New Antiaging Strategy: Resveratrol

Promoting Survival with Resveratrol
By mimicking caloric restriction, it induces one of CR’s
top antiaging benefits: mitochondrial biogenesis
By Will Block

When you come to a fork in the road, take it.
— Yogi Berra

hoice is usually a good thing, unless, as is so often true during political campaigns, it’s a choice between the lesser of two evils. In that case, the better choice will still be, well, evil. (Why can’t they both lose?) But what if there’s a choice between the greater of two goods? That kind of choice we can embrace and celebrate.

When it comes to antiaging, we have a choice between two good (and complementary) strategies, according to Leonard Guarente, a renowned biologist at MIT.1 Best of all, we don’t even have to choose between them—we can “take the fork” by pursuing both options at the same time. It’s not clear, in any case, whether one option is “better” than the other.

Everyone who’s interested in life extension is surely familiar with one of these options, but some may not be familiar with the other, because it represents a relatively new concept, born of pioneering work by Guarente and his disciples at various universities and research institutions around the world.

Even from here, I can hear you shouting, “Well, get on with it—what are they?” (Sorry.)

Retard Deterioration or Promote Survival? (Both!)

The time-honored strategy that we all know (but don’t love, because it’s burdensome) is retarding deterioration, i.e., slowing the gradual decline of bodily systems and functions that aging inflicts on everyone. Here the primary tactics are to eat sensibly, exercise regularly, avoid substance abuse, avoid undue stress, and take supplements that have been shown in medical research to be helpful in maintaining or improving health.

The other strategy—the new and still unfamiliar one—is promoting survival through interventions in the basic machinery of life: our genes and the proteins they code for. Although this strategy sounds technologically advanced and difficult, it may, paradoxically, be easier to implement than the first, as will become evident if you read on.

Resveratrol Mimics Caloric Restriction and Extends Lifespan

There is a bridge between the two strategies in the form of resveratrol, the fabled red-wine compound that protects against biochemical stressors, helps prevent diseases of aging, and extends maximum lifespan in a variety of species. Resveratrol is the rock star of antiaging medicine. (See “Resveratrol—Star Molecule Against Disease and Aging” and “Revolutionary Antiaging Discovery with Resveratrol” in the August 2006 and January 2007 issues, respectively.)

Probably the most amazing thing about resveratrol is that it appears to provide the health benefits of caloric restriction (CR) without the need for actual caloric restriction, because its biochemical effects closely mimic those that are produced by long-term CR regimens in laboratory animals.* CR has long been the only known method for extending maximum lifespan, but it’s fair to say that there are now two known methods, the second one being resveratrol. We can say this not just because resveratrol mimics CR and ought, therefore, to extend lifespan, but also because numerous studies have shown that it does do that.


*Caloric restriction, in case you’re hazy on the concept, is a dietary regimen that drastically reduces daily caloric intake. It’s defined as a diet in which caloric intake is reduced by 30–40% from that required to maintain normal weight, while providing all the nutrients that are necessary for good health. It’s extraordinarily beneficial for health and longevity, and it’s exceedingly unpopular with human beings (the lab animals probably hate it too).


It’s All in Our Longevity Genes, the Sirtuins

Resveratrol’s longevity benefit has been observed in a wide variety of organisms ranging from lowly yeasts (fungi) to roundworms to fruit flies to fish to mice. This effect is almost certain to be observed in primates as well (the experiments will take many years) and, therefore, in human beings, because we are genetically almost identical to the great apes (chimpanzees, gorillas, and orangutans).

The belief that resveratrol could extend maximum human lifespan rests not only on an already impressive foundation of experimental evidence obtained in a variety of other species but also on theoretical grounds having to do mainly with a family of enzymes called sirtuins (sir·TWO·ins), which are encoded by genes of the type called SIR2 in lower organisms. These enzymes play a fundamental role in the biochemical effects of caloric restriction.

The sirtuin genes are found, with some variations in form, in virtually all living organisms (bacteria, fungi, plants, and animals), and they seem to serve the same functions in all of them, namely, to reduce cellular stress, which can be caused by many different factors, and to promote survival (sound familiar?). In other words, the sirtuin genes are longevity genes, whose robust expression in an organism increases the organism’s chances of resisting disease and living far beyond the normal limits imposed by the ravages of aging. Clearly, these genes are of fundamental importance in biology, having been maintained through 3½ billion years of organismic evolution, from the most primitive creatures to human beings.

What’s exciting about resveratrol is that it upregulates (stimulates the expression of) the most important of these longevity genes—the one that codes for SIRT1, which is one of a seven-member family of mammalian sirtuins (SIRT1, SIRT2, . . . SIRT7). Resveratrol also activates (enhances the activity of) SIRT1, thereby increasing its stress-reducing and antiaging effects on our system. SIRT1 is the most important sirtuin because it plays a key role in the biochemical mechanism by which caloric restriction manifests its physiological effects. (SIRT3, SIRT4, and perhaps SIRT5 also play important roles in CR; the remaining three sirtuins have physiological functions that are not yet as well understood.)

Two Key Findings in Caloric Restriction Study

In an article in last month’s issue (“Resveratrol Mimics Caloric Restriction,” April 2008), we discussed the results of a study by scientists at the Pennington Biomedical Research Center in Baton Rouge, Louisiana, who were participating in a research program called the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE).2 Using 48 healthy but sedentary overweight men and women, they found that 6 months of caloric restriction (by 25%), with or without exercise, produced dramatic weight loss, as expected. This was accompanied by significant (and desirable) reductions in fasting insulin levels and core body temperature, both of which are biomarkers of aging.

Most importantly, they found: (1) an improvement in energy efficiency, as evidenced by a lower energy expenditure than would be expected on the basis of weight loss alone; and (2) a reduction in oxidative stress, as evidenced by a reduction in cellular DNA damage, which is caused primarily by harmful free radicals. Both of these changes imply better health and longer life, and both appear to be brought about by mitochondrial biogenesis.

What Is Mitochondrial Biogenesis?

Additional results from the CALERIE study were published recently as a separate paper, this one dealing with the effects of caloric restriction on mitochondrial biogenesis in healthy humans.3 Mitochondria are the tiny organelles within our cells where the process of cellular respiration, or energy metabolism, takes place. In other words, they are the chemical “power plants” that burn our nutritional fuels (glucose and fatty acids) to produce chemical energy.

Mitochondria are also, therefore, the body’s chief source of reactive oxygen species (ROS), including free radicals, which are byproducts of energy metabolism. The mitochondria themselves are the chief victims of ROS, which attack all of the cells’ biological macromolecules—nucleic acids (DNA and RNA), proteins, carbohydrates, and lipids. Oxidative stress caused by ROS is believed to underlie many degenerative diseases and the aging process itself.

Mitochondrial biogenesis means either the creation of new mitochondria or the enlargement of existing mitochondria, which increases their energy-generating capacity. Either way, it’s a good thing, as the following analogy will illustrate.

A Paradox that Leads to Reduced Oxidative Stress

A common adaptation to very high altitude is an increased red blood cell count, which tends to compensate for the reduced amount of available oxygen. Since the body’s demand for oxygen is greater than the supply of oxygen in the thin air of high altitudes, and the supply cannot be increased, the blood’s oxygen-carrying capacity has to increase somehow. This can be accomplished with a larger number of red blood cells.

With caloric restriction, there is similarly an increase in the number of mitochondria in our cells. That’s good—but it’s paradoxical, because here the demand for oxygen is less than the supply, owing to the cells’ reduced energy expenditure. Instead of shrinking in number or size, however, the mitochondria grow in number or size—biogenesis. This reduces the average workload of the mitochondria, improves their energy efficiency, and reduces their production of ROS, thus causing less oxidative stress on the system.

All of which, as noted above, implies better health and longer life—and the results in rodents prove it. But what about us humans?

The CR Protocol

In the new paper, the Louisiana researchers sought to evaluate the effects of the dietary regimen (25% CR for 6 months), with or without exercise, on mitochondrial biogenesis in their healthy but sedentary overweight subjects.3 They analyzed the data from 36 of the original 48 men (aged 25–50) and women (aged 25–45), leaving one of the four original groups out of the new analysis. The 36 subjects had been randomized into 3 groups of 12 each:

  1. Caloric restriction (CR) – A 25% reduction in calories (from the individual’s measured baseline energy requirement), with no other change in lifestyle.

  2. Caloric restriction with exercise (CREX) – A 12.5% reduction in calories, plus a 12.5% increase in energy expenditure through monitored, structured exercise (walking, running, or cycling), i.e., the equivalent of a 25% calorie reduction.

  3. Controls – These individuals could eat at will and were required only to maintain their normal weight.

Connecting the Dots via a Tongue-Twister

It would be nice if there were a blood test for mitochondrial biogenesis, but there isn’t—you have to examine tissue samples. In this study, the researchers took tiny samples from the subjects’ thighs (the quadriceps muscle). The results showed that 6 months of caloric restriction, with or without exercise, significantly increased the number of mitochondria in the muscle cells, signifying an increase in their metabolic efficiency.

(Mitochondrial biogenesis is known from other studies to occur as a result of aerobic exercise, which improves the metabolic efficiency as well as the strength of muscles. For the resveratrol connection to this subject, see “Resveratrol Boosts Strength and Endurance in Mice” in the February 2007 issue.)

Analysis of numerous genes involved in energy metabolism and oxidative stress showed large increases in the expression of the genes that code for SIRT1 and for a protein with the formidable name peroxisome proliferator-activated receptor gamma coactivator-1α (even its formal abbreviation, PPARGC-1α, is so long that it has its own abbreviation, PGC-1α). This tongue-twister is known to be a crucial cofactor in promoting mitochondrial biogenesis . . . and SIRT1 is known to activate PGC-1α . . . and resveratrol is known to activate SIRT1 . . . the dots are connected.

Nitric Oxide Also Promotes Mitochondrial Biogenesis

Also strongly correlated with both SIRT1 and PGC-1α was expression of the gene for endothelial nitric oxide synthase (eNOS), an enzyme that catalyzes the synthesis of nitric oxide (NO) from the amino acid arginine. NO is a potent signaling molecule that plays a central role in the control of blood pressure, among other biological functions. Experiments done in this study showed that it also promotes mitochondrial biogenesis in human muscle, apparently via a mechanism involving SIRT1 and PGC-1α. (For more on NO’s role in caloric restriction and mitochondrial biogenesis, see “Can Nitric Oxide Increase Lifespan?” in the January 2006 issue.)

It’s worth noting that NO (which is itself a free radical) is a double-edged sword, because it also promotes the production of reactive oxygen species in muscles. As with all other substances in the human body, its rate of production or utilization must be kept neither too low nor too high, but just right, in order to achieve optimal health.

The Two Key Findings Explained

The increase in mitochondrial mass observed in this study helped explain the two key observations from the first study, mentioned above: the improvement in energy efficiency and the reduction in oxidative stress. As mentioned above, additional mitochondrial energy-generating capacity reduces the average workload of the mitochondria and makes their function more efficient, while reducing ROS production and its consequent DNA damage—a win-win proposition. This comports with the observation in animal studies that reduced mitochondrial capacity and degraded mitochondrial function—both of which are characteristic of aging—are associated with increased ROS production, increased DNA damage, increased risk for degenerative disease, and reduced longevity.

Leonard Guarente on the
Benefits of Resveratrol

Want to know how important mitochondria are? One clue is that your body’s cells contain about 10 quadrillion (10 million billion) of them in total, and they constitute about 10% of your body weight. They are the very source of your life and the chemical energy it needs to continue.

Leonard Guarente
In a recently published paper on the therapeutic role of sirtuins in diseases of aging, Leonard Guarente and two colleagues discussed the importance of SIRT1, mitochondrial biogenesis, and the role of resveratrol in promoting the latter by activating the former.1 Let’s hear about it in their own words (literature citations omitted):
Why is mitochondrial biogenesis beneficial? Mitochondrial activity in metabolically active tissues, such as muscle, will increase metabolic rate, drive glucose metabolism, and thereby improve insulin sensitivity. Thus SIRT1 activation is a promising strategy for treating type 2 diabetes, obesity, and metabolic syndrome. In addition, the number of functional mitochondria is known to decrease with aging, so an increase in mitochondrial biogenesis could exert an antiaging effect by buffering this decline.

A second, more subtle, aspect of mitochondrial biogenesis might also have a role in antiaging. A leading hypothesis of a cause of aging is the oxidation of macromolecules in cells owing to the generation of ROS by mitochondria. . . . An increase in mitochondrial biogenesis will increase mitochondrial surface area, thereby reducing . . . the production of ROS. By this reckoning, mitochondrial biogenesis could be beneficial even if it did not result in a measurable increase in metabolic rate (because of some other limiting component), and it has been found that humans on CR induce mitochondrial biogenesis without an observed increase in metabolic rate.

More tangible evidence that SIRT1 activation might have benefit via mitochondrial function comes from studies of the polyphenol resveratrol in mice. Resveratrol and other polyphenolic compounds are made by plants in response to stress. . . . Two recent studies show that deleterious effects of high-fat, high-caloric diets in mice were mitigated by resveratrol feeding.* In one study, the shortening of lifespan by the high-fat diet was reversed. In a second study, resveratrol increased SIRT1 activation, PGC-1α deacetylation [a chemical reaction that activates it], and mitochondrial biogenesis in muscle. These studies provide a powerful indication that SIRT1 activation offers a promising approach for treating metabolic disorders. However, one must be aware of possible targets other than SIRT1 for resveratrol, for example, AMP-dependent protein kinase.


*Editor’s note: These studies were discussed in detail in “Revolutionary Antiaging Discovery with Resveratrol” (January 2007) and “Resveratrol Boosts Strength and Endurance in Mice” (February 2007).


Reference

  1. Westphal CH, Dipp MA, Guarente L. A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci 2007;32(12):555-60.

The authors summarized their results by saying,3

We show . . . that in overweight, nonobese humans, short-term caloric restriction lowers whole-body energy expenditure (metabolic adaptation), in parallel with an induction in mitochondrial biogenesis, PPARGC-1α and SIRT1 mRNA [messenger RNA], and a decrease in DNA damage. We therefore propose that caloric restriction induces biogenesis of ‘efficient’ mitochondria in human skeletal muscle as an adaptive mechanism, which in turn lowers oxidative stress.

They neglected to mention that resveratrol, by mimicking caloric restriction, apparently also accomplishes these things. It’s worth noting too that resveratrol, independently of its role as a SIRT1 activator, is a potent activator of yet another enzyme, AMPK (AMP-dependent protein kinase), that plays an important role in CR-induced mitochondrial biogenesis.* Resveratrol’s activation of AMPK is particularly important in neuronal energy metabolism in the central nervous system. (For more on this, see “Resveratrol Boosts Energy Metabolism” in the August 2007 issue.)


*It’s clear that resveratrol’s effects here arise not through any direct antioxidant activity (of which it appears to have little or none in living organisms), but indirectly via its activation of SIRT1 and AMPK.


Stay Tuned for Baby Talk


© iStockphoto.com/Michael Blackburn
By now it should be clear that promoting survival, the new antiaging strategy, is not necessarily any more difficult than retarding deterioration, the time-honored strategy. In fact, it’s a lot easier, if one accepts the premise that the benefits of caloric restriction can be obtained simply by taking resveratrol, as appears to be true in mice. (Remember, though, that we are not mice, and one must beware of leaping to unwarranted conclusions.)

The difference between the two strategies is profound. By retarding deterioration, a defensive strategy, we are trying to decelerate our rate of dying. By promoting survival, an offensive strategy, we are trying to accelerate our rate of living. Both strategies are valuable. Both offer a probability of success, albeit in different and complementary ways. Both can be—and probably should be—pursued simultaneously.

The defensive strategy is old and well understood in principle, although new tactics continue to emerge in its most dynamic arena, that of nutritional supplements. By contrast, the offensive strategy is in its infancy, like a baby whose cries for attention are compelling but only dimly understood. Stay tuned as the baby grows and learns to talk.

References

  1. Guarente L. Ageless Quest: One Scientist’s Search for Genes That Prolong Youth. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2003.
  2. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E, for the Pennington CALERIE Team. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006;295:1539–48.
  3. Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E, for the CALERIE Pennington Team. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007;4(3):485-94.


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

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