By Benjamin V. Treadwell, Ph.D.

What is resveratrol and what does it mean to our health? A polyphenolic compound, resveratrol seems to help plants and animals survive under stress. Although not yet considered a vitamin, resveratrol may also be an effective supplement against human neuro-degenerative and age-associated diseases. To better understand resveratrol's potential benefits, let's start with the plants that synthesize it. 

Very Important Plants
Plants require sunlight to generate a biologically useable form of energy that is, in turn, used by the germinating plant seed to generate proteins, carbohydrates and lipids. These building blocks, assembled in an orderly fashion, produce the magnificent variety of vegetation present on earth.

Animals, including man, rely on plants not only as a food source for energy, but also for additional nutrients required for survival and maximum health. These nutrients include essential amino acids, essential fatty acids, and virtually all our vitamins (except, perhaps, vitamin B-12, which can be obtained from the bacteria in our gut or the meat we eat). The animal kingdom is spared from using energy to synthesize these nutrients at the expense of being dependent on plants.

Plants Under Stress
Under conditions that stress its health, i.e., a drought or an infection by a parasitic organism such as a fungus, a plant synthesizes the nutrient resveratrol in increased amounts. Resveratrol appears to improve the plant's chances of survival, although precisely how is not yet known.

The theory is that resveratrol triggers a biological response in the cells of the plant, essentially shifting it into "safe mode." The plant becomes more efficient with respect to life-essential biochemical pathways, conserving energy by shifting it away from non-essential synthetic pathways. This mechanism, in theory, helps the plant survive until better times. 

Plant-Animal Communication
Who would have guessed that, by eating a stressed-out plant, an animal would be notified that members of this food source would soon be scarce? The messenger? That same, stress-produced plant chemical, resveratrol. In a fascinating extension of this story, resveratrol appears to affect  animal cells, in culture and in vivo (the live animal), the same way it does plant cells.

The resveratrol molecule seems to cue the animal ingesting it that it, too, must go into "safe mode" in order to survive tough times. The resveratrol has a similar effect on the animal's biological systems as a stress-producing mechanism known as caloric restriction (CR) in which food intake is at a bare minimum for survival. Interestingly, with both resveratrol and CR, the animal not only survives, but many of the markers of overall health also improve. (See table, "How Resveratrol May Help.")

AMPK Activation
Exactly what is resveratrol's effect on the biological systems? The chemical/nutrient, or one of its metabolites, activates a cellular enzyme known as AMPK (adenosine monophosphate kinase) that immediately goes to work on altering key regulator elements of metabolism.

For example, AMPK inhibits the rate-limiting step in the synthesis of fat. Therefore, fat synthesis in the body is shut down and, on the flip side, existing cellular fat is converted into energy in the mitochondria. Both of these actions make sense for an animal that is under physiological stress. In the stress-induced, "safe mode," the animal cannot afford to synthesize molecules such as fat and protein as it is deficient in energy and synthetic processes require significant amounts.

On the other hand, the activity of those pathways involved in the production of energy is accelerated by AMPK. This includes the production of new and more efficient mitochondria as well as an increase in the sensitivity of the receptor that recognizes glucose to promote rapid cellular uptake from the blood and its conversion to energy instead of fat. 

Resveratrol and Human Health
Can resveratrol improve our health by eliciting the same diverse, positive biological responses as demonstrated in animal and cell culture studies? The potential is exciting. In fact, numerous studies are currently examining the effects on animals and humans with respect to neurodegenerative diseases, such as Alzheimer's and Parkinson’s, as well as diabetes, cancer, atherosclerosis, and a variety of age-associated diseases.

Sources and Safety
Research has already demonstrated an age-related decrease in AMPK activation. So the older we get the more we may need a compound like resveratrol to help restore this activity. Supplements are available. Pomegranates and pomegranate juice are very high in resveratrol as well. Pomegranate nutrients can also be obtained in concentrated form as an extract. Other naturally occurring sources for high levels of resveratrol include grapes and nuts.

The amount of resveratrol required for a biological effect in humans has yet to be determined; however, it can be roughly extrapolated from animal studies. To date, there are no reported significant side effects in humans from even relatively large doses. Whether the nutrient simply functions as an antioxidant, is able to increase AMPK activation or actually protects against neurodegenerative and age-associated diseases, it seems resveratrol can be a valuable addition to our diet.

At the Washington University School of Medicine, Biplab Dasgupta, Department of Pathology, and Jeffrey Milbrandt, Departments of Pathology and Neurology and the Hope Center for Neurological Disorders, recently investigated the biochemical mechanisms involved when the polyphenol resveratrol mimics many of the positive cellular health effects previously demonstrated in animal and cell culture studies by caloric restriction (CR). Their methodology and conclusions appear in the April 16, 2007, issue of PNAS (Proceedings of the National Academy of Sciences of the United States of America) under the title, "Resveratrol stimulates AMP kinase activity in neurons." 

One key metabolic regulator believed to be involved in promoting CR-induced cellular health is an enzyme activated by depletion in cellular energy levels (as a consequence of decreased food intake) and referred to as AMPK. Similar cellular health benefits led Dasgupta and Milbrandt to hypothesize that neuronal activation of AMPK could also be an important component of resveratrol activity.

By adding resveratrol to cultures of neurons, the authors found that the nutrient did indeed stimulate AMPK. (Resveratrol also stimulated AMPK-dependent mitochondrial biogenesis.) Dasgupta and Milbrandt speculate that previous work demonstrating nervous system protection by resveratrol is supported by their findings regarding the nutrient's effect on AMPK.

To read the abstract, click here.
"Resveratrol stimulates AMP kinase activity in neurons."
PNAS | April 24, 2007 | vol. 104 |
no. 17 | 7217-7222.

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

QUESTION:   What is your opinion about DHEA? I have been taking 25mg five days a week because I have read that levels decrease with age. I am a 54-year-old woman on low dose estradiol. — M.

ANSWER: I don't recommend DHEA unless prescribed by a qualified health professional. However, there are indications that this steroid hormone precursor does decrease with age. There is also little evidence that taking DHEA supplements produces significant side effects. But more research is needed to determine if taking this steroid has only positive effects without any potential danger to our health.

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Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor and member of Juvenon's Scientific Advisory Board.