in a trend-setting medical journal speaks volumes about how far we have come in our understanding of chronic diseases and their relationships with inflammation, which is an immune system phenomenon. What truly sets Dr. Curtiss’s article apart, though, is her description of a dramatic new phenomenon mediated by the grape polyphenol resveratrol. Curtiss’s excitement comes from work done by Cleveland Clinic cell biologist Young-Mi Park, MD, who was exploring the role of oxidant stress and inflammation on the pathogenesis, or disease-causing mechanisms, of atherosclerosis.68 Knowing that fat-laden inflammatory cells called foam-cell macrophages trigger inflammation when they become trapped beneath the lining of blood vessels,69-72 Park’s team sought to understand why the cells become trapped, and how they could be freed from their “endothelial bondage,” thereby reversing the inflammatory process. The most natural approach to take, Park’s group decided, was simply to test known antioxidants’ ability to prevent the foam cells from migrating into the endothelial lining in the first place, and their ability to release any cells that were already present.68 Specifically, they studied how oxidized low-density lipoprotein (LDL) promotes foam-cell formation and impairs migration. To do this they blocked LDL oxidation with several potent antioxidants. They found that oxidized LDL actually triggered production of a sort of cellular “glue” in the form of filaments of actin, one of the proteins also found in muscle tissue. The actin filaments were entangling the foam cells, preventing their natural migration out of the endothelial lining, leading to progressive inflammatory changes. Park’s group chose resveratrol as one of the two antioxidants to test—another testimony to the respect that mainstream researchers are according this remarkable molecule (the other was N-acetylcysteine, also an antioxidant available in supplement form).68 Resveratrol treatment of the foam cells inhibited production of reactive oxygen species by greater than 90%, an important first step in breaking the cycle. Even more impressively, resveratrol partially restored the foam cells’ ability to move out of the entangling actin filaments, and migrate away from the endothelial lining! This brings us back to Dr. Curtiss’s astounding initial observation that atherosclerosis is a reversible condition—through the use of powerful antioxidants such as resveratrol, we can now understand how oxidized LDL contributes to invasion of endothelium by inflammatory cells, and how prevention or reversal of LDL oxidation promotes mobilization of inflammatory cells and their emigration away from vessel linings. As Dr. Park concluded, “[these studies] also provide additional mechanistic support for the atheroprotective effect of antioxidants.”68 Resveratrol is already well-known as a cardiovascular protective supplement—the work of Park and others is now showing us that resveratrol must also be considered a valuable cardiovascular therapeutic supplement, one that can literally “turn back the clock” on chronic vascular diseases of aging!

Inflammation and Arthritis

A common culprit in heart disease, cancer, and arthritis is chronic inflammation, mediated by naturally produced compounds in the body known as prostaglandins and cytokines. By blocking the activity of such inflammatory compounds, resveratrol may have therapeutic applications for all of these conditions.35,36

In a recently published study, scientists reported that resveratrol shows promise as a potential therapy for arthritis. When administered to animals with experimentally induced inflammatory arthritis, resveratrol protected cartilage against inflammatory changes related to the disease.37

Neuroprotection

Resveratrol shows promise in protecting the brain and nervous system against disorders associated with aging and genetic factors. In laboratory studies, resveratrol’s antioxidant effect has been shown to protect against nerve cell damage caused by beta-amyloid peptide, which accumulates in the brains of Alzheimer’s sufferers.38-40 This has led several research teams to propose that resveratrol may be a useful treatment for Alzheimer’s disease.41-43

According to a recent report, resveratrol demonstrated a protective effect against Huntington’s disease in animal models.44 Huntington’s is a genetic disease associated with impaired motor skills and reduced mental abilities.

Additionally, grape seed extract appears to protect rat brain cells and maintain the overall viability of the nervous system. Grape seed exerts these effects by modulating proteins implicated in cognitive disorders.24

Extending human life span

Based on his study of experimental life-span extension in mice,45 Dr. Richard A. Miller of the University of Michigan suggests that resveratrol may extend the human life span.

Dr. Miller speculates that with effects similar to those of caloric restriction, resveratrol could extend human longevity to about 112 or even 140 years of healthy life.

Practical Considerations for Optimal Supplementation

While plentiful data attest to resveratrol’s potential benefits for health and longevity, certain practical concerns must be addressed to obtain its optimal effects as a dietary supplement. These include resveratrol’s stability, shelf life, dosage, and the variability of different available preparations. Even today, much remains to be learned about the pharmacokinetics of resveratrol—that is, how it is absorbed, utilized, broken down, and excreted in humans.

Bioavailability

Laboratory and animal studies clearly show that resveratrol and its derivatives are biologically active. However, Dr. Zhao-Wilson notes that there are “significant issues related to what is currently known about resveratrol’s bioavailability—it appears to be rapidly metabolized in humans.” Dr. Sovak agrees, commenting, “One problem with resveratrol is that we do not know that much about its resorption and bioavailability in humans, but as expected, the compound is rapidly metabolized and excreted.”

Scientists are exploring ways to optimize resveratrol’s pharmacokinetics. For example, in the Czech Republic, where resveratrol has been approved as a nutritional supplement, Dr. Sovak and his colleagues conducted a pilot study in humans comparing high-purity, pharmaceutical-grade resveratrol to resveratrol glycon, the natural form of resveratrol extracted from the Polygonum plant. Of the two preparations, resveratrol glycon was found to be more easily absorbed in the body and to have better pharmacokinetics.

Another method under investigation to improve resveratrol’s bioavailability is administering it concomitantly with plant-derived flavonoids. Numerous studies suggest that the bioflavonoid quercetin slows the inactivation of resveratrol, thus improving its bioavailability.46,47 A novel type of quercetin, quercetin chalcone, demonstrates superior absorption and solubility, and may thus be the optimal form of this bioflavonoid.48

Stability

Previously, scientists were concerned that the clinical usefulness of certain resveratrol-encapsulated preparations could be limited by poor stability, limited shelf life, or exposure to light and air. However, recent stability studies by Dr. Sovak and his colleagues at the Czechoslovak company Interpharma Praha have demonstrated these concerns to be unjustified. Resveratrol is generally stable for at least two years and does not require special packaging or storage.49

Purity

Not all resveratrol preparations are of equal quality. “As for the variability of different available preparations, this is always an issue with respect to manufacturing and quality control associated with dietary supplements in general,” says Dr. Zhao-Wilson. “It is ‘buyer beware,’ and one must find a high-quality source with a vested interest in providing consumers with the best available products and scientific evidence to back them up.”

Dr. Sovak agrees, and recommends only pure forms of resvera-trol for study and consumption. Interpharma Praha has developed technology to produce high-purity resveratrol and resveratrol glycon according to GMP (good manufacturing practice) standards.

Dosage

In addition to exploring resveratrol’s many potential health applications, researchers are also trying to determine the optimal dose needed to capture its benefits.

“There have been insufficient studies to date in humans to address issues related to optimal dose,” notes Dr. Zhao-Wilson. “Extrapolation of optimal dose from animal studies to humans is always more of an art than a science, and the appropriate studies still need to be done. Nevertheless, reasonable assumptions can be made, and there is even evidence that low doses may be effective for certain conditions.”

Many commercially available supplements provide 20 mg of resveratrol daily. The rationale behind this dosage is that prior to the widespread use of pesticides, French red wine contained approximately 20 mg of resveratrol per liter, and those drinking about a liter daily appeared to derive the cardioprotective benefit associated with the French paradox. Now that the resveratrol content in red wine has decreased to 90 micrograms per fluid ounce,50 a 20-mg (20,000-mcg) resveratrol supplement contains approximately 220 times the amount of resveratrol in one fluid ounce of red wine, or about 41 times the amount in one glass of red wine.

Studies by BioMarker have shown that resveratrol offers benefits for gene expression and longevity in a variety of species using a dosage comparable to 20 mg daily in humans. However, given the extraordinary findings of recent studies using high-dose resveratrol supplements—and their profound implications for human health—some resveratrol researchers and other health-conscious people are now consuming even larger daily dosages.

As for who should supplement with resveratrol, leading researchers maintain that in addition to benefiting patients with specific disease conditions, resveratrol may confer broad-spectrum protection to anyone seeking to live a long life in optimal health.

According to Dr. Zhao-Wilson, “the properties associated with resveratrol appear to be largely protective—cardioprotective, neuroprotective, anticarcinogenic, anti-inflammatory—and the current data suggest that most people could benefit from dietary supplementation with resveratrol obtained from a high-quality source.” Dr. Zhao-Wilson adds that resveratrol is generally safe when taken in conventional dosages.

Dr. Sovak similarly recommends resveratrol as a health-protective agent, noting that resveratrol may be helpful both alone and in combination with other antioxidants, such as epigallocatechins derived from green tea.51,52 Turn to the next article for more precise information about optimal resveratrol dosing.

Engineering Biological Immortality

When we discuss the ability of nutrients like resveratrol, drugs like metformin, and experimental regimens such as caloric restriction to induce favorable changes in gene expression in experimental animals, most people do not realize the ultimate objective of this type of research. While the DNA in the nucleus of our cells includes thousands of genes, it appears that relatively few of these genes control functions that are critical to optimal health and longevity. As mammals (including humans) age, beneficial genes are “turned down,” whereas genes that are detrimental to cellular function are “turned up.” Some genes may be turned off and on with advancing age, and others may have positive influences in youth, but negative influences as we grow older. Examples of beneficial genes that are “turned down” during normal aging are genes that: suppress aberrant cellular proliferation induce DNA repair enable insulin to assist glucose uptake into cells facilitate production of beneficial high-density lipoprotein (HDL). Examples of detrimental genes that are “turned up” during normal aging include those that: induce excess production of potentially harmful low-density lipoprotein (LDL) and cholesterol override normal patterns regulating cell division promote excess production of insulin and inflammation interfere with apoptosis (programmed cell death) of cancer cells. By causing the genes involved in aging to function as they did in youth, it may become possible in the future to reprogram our genes to keep us alive in a state of perpetual youth, which could lead to biological immortality. Just consider: although caloric restriction was discovered to extend maximum life span in mammals in the 1930s, only recently have scientists begun to identify the molecular mechanisms that may explain the benefits of caloric restriction, as well as potential caloric-restriction mimetics such as resveratrol and metformin. The implications of these findings—which have made headline news around the world—is that it may someday be possible to engineer our genes in a way that will make us invulnerable to atherosclerosis, cancer, dementias, arthritis, and all other age-related disorders, as well as aging itself. The net effect would be a radical extension of the healthy human life span. We at Life Extension hope that you are as excited as we are to be part of this fantastic voyage into the outer frontiers of medical research. We urge you to continue to support us so that we can play an ever-increasing role in funding this type of revolutionary scientific research.

What Dose of Resveratrol Should Humans Take?

In response to the many media reports about resveratrol, it seems like every supplement company is offering some form of grape complex for sale that claims to contain some resveratrol.

Recent attention has focused on a publication in the journal Nature that demonstrated improved health and survival in mice fed a high-fat diet supplemented with resveratrol, the same flavonoid that has been shown to increase the life span of a variety of organisms, including yeast, worms, flies, fish, and mice.1-5 This research tied the beneficial effects of resveratrol to mechanisms that underlie caloric restriction, and showed that such approaches could be used to treat certain chronic disorders and diseases of aging.

However, some popular press reports that accompanied this scientific article generated a fair amount of controversy, especially related to the dose used in the experimental mice and the estimated human-equivalent dose that may be required to exert the same biological effects. The Life Extension Foundation, however, is the only organization that has taken a grape-seed/resveratrol product already being used by health-conscious individuals and shown that the favorable biological effects of resveratrol can be achieved at a dose that is more than 10-fold lower than that used in the most-referenced study (referred to as the Harvard study).

Just recently, Life Extension reported that experimental animal studies conducted by BioMarker Pharmaceuticals were under way using the same grape extract fortified with resveratrol that is currently used by Foundation members.6 These studies were designed to evaluate the gene-expression response in mice fed resveratrol from the whole-grape extract found in the Grapeseed Extract with Resveratrol encapsulated product. The gene-expression data obtained from the grape extract group were compared to data from a group of animals subjected to caloric restriction. The preliminary data suggested a significant overlap in the favorable pattern of gene expression between the grape extract-fed mice and the calorie-restricted mice. In addition, experimental fruit flies (Drosophila) fed grape extract showed improvement in a model of Parkinson’s disease, as well as an extended life span. These findings paved the way for further analysis identifying the specific molecular pathways involved in these effects. Here we provide an update to these earlier findings.

Resveratrol and Other Health-Promoting Grape Constituents

The Life Extension Foundation constantly surveys the scientific literature in order to utilize the most important findings in promoting health and extending life. Mounting evidence demonstrates the broad-spectrum effects of biologically active molecules such as resveratrol, which is derived from natural plant extracts. In nature, molecular compounds like resveratrol are found in complex mixtures containing a diverse array of physiologically relevant molecules. Many of these constituents may be required in order to provide phytomedicinal agents with optimal bioavailability and synergistic action. Scientists must consider these points when conducting studies using either a single phytochemical (such as resveratrol alone) versus resveratrol combined with grape skin and grape seed extracts.

Classes of molecules found in natural whole grape, grape skin, and grape seed extracts include potent effectors like proanthocyanidins (in grape seed), anthocyanins (which give purple and red grapes their color), and single molecular entities such as resveratrol and quercetin. Scientific studies document the multiple health effects of these components, which can be characterized as antibiotic, anti-tumor, anti-diabetic, anti-ulcer, cardioprotective, anti-inflammatory, and anti-brain aging.7

The cardiovascular health benefits of grape seed extract include favorable effects on blood pressure, enhanced endothelial function, and decreased oxidative stress.8 The potent antioxidant activity of grape seed extract may be responsible for its reported neuroprotective effects, as observed in animal models of Alzheimer’s disease.9,10 Recently, grape seed extract combined with calcium was found to be more effective than calcium alone in building healthy bone mass.11 Grape seed extract has effectively inhibited the growth of human colorectal tumor cells in the laboratory and in animals.12

Recent findings on resveratrol’s effects in experimental animal models are attracting a great deal of interest from the scientific community, while raising many questions about resveratrol’s applications in humans. One of the most intriguing questions is what dose of resveratrol may help humans achieve the beneficial health effects that have been observed in animals. While extrapolating animal dosage to human dosage is difficult at best, scientists are using several approaches to address this question. The accumulating data from gene-expression studies in mice provide some clues. These findings are also helping to illuminate the molecular basis of the biological effects of resveratrol and grape extracts.

The Harvard Study generated a great deal of enthusiasm by showing that mice fed high-fat diets (60% of calories from fat) avoided numerous diet-related health problems when supplemented with res-veratrol. Compared to mice that were not given resveratrol, the supplemented mice exhibited increased survival, increased insulin sensitivity, decreased organ pathology, and in-creased numbers of mitochondria.1 Resveratrol was also responsible for shifting the gene-expression patterns of mice on the high-fat diet towards those of mice on a standard (moderate-fat) diet. These results were achieved by feeding the mice a daily resveratrol supplement equivalent to 22.4 milligrams per kilogram of body weight.* In preliminary studies of this type, scientists often choose relatively high individual doses that are likely to generate an observable effect. Typically, more formal dose-ranging studies would be conducted later to identify optimal doses to attain specific effects. This is partly responsible for the controversy in the popular press regarding the relatively high dose of resveratrol used in this study.

While the Harvard study was under way, BioMarker Pharmaceuticals had already completed an eight-week controlled feeding study in which mice received either resveratrol (a synthetic version) or grape extract (containing resveratrol and other constituents), along with a “normal” diet. Gene-expression profiles were completed on these animals and compared to those of a group of calorie-restricted mice. Genes affected by either resveratrol formulation (synthetic or natural grape extract) or by caloric restriction were then compared. Importantly, the resvera-trol dosage used in this study was much lower—approximately 12-fold lower—than that used in the Harvard study (see Table 1).

Mice on normal diets were fed a daily, relatively low dose of resveratrol obtained from either a synthetic source or from a whole-grape extract enriched with resveratrol. A control group of mice fed a normal diet without resveratrol supplementation and a calorie-restricted group were also evaluated. Total calorie intake was identical in the resveratrol, grape extract, and control groups, and 40% less in the calorie-restricted group.

At the end of an eight-week feeding schedule, the animals’ livers were harvested in order to prepare RNA (the biochemical cousin of DNA) for gene-expression profiling. The samples were specially prepared for analysis with DNA microarrays, or “gene chips,” containing a full set of characterized mouse genes (the Affymetrix GeneChip® contains a total of over 45,000 probe sets, representing a complete set of over 34,000 genes of the mouse genome). Gene-expression levels were determined using statistical methods that ensure a high degree of confidence in the data.*

Both mouse groups that received resveratrol showed significant changes in the expression of key genes, confirming that even at the relatively low doses used in this study, there was a notable biological effect. The differentially expressed genes control over 100 different molecular pathways, including those related to metabolism (primarily metabolism of carbohydrates and lipids), DNA repair, and the regulation of cell death. Since the genes involved are in key biological pathways, they are likely to be responsible for at least some of resveratrol’s biological effects. Furthermore, significant results were achieved using a dose of synthetic resveratrol that was more than 10-fold lower than that used in the Harvard study.

Animals fed grape extract received resveratrol and other components of whole-grape extract.** Their gene-expression response would therefore be expected to reflect effects of both resveratrol and other grape components. Genes that significantly changed in expression in the grape extract group are found in molecular pathways involved in carbohydrate metabolism and biosynthesis (such as the creation of blood sugars), and lipid metabolism and biosynthesis (such as the creation or reduction of cholesterol and fatty acids).

Interestingly, scientists noted a significant overlap—about 65%—when they compared the gene-expression patterns of the resveratrol and grape extract groups. While expected, these results confirm the similar effects of pure synthetic resveratrol and grape extract-derived resveratrol on gene expression in animals.

The gene-expression effects of “low-dose” resveratrol were similar to those seen in calorie-restricted mice: about 55% similarity between the calorie-restricted and resveratrol groups, and 52% similarity between the calorie-restricted and grape extract-supplemented groups.

A method known as molecular pathway analysis can be applied to the gene-expression profiling results in order to identify the key regulatory pathways affected by the various treatments of resveratrol, grape extract, and caloric restriction. Displayed in Figures 1 and 2, these data show which pathways are specific to the different treatments, as well as pathways that are shared between or among the treatments.

Figure 1 shows the results for genes in pathways that are related to biological processes involving DNA; as shown by the overlap, 20 differentially expressed genes involved in DNA-related processes are regulated in the same fashion in animals receiving synthetic resveratrol, grape extract, or caloric restriction. These data suggest that the three treatments share some common features with respect to how genes involved in DNA processing are controlled through gene expression.

A similar approach was used to analyze genes involved in lipid metabolism. As shown in Figure 2, 10 genes involved in pathways related to lipid metabolism are commonly regulated by resveratrol, grape extract, and caloric restriction. These data are just a subset of the entire analysis. In total, 159 different molecular pathways were found to be commonly regulated by these three different treatments.

Resveratrol and grape extract produce strongly similar effects, based on the gene-expression responses demonstrated in mice fed a relatively low dose of these compounds. Comparison of these groups with calorie-restricted mice shows a significant overlap in the three treatments’ regulation of similar biological pathways. These data add to the accumulating evidence that resveratrol triggers a biological response in mammals that is similar to that observed with caloric restriction, an intervention that is known to extend life span and protect against age-related diseases.2-5 These effects are observed even at a relatively low dose of resveratrol, indicating that a human-equivalent dose can be obtained through dietary supplementation with high-quality resveratrol products.

What This Means to Aging Humans Today

A fluid ounce of red wine averages around 90 micrograms of resveratrol.13 The resveratrol supplements used by Life Extension members contain 20 mg (20,000 mcg) of resveratrol in each capsule. Therefore, these 20-mg resveratrol supplements provide approximately 220 times the amount of resveratrol found in one fluid ounce of red wine.

Since a glass of wine is approximately 5 and 1/3 ounces, a person taking one 20-mg resveratrol supplement may ingest the equivalent amount of resveratrol found in 41 glasses of red wine. Needless to say, that is a lot of red wine.

In the studies conducted by BioMarker Pharmaceuticals, mice demonstrated favorable anti-aging gene-expression changes in response to receiving the human equivalent of 20 mg of resveratrol a day.

The very positive study results reported in the media in late 2006 used human-equivalent doses of resveratrol in the hundreds or thousands of milligrams a day.

So what we have now are extremely favorable data on resveratrol (along with other grape constituents), with a wide range of probable optimal doses for aging humans to consider.

Those who choose to consume 20 mg of resveratrol a day can take comfort in the BioMarker research showing that this potency exerted impressive changes in critically important genes involved in various aging processes and degenerative diseases.

Those who choose to consume higher doses of resveratrol can look at the media-reported studies that also showed very impressive results. The good news for consumers is that they can obtain standardized resvera-trol and other grape constituents in 20 mg and 100 mg capsules, at a very moderate cost.

Footnotes:

* Doses of drugs in experimental animals are often calculated in milligrams (mg) per kilogram (kg) of body weight. This enables the doses to be standardized among treatment groups.

** A threshold p-value of 0.001 for a minimum two-fold change in level of gene expression was used; this means that the probability that the gene-expression level is statistically significant is 99.9% or more.

*** Polyphenolic acids, flavonoids, anthocyanins, and oligomeric proanthocyanidins.