Resveratrol—Star Molecule Against Disease and Aging

Resveratrol May Be the Key Molecule of Our Age

Resveratrol—Star Molecule
Against Disease and Aging

Ingesting it dramatically extends the average and
maximum lifespans of various organisms
By Will Block

It is becoming clear that resveratrol and more potent mimetics show great promise in the treatment of the leading causes of morbidity and mortality in the Western world.
— Joseph A. Baur and David A. Sinclair

eading the scientific literature may not rival skiing or skydiving for thrills and chills, but the potential for great excitement is always there. You never know what stunning new development or insight might be found in the next journal article you’ll read. Every so often, something an author says elicits a “Wow!” Only rarely, though, does a scientific paper stop you in your tracks with its portent.

Case in point: a paper just published online in the British journal Nature Reviews Drug Discovery, entitled “Therapeutic potential of resveratrol: the in vivo evidence.”1* It reviews the rapidly accumulating evidence that resveratrol is … well, just reread the quotation shown above. Joseph A. Baur and David A. Sinclair, the paper’s coauthors, are affiliated with Harvard Medical School’s Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, which is “dedicated to understanding the mechanisms of normal aging and the development of interventions to delay its onset and progression, thereby extending the healthy years of human life.”


*In vivo means “in a living organism,” such as an animal or a human being. Its opposite, in vitro, means “in glass,” i.e., in laboratory equipment, such as is used for the study of cell cultures or chemical mixtures. For studies relating to potential therapies, in vivo results are more important and meaningful than in vitro results, because the latter can much more easily be misleading.


Caloric Restriction Is the Key to Antiaging

Dr. Sinclair, the director of the laboratories and an associate professor of pathology at Harvard Medical School, is a renowned authority in the field of antiaging biology. His research focuses on the genetic basis and molecular mechanisms underlying the effects of caloric restriction, which is currently the only known way to prevent or delay all the major diseases of aging—cancer, heart disease, osteoporosis, diabetes, neurodegeneration, and others. What’s more, caloric restriction (CR) greatly extends the lifespan of every species of organism tested thus far, from yeasts to worms to flies to rodents. (For a primer on CR, see the sidebar.)

A Primer on Caloric Restriction

Caloric restriction (CR) is a drastic (30–40%) reduction in daily caloric intake, to a level that provides all the nutrients sufficient for healthy life, but no more; it does not cause malnutrition. CR was long considered to be the only way to prolong average or maximum lifespan in living organisms, but resveratrol has changed that perception. Among the characteristic features of calorically restricted mammals (in addition to their being very lean) are: increased insulin sensitivity and lower circulating insulin levels; lower core body temperature; reduced incidence or delayed onset of age-related diseases, including cancer, cardiovascular disease, and cognitive disorders; slower age-related decline in many functional tests; and longer life.

CR-based longevity studies have not yet encompassed primates (which have inconveniently long lifespans to begin with), but studies of the health benefits of CR have shown that primates do benefit from this regimen.

The enormous potential benefits of CR to human beings, and the enormous reluctance of human beings to obtain the benefits in that particular way, have inspired researchers to look for chemical compounds that could mimic the effects of CR without the chronic hunger pangs. Leading the pack of candidate compounds is resveratrol, whose stunning ability to extend lifespan in lower organisms is surely one of the greatest discoveries in antiaging biology.

A major goal of Sinclair’s research is to find small, biologically active molecules that can stimulate or simulate the genetic and molecular mechanisms underlying the health and longevity effects of CR so that these effects can be achieved without the privation of what most people would consider a starvation diet. Until about a decade ago, almost all scientists believed that aging was too complex a phenomenon for such an audacious effort to succeed. Then, however, geneticists began discovering genes that could greatly extend lifespan in a wide variety of organisms, including the same ones in which CR has such dramatic antiaging effects.

If aging can be attributed, at least in part, to the actions of a few genes that appear to underlie the effects of CR, then it makes sense to seek chemical compounds that can directly affect the expression of those genes. (Gene expression means the detectable effect of a gene, most commonly the synthesis of a protein and the physiological action of that protein.)

Resveratrol May Be a Key to Caloric Restriction


David A. Sinclair
The leading contender in this molecular treasure hunt is resveratrol (pronounced rez·VEER·ah·troll), a natural polyphenolic compound found primarily in grape skins and red wine. The fact that it’s a phytoalexin—a protective compound produced by plants in response to environmental stresses, such as dehydration, nutrient deprivation, and attack by pathogenic organisms—may help explain its remarkable properties in combating disease and aging.

Resveratrol was discovered in 1940 but remained obscure until 1992, when it was credited with playing a key role in the cardiovascular health benefits of red wine (the “French Paradox” phenomenon). That triggered a surge of scientific interest in resveratrol. The interest intensified in 1997, with the discovery that resveratrol can prevent cancer. It intensified even more in 2003, when Sinclair and his colleagues discovered that resveratrol is a longevity molecule: it extends the lifespan of lower organisms when they consume it. Thus the Holy Grail of antiaging research now appears to be within our reach.*


*For more information on some of the health and longevity benefits of resveratrol, see “Resveratrol May Be a Longevity Molecule” (November 2003), “Resveratrol and Quercetin—Puzzling Gifts of Nature” (July 2005), “Resveratrol Fights Brain Plaque” (November 2005), “Can Resveratrol Help Prevent Alzheimer’s?” (February 2006), and “Resveratrol Prolongs Life in a Vertebrate!” (April 2006).


Sinclair and his postdoctoral student Baur have reviewed the state of the art for resveratrol.1 Following is a discussion of the evidence they have marshaled and their expert opinion of its significance, especially in terms of its therapeutic potential for human beings. We will cover all the major topics they did, in the same sequence.

Introduction to the Baur/Sinclair Paper

Since resveratrol burst onto the scientific scene in 1992, dozens of laboratory and animal studies have documented its ability to prevent or treat a wide variety of diseases, including cardiovascular disease, cancer, and neurodegenerative diseases, as well as to enhance stress resistance and extend lifespan. Laboratory studies, in particular, have met with almost universal success and have revealed multiple direct targets for resveratrol’s physiological actions.

Ample evidence suggests that this multiplicity of targets is no coincidence, but rather the result of resveratrol’s acting through one or more specific genetic pathways that play key roles in health and longevity. It seems likely, but remains to be proved, that resveratrol would use the same CR-related genetic pathways in mammals, including primates and humans, that it uses in lower organisms.

Resveratrol Protects Against Cancer

Resveratrol inhibits the development of tumors in a wide variety of cancers in rodents. One mechanism is by inhibiting the expression of the genes that code for the cyclooxygenases (COX-1 and COX-2), which are implicated in many cancers, as well as the expression of the gene for another cancer-related enzyme called ornithine decarboxylase. Another mechanism is by suppressing angiogenesis, the growth of new blood vessels (angiogenesis is a good thing in most circumstances, but not in tumors, because it speeds their growth). The enzymes just mentioned promote angiogenesis, so resveratrol’s suppression of that process may be due in part to its inhibition of the enzymes.

Yet another way in which resveratrol acts is through its modulation of various drug-metabolizing enzymes. In so doing, it may prevent the activation of certain carcinogenic compounds while simultaneously enhancing the body’s capacity to excrete other harmful compounds. In tumor cells in vitro, and also in actual tumors in vivo, resveratrol promotes apoptosis (ap·oh·TOE·sis), also called “programmed cell death” or “cell suicide.” This is the natural process by which many cells of the body die when they’ve become worn out or damaged; it’s a particularly good thing in cancer cells.

Resveratrol Protects Against Heart Disease

The cardiovascular health benefits of drinking any kind of alcoholic beverage—in moderation—are now widely acknowledged, but epidemiological studies indicate that red wine is particularly beneficial. Wine and grape extracts have been shown to inhibit platelet aggregation (which forms blood clots), induce vasodilation (which improves blood flow and lowers blood pressure), inhibit lipid peroxidation and thus the development of atherosclerosis, and improve blood lipid levels (cholesterol and triglycerides).


“Could resveratrol and similar
molecules form the next class of
wonder drugs?”


The agent believed to be primarily responsible for these benefits is resveratrol, and there is direct evidence of its positive action in all these arenas except for the last one: lipid levels. A possible explanation for resveratrol’s cardiovascular protection is its strong antioxidant action (not uncommon in polyphenolic compounds), particularly in preventing the oxidation of LDL-cholesterol (the “bad cholesterol”). Resveratrol’s antioxidant properties are also believed to play a role in its anticancer potency, by protecting DNA from oxidative damage.

Some evidence suggests that resveratrol is a phytoestrogen (a plant compound possessing estrogenic activity), which might help explain its cardioprotective effects. This is a matter of controversy, however, as is the question of whether estrogen replacement therapy in women is cardioprotective or not.

Resveratrol Inhibits Inflammation and Enhances Immunity

Inflammation is central in arthritis, Crohn’s disease, and psoriasis, among others, and it can play an important role in the development of cancer and cardiovascular disease. There is much evidence of resveratrol’s anti-inflammatory action in various conditions, partly through its inhibition of the cyclooxygenases and partly through its activity in detoxifying or slowing the production of harmful superoxide radicals. In discussing the fact that resveratrol preferentially inhibits COX-1 over COX-2, and the implications of that fact with respect to platelet aggregation, Baur and Sinclair point out that even a transient exposure to resveratrol could have lasting effects in vivo. They state,

Interestingly, this is the mechanism by which aspirin is thought to exert its cardioprotective effects. … Resveratrol could present an attractive alternative to current treatments for chronic inflammation, as long-term use of aspirin can damage the stomach lining, and selective COX-2 inhibitors developed to avoid this problem have been linked to cardiovascular complications.

In addition to suppressing inflammation, there is evidence suggesting that resveratrol can enhance various aspects of immune-system function.

Resveratrol May Protect Against Tissue Damage in Heart Attack and Stroke

Resveratrol has proved to be effective in protecting tissues from the effects of ischemia, or insufficient blood supply, which deprives our cells of vital oxygen and nutrients. The consequences of ischemia can be devastating in cases of heart attack and stroke (“brain attack”). Resveratrol’s action is attributed in part to its antioxidant properties, which play a role in its effect on nitric oxide (NO), a critical molecule for vasodilation. Resveratrol both stimulates the synthesis of NO and neutralizes free radicals that attack and destroy NO. In the authors’ view,

These data strongly suggest that resveratrol might protect against ischemic damage during myocardial infarction [heart attack]. … Numerous studies have raised the possibility that resveratrol might be useful in protecting against brain damage following cerebral ischemia. … These results suggest that resveratrol is capable of penetrating the blood–brain barrier and exerts strong neuroprotective effects, even at low doses.

Resveratrol Appears to Be Very Safe

Animal studies have found resveratrol to be very safe. One study with adult rats used a daily dose of 20 mg per kg of body weight [which, for a 75-kg (165-lb) human, would be 1500 mg (1.5 g)] and found no effects on body weight, food or water consumption, blood chemistry, or other clinical biochemistry variables; and there was no evidence of tissue pathology. In another study, no adverse effects were seen even at doses of up to 300 mg per kg of body weight (22.5 g for the 75-kg human).

Resveratrol Is Amazingly Versatile

The authors cite reports indicating that resveratrol acts as an analgesic and protects against hearing loss, as well as evidence that it reduces injuries to the kidneys, spinal cord, liver, lungs, intestines, and colon. Obviously, resveratrol’s preventive actions are not limited to the heart and brain—they seem to provide health benefits throughout the entire body. This may reflect resveratrol’s “roots” as a phytoalexin, and it seems consistent with the fact that …


Resveratrol increases both average and maximum lifespan across a vast range of organisms. The largest recorded percentage increases are shown here. [Adapted from Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature Rev Drug Disc 2006 Jun;5(6):493-506.]
Resveratrol Slows the Aging Process

This is the Big One. Resveratrol is the substance that scientists have long dreamed of—a safe, simple, inexpensive substance that, merely by being ingested, can prolong both average and maximum lifespan. This is true in yeasts, roundworms, fruit flies, and a certain fish (see the diagram), and there is good reason to believe it will turn out to be true in mammals as well. (The yeast used in most longevity studies, by the way, is Saccharomyces cerevisiae, or brewer’s yeast, the same species that helps convert grape juice to wine. How’s that for irony?)

As mentioned in the sidebar, resveratrol’s longevity effects are probably the result of its biochemical mimicking of the mechanisms involved in caloric restriction. We already know that CR prolongs lifespan not just in yeasts, roundworms, and fruit flies, but also in rodents (we don’t know about the fish), and there is good reason to believe that it will do so in primates as well. It would probably be effective in us humans, except that the whole idea of CR is about as attractive to us as poking ourselves in the eye with a sharp stick. Hence our quest for a molecular end run around CR.

Antiaging’s Trinity: Caloric Restriction, Resveratrol, and Sirtuins

The result is that three key avenues in modern antiaging research are converging: the biology of caloric restriction, the biochemistry of resveratrol, and the genetics that apparently underlies the link between them. It involves a family of longevity genes coding for proteins called sirtuins (sir·TWO·ins). These genes are found in virtually all organisms, from bacteria and fungi to plants and animals. Their induced overexpression (i.e., their expression beyond what is normally seen) greatly extends the lifespan of yeasts, roundworms, and fruit flies, and biologists believe this will probably hold true in higher organisms as well.

The key sirtuin in most lower organisms is called Sir2; the most important of the seven mammalian sirtuins is called SIRT1. Scientists believe that the sirtuins’ most important function may be to provide stress resistance and to enhance survival in times of environmental adversity, (just as phytoalexins do). The fact that they apparently exist in all organisms, from the ancient and primitive to the modern and complex, is testament to the important evolutionary advantages they seem to confer.*


*The sirtuins act on cellular DNA though a process called gene silencing, which depends critically on NAD (nicotinamide adenine dinucleotide) as a cofactor. NAD is a derivative of nicotinamide (aka niacinamide), which is itself a derivative of niacin, or vitamin B3. For more on the NAD connection, see “Can NAD Help Extend Human Lifespan?” in the July 2002 issue.


Research on sirtuins and on resveratrol is growing explosively. Baur and Sinclair state, “The question of whether enhanced SIRT1 activity and/or resveratrol treatment will increase mammalian lifespan looms large in the aging-research community.” A major step in that direction was taken with the recent discovery that resveratrol greatly extends lifespan in a fish—not quite a mammal, but a vertebrate nonetheless, and therefore far above yeasts, worms, and flies on the evolutionary tree (see the April 2006 article cited above). The study also showed, furthermore, that resveratrol provided strong neuroprotection, resulting in the preservation of the fishes’ motor function and cognitive function as they grew very old.

Resveratrol’s Bioavailability Problem

The fly in the ointment with resveratrol is that its bioavailability is very poor. Resveratrol is metabolized so rapidly and extensively in the duodenum and liver that its concentration in our blood quickly drops to near zero. Nonetheless, the health benefits are tangible, suggesting that resveratrol’s metabolites, whose concentrations can be more than ten times higher, may be primarily responsible. It’s also possible that the benefits accrue mainly through additive or synergistic interactions between resveratrol (or its metabolites) with other chemical compounds found in wine or food.

It is known, for instance, that many of resveratrol’s biological functions are affected by its synergistic interactions with various other substances, including ethanol, vitamin E, and the flavonoid quercetin. This potent antioxidant, which is also present in red wine, helps prevent the metabolism of resveratrol; it may thus increase resveratrol’s bioavailability.

When Is a “Drug” a Supplement?

We will allow Baur and Sinclair to summarize. In their words,1

In mammals, there is growing evidence that resveratrol can prevent or delay the onset of cancer, heart disease, ischemic and chemically induced injuries, diabetes, pathological inflammation, and viral infection. These effects are observed despite extremely low bioavailability and rapid clearance from the circulation. … caloric restriction is probably the only other treatment for which such a broad array of protective effects is observed in mammals. In addition, resveratrol treatment increases mitochondrial biogenesis … and, at least under certain conditions, improves insulin sensitivity, which is consistent with observations in calorie-restricted animals. … Intriguingly, reported effects are overwhelmingly in the direction that would be considered beneficial and in many cases seem to suggest cooperative action.

The authors conclude by asking, “Could resveratrol and similar molecules form the next class of wonder drugs?” We might ask: Is resveratrol already a wonder supplement?

Reference

  1. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature Rev Drug Disc 2006 Jun;5(6):493-506.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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