By Benjamin V. Treadwell, Ph.D.

A biological/biochemical mechanism, seemingly evolved to protect plant and animal life during hard times, may help us better understand the aging process and, perhaps, even slow it down in man.

The Xenohormesis Hypothesis
Do organisms respond to stress-signaling molecules produced by other species in their environment? This recent hypothesis may explain the connection between certain chemical compounds, polyphenols, especially common in plants during stressful environmental conditions (fungus, lack of sufficient water, etc.) and the effect they have on animals that eat the stressed plants.
The polyphenolic compounds put the plant into a hibernation-like biological state until conditions improve. When the low food-supply message is relayed to the animals, their biochemistry changes to a more life-sustaining state as well.

Less Food, Similar Effect
A similar life-sustaining and extending effect can be achieved with mammals using caloric restriction (CR). For instance, a rat's life span can be increased 30-50% with a 40% decrease in normal caloric intake.
More detailed analysis of the mechanism involved in this peculiar effect has shown that numerous biochemical pathways are reset, so to speak, to a more efficient and healthier state. For example, plasma insulin levels drop, insulin sensitivity increases, fat synthesis decreases, and virtually all health parameters measured improve. The caloric restricted animal has a lower incidence of cancer, heart disease and diabetes, and is mentally sharper as well as much more energetic.
The CR-stimulated increase in energy is the consequence of an increased production of a transcriptional factor, PGC-1 alpha, that turns on genes involved in the synthesis of the energy producing cellular organelles, the mitochondria. So how does that relate to the polyphenolic compounds present in stressed plants?

Plant Compound with CR-Like Effect
A number of years ago a group at MIT (Cambridge, MA) reported a gene present in the lowly yeast that was somehow involved in determining how long the yeast lived. The gene, SIR2, was later demonstrated to code for an enzyme, deacetylase, that acted on numerous biological molecules with life-extending consequences.
Many of these effects on cellular metabolism were later observed in other cells, including those of the fruit fly, and a nematode, C. elegans. It was also demonstrated that CR stimulated the synthesis of this enzyme in these lowly organisms.
One of the inquisitive post-doctoral students, David Sinclair, wondered whether it was possible to activate this enzyme by some other means than CR. Later, he set up his own laboratory and screened numerous compounds, discovering a chemical, commonly found in some plants and especially rich in fungus-infected grape skins, known as resveratrol.
With the introduction of resveratrol, the enzyme was activated in the yeast, the fruit fly and the nematode, and all three lived longer. What's more, if the organisms were CR-treated and then fed resveratrol, there was no additional effect on longevity. In other words, the biological mechanism by which CR and resveratrol extended life was similar, most likely via the activation of the SIR2 enzyme.

From Nematode to Mouse
So what? Extending the life of a yeast cell or a nematode is a far cry from doing the same to a mammal or man.
David Sinclair and colleagues apparently realized this. A very recent paper, published in Nature (see Research Update, this issue), reveals that resveratrol has similar health-promoting effects in a mammal, the mouse.
The excitement surrounding this work is that it demonstrates that mice fed a diet high in calories are, as expected, overweight and develop all the problems associated with obesity (diabetes, heart disease, liver disease, and decline in overall health parameters). However, mice on the same high-fat diet but also fed the resveratrol compound are, in virtually all respects, as healthy as the control animals fed a normal calorie diet. Furthermore, the resveratrol-treated, high-fat-diet mice are much more physically active than their resveratrol-less counterparts.
With analysis of liver and muscle cells, the investigators also discovered a significant increase in the number of mitochondria for the resveratrol-treated group, versus the high-calorie diet without resveratrol group. Since the mitochondria are the powerhouses of the cell, the increased energy is clearly the result of resveratrol-activated mitochondrial synthesis.
These experiments have not yet shown whether the mice on the resveratrol-high fat diet have extended life-spans. This result will not be known for a year or two as the mice have not reached their normal life-spans.
One caveat to this work is the dose of resveratrol used in the experiment. Each animal received a dose equivalent to an average size human ingesting 1.6 grams per day. The amount of resveratrol in an average bottle of red wine is about 1/70th of this dose. Do you want to drink 70 bottles of wine per day?
Actually, it turns out that resveratrol appears to be very non-toxic, as judged by animal studies even at this high dose. Furthermore, chemical compounds will most likely be synthesized that are much more active in eliciting the same or even better results at much lower doses.

From Mouse to Man
Whether resveratrol will produce similar results in humans remains to be seen, but the best guess is that it will, at minimum, have health benefits. How much we need is another question.
Overall, these studies should help us understand why certain diseases, such as diabetes, develop and why so many diseases are associated with aging. The results also show promise for the development of therapeutics to help reset the aberrant or dysfunctional biochemical pathways to prevent or attenuate the diseased state. The icing on the cake, of course, would be if this information helped extend our life span.

As mentioned in Dr. Treadwell's article, David Sinclair, who discovered resveratrol, along with several of his colleagues, recently published "Resveratrol improves health and survival in mice on a high-calorie diet."

On the basis of the unprecedented ability of resveratrol to improve health and extend lifespan in simple organisms, a study, detailed in the article, contrasted a group of mice on a high calorie diet supplemented by Resveratrol (HCR), with groups on an unsupplemented high calorie/fat diet (HC) and on a standard diet (SD), as well as with the results of previous research.

Taken together, the findings show that resveratrol shifts the physiology of mice consuming excess calories towards that of mice on a standard diet, modulates known longevity pathways, and improves health, as indicated by a variety of measures including survival, motor function, insulin sensitivity, organ pathology, PGC-1a activity, and mitochondrial number. Notably, all these changes occurred without a significant reduction in body weight.

This study also shows that an orally available small molecule at doses achievable in humans can safely reduce many of the negative consequences of excess caloric intake, with an overall improvement in health and survival.

To read the abstract, click here.
"Resveratrol improves health and survival of mice on a high-calorie diet."
Nature. 2006 Nov 16;444(7117):337-42

QUESTION: Any side effects associated with Juvenon™ Cellular Health Supplements and what side effects would you expect taking two Juvenon and two 300 mg capsules of CoQ 10 daily? I have noticed more energy throughout the day, but also feel a nervous twitchy antsy sensation.
ss, via email

ANSWER: I have two suggestions. First, for best results with Juvenon, take the tablets early in the day, at least 6-8 hours before bedtime. Second, unless a specialist has suggested you take 600 mg of CoQ10/day I would lower that dose to between 100 and 150mg once a day, and take it with your evening meal. The nervous sensation could be an effect from the large dose of CoQ10 and/or taking Juvenon too close to bedtime. The Juvenon supplement has very few side effects, and those are listed on the Juvenon web site.

Send your questions to AskBen@juvenon.com.
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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.