Resveratrol Prolongs Life in a Vertebrate!

Resveratrol for Life Enhancement

Resveratrol Prolongs Life in a Vertebrate!
Research with a rare species of fish shows that it also
delays age-related motor and cognitive decline
By Will Block

hat does a fish have to look forward to? If fish do look forward (a questionable premise in itself), it’s probably to the next meal, the next opportunity to mate, or the next place to hide from bigger fish. That’s it—no job promotions, no vacations, no long walks on the beach (they’re so close, though!). It makes you wonder why, like all other creatures, fish try so hard to live as long as they can.

“Life is hard, and then you die” goes the old saying. Yet we all want to live long, even though life is hard, and messy, and sometimes painful. The will to live is overwhelming. Besides, we all have our dreams and aspirations, and the hope of attaining them helps keeps us going when the going gets rough. For many people, the greatest driving force in life is the desire to see their children grow and prosper and have children of their own, and to see them grow and prosper, etc. For those people, being an integral part of the eternal cycle of life—by nurturing, teaching, encouraging, and helping their young ones to do well in the world—is the most satisfying aspect of human existence.

This Is No Way to Live . . .

Pity, then, the countless species of animals in which parents never even see their own young, because they die before—sometimes long before—the young are born. Having laid their eggs, their purpose is fulfilled, and nature has no more need of them—so they quickly age and die, or they get eaten before they have a chance to age. When the eggs finally hatch, the cycle begins anew. Each generation thus exists in isolation, devoid of any knowledge of a preceding or succeeding generation. There are no parents and no children in the usual sense—just creatures that live and die on their own.

Among the many kinds of animals whose existence is defined in this melancholy way are freshwater fish that live in exceptionally harsh environments, such as seasonal pools, which exist only during the rainy season. When the rains stop and the sun broils the earth for months on end, the fish are doomed as the pools dry up. Their eggs, however, lie buried in the hardened mud and remain dormant until the rains begin again. When the mud softens, the eggs will hatch, and the miracle of life is reasserted in spectacular fashion.

. . . But the Turquoise Killifish Does

Just such a spectacle occurs every year with a rare species of fish called the turquoise killifish (Nothobranchius furzeri), which is native to southeastern Africa. Until 2005, this fish had the dubious distinction of having the shortest known lifespan—12 weeks—of any of the vertebrates (animals with backbones—fish, amphibians, reptiles, birds, and mammals). That drew the attention of some longevity researchers in Italy, who had been looking for ways to shorten the time required for conducting experiments in the physiology of aging—and antiaging.1 (For more on the remarkable killifish, see the sidebar “When Shortevity Is a Virtue.”)

When Shortevity Is a Virtue

In a nice irony, scientists who study longevity are ever on the lookout for creatures that obligingly show “shortevity”—a very short natural lifespan for organisms of their general type. Most longevity studies require observation (and, often, treatment of some kind) over at least one whole generation, and some require several or many generations. Thus a very short lifespan makes it possible to study and manipulate the cycle of life and death in a convenient and cost-effective manner.

Ideally, of course, we would want to study our closest living relatives on earth: bonobos and chimpanzees. But because that’s out of the question (as is the study of any large mammal), we must lower our expectations. We can settle for small, short-lived rodents, such as rats and mice, but even they live for more than 2 years, which means that experiments requiring a lifespan’s worth of treatment and observation are tedious, costly, and impractical.

Many experiments are done on organisms much farther down the evolutionary tree, such as yeasts, roundworms, and fruit flies, whose lifespans are in the range of hours to days to weeks. That’s convenient and practical, but not too reassuring in terms of physiological similarity with humans. The lifespans of vertebrates, on the other hand, range from months to years to decades, and to operate at the low end of that range, we must look to fish. What we want is a fish that is considerate enough to grow old and die very quickly.

Enter the turquoise killifish (Nothobranchius furzeri), a small, brightly colored freshwater fish whose maximum lifespan is only 12 weeks—about the same as a fruit fly’s.1* This 2-inch-long fish lives its fast and furious life in seasonal pools in the forbidding, tsetse fly-infested border area of Zimbabwe and Mozambique, where rainfall is extremely variable and erratic. It’s a bottom spawner that lays its eggs in the mud, lives a few more weeks while undergoing rapid decline, and then dies of old age. When the rainy season ends, the pools dry up, and the eggs remain dormant for 5 to 7 months. Comes the next rainy season, a new generation of fish emerges from the mud and continues the cycle of life and death.


*This was the shortest known lifespan for any vertebrate until last year, when Australian scientists discovered that a tiny coral-reef fish called the pygmy goby (Eviota sigillata) has a maximum lifespan of only 8 1/2 weeks. Its “live fast and die young” existence is terminated not by aging in the usual sense but by intense predation by many other species of fish, for which the pygmy goby is a favorite snack.



Turquoise killifish (Nothobranchius furzeri)
There are over 700 species of killifish, most of which have not yet been fully characterized by biologists. All are short-lived, but N. furzeri is the shortevity champ. Its growth and sexual maturation are extremely rapid, as is the aging process that leads to its death. The fact that it ages at all is remarkable and is a key factor in the fish’s utility as an experimental model for aging and longevity research.

Aging in the turquoise killifish is the result of a biological adaptation for the accelerated life cycle demanded by the fish’s extreme environment. Because the signs of aging that the fish exhibits are typical of vertebrates, the answers it can provide regarding the effects of various chemical compounds, such as resveratrol, on the aging process may also be applicable to higher organisms, including humans.

The turquoise killifish offers scientists the opportunity to perform experiments that have hitherto been unthinkable in vertebrates, and it is now being bred in captivity for use in laboratories worldwide.2 Few people have ever seen its native habitat. There are African tribespeople who live there, though, and they have a name for this fish: xibaheuxlha. If you can pronounce that correctly, you’ll get a prize.

References

  1. Valdesalici S, Cellerino A. Extremely short lifespan in the annual fish Nothobranchius furzeri. Proc R Soc Lond B Biol Sci 2003;270 (Suppl 2): S189-91.
  2. Genade T, Benedetti M, Terzibasi E, Roncaglia P, Valenzano DR, Cattaneo A, Cellerino A. Annual fishes of the genus Nothobranchius as a model system for aging research. Aging Cell 2005;4:223-33.

Resveratrol Fights Heart Disease and Cancer

The Italian researchers were interested in testing one of the most exciting substances to be discovered in modern times: resveratrol. This grape-skin compound, which is found in varying amounts in red wine, became famous in the 1990s for its beneficial effects on cardiovascular health. Resveratrol (pronounced rez-VEER-ah-troll) is an antioxidant polyphenol. In laboratory studies, it inhibits lipid peroxidation, the process by which LDL-cholesterol (the “bad cholesterol”) is induced to form artery-clogging atherosclerotic plaque; it inhibits platelet aggregation, the process that induces dangerous blood clots to form at the site of a ruptured plaque; and it promotes the nitric-oxide-mediated dilation of blood vessels, which is important for maintaining proper blood pressure. (For yet another heart benefit, see the sidebar “Resveratrol Protects Against Arrhythmias.”)

Resveratrol Protects Against Arrhythmias

In addition to its numerous other beneficial effects on heart health, resveratrol is known to protect against cardiac arrhythmias (irregular heartbeats) in laboratory animals. Chinese researchers have published a new study in which they used three techniques for inducing arrhythmias:1

  • A group of guinea pigs received ouabain, a highly toxic steroidal glycoside derived from the seeds of certain African trees and used by the natives as a dart poison. It’s now used (in small amounts) as a cardiotonic drug in the treatment of heart failure and other conditions.
  • One group of rats received aconitine, a highly toxic plant alkaloid derived from the herb aconite (also called monkshood and wolfsbane).
  • Another group of rats had their left anterior descending coronary arteries ligated (tied); the control rats underwent the same operation but without the actual ligation.

All three groups of animals were given resveratrol intravenously at various doses, with positive results. Resveratrol significantly and dose-dependently increased the amounts of ouabain and aconitine required to induce arrhythmias in the guinea pigs and rats. In the rats with ligated coronary arteries, resveratrol shortened the duration of arrhythmia and decreased the incidence of ventricular tachycardia (very rapid heartbeat) and death.

The authors suggested that resveratrol may be an attractive alternative to currently used antiarrhythmic drugs, all of which are unsatisfactory in one way or another.

Reference

  1. Zhang Y, Liu Y, Wang T, Li B, Li H, Wang Z, Yang B. Resveratrol, a natural ingredient of grape skin: antiarrhythmic efficacy and ionic mechanisms. Biochem Biophys Res Comm 2006;340:1192-9.


Resveratrol
Resveratrol is also known to have anti-inflammatory properties. And it has an inhibitory effect (in cell cultures) on all three of the major steps in carcinogenesis: initiation, promotion, and progression. Indeed, it has demonstrated activity against many forms of cancer in laboratory studies.

Resveratrol Fights Neurodegeneration and Promotes Longevity

Resveratrol has strong neuroprotective effects that help prevent brain damage caused by oxidative stress, and it has been found to be beneficial in disposing of amyloid-beta, the senile plaque that destroys brain tissue in Alzheimer’s disease. It provides further protection against neurotoxicity by stimulating the action of a gene, SIRT1, that plays a role not only in neuroprotection but also—perhaps not coincidentally—in longevity. This gene is a member of a class of genes called sirtuins (sir-TWO-ins), which are intimately involved in regulating the lifespans of a vast range of organisms, from yeasts to roundworms to fruit flies to rodents—and, probably, to primates, including humans.*


*For more information (and literature citations) on the various health benefits of resveratrol mentioned above, see “Resveratrol May Be a Longevity Molecule” (November 2003), “Resveratrol and Quercetin—Puzzling Gifts of Nature” (July 2005), “Resveratrol Fights Brain Plaque” (November 2005), and “Can Resveratrol Help Prevent Alzheimer’s?” (February 2006).


Italian Researchers Test Resveratrol in Killifish

Little wonder, then, that the Italian researchers (and many others) are interested in resveratrol’s potential as an antiaging compound. Which brings us back to the turquoise killifish, whose rate of aging is phenomenal: these fish compress into a few weeks the kinds of aging effects that take a few decades to occur in us humans. In other words, they age about 500 times as fast as we do—a boon for researchers trying to see what effects a chemical compound, such as resveratrol, might have on the aging process.2

Using 157 turquoise killifish bred by an Italian drug development company, Lay Line Genomics (which funded the study and which holds the rights for commercial exploitation of this aging model), the researchers conducted experiments on the antiaging effects of resveratrol.3 Beginning when the fish reached sexual maturity at 4 weeks of age, the researchers gave them food (bloodworm larvae—yum!) that was supplemented with resveratrol at three different concentrations: 24, 120, and 600 micrograms of resveratrol per gram of food.* (A fourth group, the controls, received no resveratrol.) The fish were given defined amounts of food twice daily so that their resveratrol intake could be accurately known.


*One microgram per gram of food is equal to one milligram per kilogram of food. Thus, assuming an average daily intake of 0.5 kg (1.1 lb) of food for humans, these fish doses would correspond to daily resveratrol intakes of 12, 60, and 300 mg, respectively, for humans.


Major Life Extension with Resveratrol

The results were astonishing: whereas all the control fish died by 12 weeks of age (as did the fish receiving the lowest dose of resveratrol), the fish receiving the two higher doses of resveratrol lived much longer. In the fish receiving 120 mcg/g of food, the median lifespan increased by 33%, and the maximum lifespan increased by 27%. In the fish receiving 600 mcg/g of food, the median and maximum lifespans increased by 56% and 59%, respectively.

Life extension occurred equally in both sexes and was not linked to a loss of fertility: at 12 weeks of age, when all the controls were dead, the resveratrol-fed females continued to lay eggs, and the resveratrol-fed males were still able to fertilize them. Furthermore, the eggs hatched normally, and the fry developed into normal adults.

Major Protection of Motor Function with Resveratrol

Increased longevity was not the only result of resveratrol treatment, however. Using an automated video tracking system that constantly monitored the location of each fish in the tank, the researchers measured the fishes’ motor activity, a reduction in which is an age-related marker of neuromuscular decay.

The analysis of three measures—spontaneous swimming, average swimming speed, and time spent moving—showed an age-related reduction in activity by 9 weeks of age in the control fish. In the resveratrol-fed fish (120 mcg/g of food), however, the reduction in spontaneous swimming was significantly retarded, and the reductions in swimming speed and time spent moving were temporarily abolished—they didn’t catch up (or catch down, one might say) with the controls until the fish were 13 weeks old. This 4-week delay in decay represents one-third of a normal lifetime for the turquoise killifish.

Major Protection of Cognitive Function with Resveratrol

The researchers also measured resveratrol’s effect on the fishes’ age-related cognitive decline by means of an operant-conditioning device in which the fish learn to avoid a certain stimulus (in this case, a red light in the tank) by receiving a punishment when they fail to do so. (How do you punish a fish? The researchers didn’t say, so we are left to wonder.)

After 50 consecutive trials, young control fish (5 weeks old) had a 73% success rate in learning the avoidance trick, whereas old control fish (9 weeks old) had only a 42% success rate. When the researchers tested equally old fish that had been supplemented with resveratrol (120 mcg/g of food), they found that the age-dependent decline in cognitive ability had been abolished: the fishes’ success rate in learning the trick was 74%.

A possible explanation for this extraordinary result was found in the fishes’ brains, which the researchers examined for evidence of neurofibrillary degeneration similar to that seen in the brains of Alzheimer’s victims at autopsy. Whereas the brains of the old control fish showed abundant evidence of such neurodegeneration, the brains of the young control fish showed no evidence of it—and neither did the brains of the old resveratrol-supplemented fish.

Climbing the Evolutionary Tree

Resveratrol’s dramatic longevity effects in the turquoise killifish—a vertebrate—are similar to those observed previously in lower organisms, namely, yeasts, roundworms, and fruit flies.4,5,6 It’s tantalizing to think that these effects might also occur in organisms still farther up the evolutionary tree, perhaps all the way up to human beings. If that proves to be true—and only time and much more research will tell—resveratrol may indeed turn out to be the Holy Grail of antiaging research, as we first speculated in our November 2003 article on this subject (“Resveratrol May Be a Longevity Molecule”). Meanwhile, let’s conclude with the Italian researchers’ concluding statement:3

The mechanisms by which resveratrol prolongs lifespan in model organism [sic] are not clear, but the observation that its supplementation with food extends vertebrate lifespan and delays motor and cognitive age-related decline could be of high relevance for the prevention of aging-related diseases in the human population.

References

  1. Valdesalici S, Cellerino A. Extremely short lifespan in the annual fish Nothobranchius furzeri. Proc R Soc Lond B Biol Sci 2003;270 (Suppl 2):S189-91.
  2. Genade T, Benedetti M, Terzibasi E, Roncaglia P, Valenzano DR, Cattaneo A, Cellerino A. Annual fishes of the genus Nothobranchius as a model system for aging research. Aging Cell 2005;4:223-33.
  3. Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 2006;16:296-300.
  4. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003;425:191-6.
  5. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004;430:686-9.
  6. Kang HL, Benzer S, Min KT. Life extension in Drosophila by feeding a drug. Proc Natl Acad Sci USA 2002;99:838-43.

Resveratrol for Life Extension?

For those who wish to avail themselves of the antioxidant, anti-inflammatory, antimutagenic, neuroprotective, and, perhaps, antiaging properties of the plant polyphenol resveratrol, a PEGylated liposomal form is a good choice. When resveratrol molecules are encapsulted within a lipid bilayer similar to that which constitutes the walls of natural cells this plant material becomes more bioavailable. The PEGylated liposomes are able to penetrate readily into the system through the mucous membranes of the mouth, thus avoiding the digestive tract.


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

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