And wine can of their wits the wise beguile.

–Alexander Pope, translated from Homer¿s Odyssey

n the early years of the 1990’s a particularly influential television newsmagazine familiarized millions of Americans with an epidemiological observation known as the French paradox – i.e., the seemingly puzzling observation that the French population suffers from relatively low levels of coronary heart disease, despite consuming a diet rich in saturated fats from foods such as butter, cream, and full–fat milk.

But despite the many cultural and dietary differences which could account for such a “paradox,” most Americans still seem drawn to the hypothesis which holds that the French population’s consumption of antioxidant–rich red wine is largely responsible.

Of course, most researchers now believe that the French paradox is far too multifaceted to be attributed to a single dietary component, but the idea of red wine as an acceptable, and even healthy, intoxicant is psychologically powerful – it allows us the comfort of knowing that living a healthy lifestyle may not always be a test of our will power and asceticism.

So, with this pro–red–wine bias firmly entrenched in the American consciousness, two decades after the French paradox received its first spate of media attention in America, the mass media has now turned their attention to resveratrol, a chemical found in red wine which some researchers believe may hold the key to red wine’s possible health benefits. As such, resveratrol and related substances are now being studied for their possible role in helping to combat heart disease, diabetes, and even aging itself.

Network news programs and major national newspapers have recently publicized the resveratrol research being conducted at prestigious institutions like Harvard Medical School and MIT; and implicitly, by concocting images of top–level scientists toiling to create a 21st Century fountain of youth, such stories have given many people the impression that resveratrol is a “well–researched” substance.

This, coupled with the fact that resveratrol is found in food has caused many people to simply assume that resveratrol supplementation is safe. As a natural substance found in red wine (and some other foods such as peanuts and berries), the nutritional supplement industry has been quick to embrace resveratrol, and to produce (and aggressively market) resveratrol supplements for human consumption.

But the research conducted on resveratrol hasn’t yet given us any reason to assume that resveratrol supplements are either a safe or effective way to slow the ravages of aging. The public’s willingness to accept the promise of resveratrol on the flimsiest of scientific evidence, while ignoring the possible harm such a substance could cause when consumed long–term in high doses, is yet another example of commercial interests preying on emotions (the fear of death and disease) while at the same time exploiting the public’s lack of scientific acumen.

The breadth of current resveratrol research actually seems to indicate that the resveratrol craze is largely based upon numerous unproven assumptions and logical fallacies. With an increasing of people consuming the substance as a supplement, a rational perspective on resveratrol’s role in aging and disease is desperately needed.

Calorie Restriction And Aging

One of the foremost claims for resveratrol is that it may mimic the longevity–enhancing effects of caloric restriction (CR) without us having to endure the austere practice of dramatically reducing our food intake. But even if resveratrol does mimic some effects of caloric restriction, there still exists significant debate as to whether caloric restriction can be expected to extend the lifespan of humans in the first place.

In lower animals, to be sure, consuming fewer calories in the context of an otherwise nutritionally adequate diet has often been shown to extend lifespan:

Study Link – Caloric restriction and aging: studies in mice and monkeys.

Quote from the above study:

It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents. The mechanism underlying this phenomenon is still unknown… In mice and monkeys, a chronic 30% reduction in energy intake yields a decrease in adiposity of approximately 70%.

And quite logically, as the above study indicates, caloric restriction will prevent weight gain and obesity. This effect alone will result in remarkably positive changes in certain markers of heart disease and diabetes – as has been documented in humans following long–term caloric restriction:

Study Link – Long–term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.

Quote from the above study:

The CR group were leaner than the comparison group (body mass index, 19.6 +/– 1.9 vs. 25.9 +/– 3.2 kg/m(2); percent body fat, 8.7 +/– 7% vs. 24 +/– 8%). Serum total cholesterol (Tchol), low–density lipoprotein cholesterol, ratio of Tchol to high–density lipoprotein cholesterol (HDL–C), triglycerides, fasting glucose, fasting insulin, CRP, PDFG–AB, and systolic and diastolic BP were all markedly lower, whereas HDL–C was higher, in the CR than in the American diet group.

But while there’s no doubt that heart disease and diabetes are major health threats directly associated with consuming a chronic excess of calories, long–term caloric restriction hasn’t yet proven itself as a way to increase the human lifespan.

Some researchers, in fact, believe that long–term caloric restriction is destined to fail as a life–extending intervention in humans. Unlike short–lived rodents, for example, humans are unlikely to respond to the “stress” of caloric restriction with the same sort of profound biological changes which could prolong lifespan:

Study Link – Caloric restriction increases longevity substantially only when the reaction norm is steep.

Quote from the above study:

Our previous work crudely estimates that the dietary reaction norms of rodents and humans have diverged substantially, with a very flat dietary reaction norm for human longevity. These general principles and our specific results suggest that the benefits from human caloric restriction would be minor.

Study Link – Why dietary restriction substantially increases longevity in animal models but won't in humans.

Quote from the above study:

Applying this general model to the special case of human longevity and diet indicates that the benefits of caloric restriction in humans would be quantitatively small.

There’s even some evidence to support the belief that long–term caloric restriction may be associated with unique risks to humans. Although caloric restriction does reduce biological markers associated with obesity–related diseases, some researchers have presented evidence that long–term caloric restriction may be associated with the development of neurological disorders such as amyotrophic lateral sclerosis (i.e., ALS or Lou Gehrig’s disease):

Study Link – Energy intake and amyotrophic lateral sclerosis.

Quote from the above study:

One reason that motor neurons might be selectively vulnerable to low–energy diets is that they are unable to engage neuroprotective responses to energetic stress response involving the protein chaperones, such as, heat–shock protein–70.

The brain’s neurons consume an extraordinary amount of energy and there’s reason to suspect that caloric restriction may significantly impair energy production in these cells. The stress of “starvation” in neurons is likely to manifest in inappropriate neuronal “firing” and the phenomenon known as excitotoxicity – where the cells exhibit a hypersensitive reaction to stressful stimuli, and are activated to the point of exhaustion and cell death.

Degenerative neurological disorders are characterized by excitotoxicity, and in 2004, gerontologist and leading advocate and practitioner of caloric restriction for life extension, Dr. Roy Walford, died from complications related to ALS at the age of 79. Of course, it’s impossible to draw valid conclusions from the fate of a single individual, but the entirety of current evidence indicates that the long–term effects of calorie restriction in humans remain unknown. It certainly seems possible that severe caloric restriction may simply allow us to trade our modern diseases of abundance for diseases of paucity.

So even if resveratrol is able to extend the lifespan of some animals, and even if resveratrol is able to activate some of the same genes as caloric restriction does, this doesn’t give us the assurance that it will extend lifespan or prevent aging in humans.

In fact, some research has shown that the “anti–aging genes” which are so much a focus of resveratrol research may not be quite so “anti–aging” in humans after all.

Resveratrol And The Sirtuins

The biochemical foundation of resveratrol research involves the compound’s effects on genes called sirtuins. Sirtuins genes are often activated in response to stressors, and can alter the expression of certain cellular proteins. In particular, sirtuins remove acetyl groups from proteins in the presence of NAD (nicotinamide adenine dinucleotide) – thus, they are known as NAD–dependent deacetylases.

In yeast cells, both resveratrol and caloric restriction have been found to activate the sirtuin called silent information regulator 2 (Sir2). Activating this gene can alter the way yeasts metabolize fuels – it can shift the yeast’s metabolism towards cellular respiration, and away from fermentation:

Study Link – Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration.

Quote from the above study:

Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process.

And like caloric restriction, resveratrol’s similar effect on Sir2 has been deemed responsible for resveratrol’s longevity–enhancing effects in yeast:

Study Link – Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.

Quote from the above study:

In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%.

The Sir2 gene, which is found in lower animals such as yeast, worms, and flies, has a counterpart in mammals (including humans) called SirT1. The hope of resveratrol researchers is that activating SirT1 will extend lifespan in larger, more complex animals as it seems to in simpler ones.

But, not only does the low bioavailability of resveratrol raise questions as to whether resveratrol can influence human sirtuins, but the sheer number of differentiated cells in higher organisms makes it likely that activating SirT1 will have some unpredictable and potentially negative effects.

For example, some studies have shown that energy–consuming neurons are actually protected by inhibiting SirT1:

Study Link – SirT1 Inhibition Reduces IGF–I/IRS–2/Ras/ERK1/2 Signaling and Protects Neurons.

Quote from the above study:

In agreement with our results in S. cerevisiae, here we found that inhibition of SirT1 reduces IGF–I signaling and increases the resistance of mammalian cells to oxidative stress… These results are consistent with the existence of a pro–oxidative stress role for mammalian SirT1 and Ras similar to that described for Sir2 and Ras in S. cerevisiae but confirm that sirtuins can play both positive and negative roles.

In the right environment, a little bit of stress can make our body grow stronger and more resilient (e.g., exercise, ultraviolet light), but if the body doesn’t have the energetic reserves available to deal with these stresses efficiently, these same cellular assaults can easily become harmful. This well–known biological phenomenon makes self–medication with resveratrol a potentially risky proposition. Where the consumption of berries and red wine may supply us with tiny amounts of resveratrol, commercially–available nutritional supplements of the compound allow us to consume doses thousands of times higher than what would be found in any diet – and, importantly, it’s simply impossible to tell what concentration of resveratrol different cells are exposed to when supplemental doses are taken. Considering that resveratrol is likely to exert benefits only if our body can sufficiently adapt to the subtle harm it causes, consuming resveratrol in supplemental form starts to seem like a gamble with little upside potential.

As further evidence, studies have shown that while very low doses of resveratrol may be protective to neurons, high doses have worsened excitotoxic neuronal death:

Study Link – Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons.

Quote from the above study:

At a low concentration (25 mM) resveratrol protected neurons from being killed by glutamate and NMDA, whereas high concentrations of resveratrol had either no effect or exacerbated excitotoxic neuronal death. In contrast to the preservation of cellular NAD + levels in nicotinamide–treated neurons, resveratrol did not prevent glutamate/NMDA–induced NAD + depletion.

Often, substances which produce exitotoxicity can seem to have an “energizing” effect. Long before the harmful nature of these substances is realized many people assume that the energy they feel must be a sign that the substance is somehow needed or beneficial. But, as we have seen, brain cells often respond to stressful stimuli by increasing energy production temporarily as a defensive measure. As such, we can reason that the long–term effects of consuming a substance like resveratrol cannot be assessed subjectively in the short term.

Extreme examples of stimulants which damage neurons through exitotoxicity include substances such as methamphetamine and cocaine. Yet even hormones such as estrogen and food additives such as aspartame and MSG may exhibit energizing effects as a result of their excitotoxicity.

Empirically, some people who have experimented with resveratrol supplementation have noted feeling “increased energy” as a result. Of course, it’s entirely possible that such a subjective assessment could be due entirely to the placebo effect, but if resveratrol does indeed lead to an increased feeling of energy, it’s worth wondering what its mechanism of action is.

Similar to the studies referenced previously, researchers have found low doses of resveratrol to be protective against glutamate toxicity (the hallmark of excitotoxicity) in brain cells, called astrocytes; whereas higher doses, again, were harmful. Because these studies give no indication of the effects of long–term resveratrol usage in humans, the researchers warn that elevated levels of resveratrol could potentially aggravate neurodegenerative disorders:

Study Link – Resveratrol Increases Glutamate Uptake, Glutathione Content, and S100B Secretion in Cortical Astrocyte Cultures.

Quote from the above study:

Our findings reinforce the protective role of this compound in some brain disorders, particularly those involving glutamate toxicity. However, the underlying mechanisms of these changes are not clear at the moment and it is necessary caution with its administration because elevated levels of this compound could contribute to aggravate these conditions.

Similarly, other studies have shown that resveratrol’s supposed benefits may be a function of its ability to alter energy production (oxygen consumption) in a manner similar to ischemic preconditioning:

Study Link – Resveratrol mimics ischemic preconditioning in the brain.

Quote from the above study:

[W]e report that resveratrol pretreatment mimics IPC [ischemic preconditioning] via the SIRT1 pathway.

Ischemic preconditioning is the phenomenon whereby the blood and oxygen supply to a tissue is halted temporarily. Under ideal conditions, the adaptive response of the tissue (i.e., the heart or brain) to this lack of oxygen is for the cells to “super–compensate,” and become more resilient to subsequent, and more serious, shortages of blood and oxygen as occur during a heart attack or stroke. But obviously, impairing cellular energy production and oxygen consumption, in order to elicit a possible beneficial response is a biological tightrope most people don’t realize they’re walking when they consume resveratrol supplements.

So, we know that both caloric restriction and resveratrol are “stressful” to the body, and as such, they both may activate the stress–induced sirtuin genes. This effect could be beneficial if the cells are able to adapt positively to the amount of stress inflicted upon them. But the above studies indicate that both caloric restriction and high concentrations of resveratrol can potentially damage neurons by inhibiting their high–energy metabolism. Caloric restriction has been linked with neurological disorders such as ALS, and there’s reason to believe that resveratrol may, at the very least, damage neurons similarly at doses which exacerbate excitotoxicity. Short–term studies may make these actions of resveratrol seem therapeutic (as in ischemic preconditioning) but the effects of long–term use in humans haven’t even begun to be reported. Those consuming resveratrol are likely to have no idea what concentrations are present in blood or various bodily tissues, and whether or not these concentrations will prove harmful over time. As we’ve repeatedly mentioned in our series on natural toxins, it’s always the dose which makes the poison.

Many well–documented health–promoting activities are now thought to manifest benefits through similar “hormetic” mechanisms. Generally speaking, hormesis is the phenomenon whereby small biological stresses gently nudge our bodies’ protective mechanisms into action – while higher amounts of the same stresses would prove decidedly harmful. Exercise, exposure to ultraviolet light, alcohol consumption, and eating various “plant chemicals” are all thought to exert their benefits hormetically only insofar as our body is able to build its defenses against them.

The take–home lesson is that we simply don’t know enough about the body’s adaptive responses to be able to predict whether a certain hormetic chemical, at any particular dose, will have health benefits or extend lifespan when consumed in the long–term. To complicate matters further, the cumulative effect of several hormetic interventions (many of which are often practiced simultaneously by health–conscious individuals) makes meaningful extrapolation from the laboratory data almost impossible. In other words, if it’s the subtly harmful nature of these stressors which produces health benefits, can adding many of these stressors together simultaneously be expected to produce benefits as well – or will the cumulative burden ultimately do harm? In an era where high–potency nutritional supplements are becoming increasingly popular, the answer to this question is more important than ever.

(To Be Continued In The Next Integrated Supplements Newsletter)