Resveratrol Extends Lifespan of Obese Mice
Revolutionary Antiaging Discovery with Resveratrol
Fabled red-wine compound provides health and longevity
benefits of caloric restriction without caloric restriction!
By Will Block
To get back my youth, I would do anything in the world,
except take exercise, get up early, or be respectable.
— Oscar Wilde
t’s a safe bet that Mr. Wilde, a hedonist par excellence, would have drunk a lot of red wine if he had thought that that would bring back his youth. This would have fit nicely with his guiding philosophy, as it’s rather difficult to take exercise, get up early, or be respectable when one is, well, dead drunk. The term is apt, because the amount of red wine one would have to drink to achieve significant “youthening” effects from its celebrated chemical constituent resveratrol would be about 1000 bottles a day—a challenge even for dedicated enophiles.
But the key questions are: Could that much red wine really make us younger? Or could the proportional amount of the resveratrol in the wine really make us younger? Or could resveratrol at least make us live longer? Or, if not that, could it at least make us healthier while we were alive? The answers are no, no, probably, and very probably. This article will explain why. We raised a few common misconceptions at the outset so we could get them out of the way.
Here’s the deal: nothing can make us younger—that’s impossible under the laws of physics. Many things, however, can make us healthier—and, therefore, happier (if not wealthier and wiser)—which is what life enhancement is all about. Being healthier may, of course, make us feel and act younger, which is always a good thing. More to the point, though, it will definitely improve our chances of living longer. Thus, one key to longevity is good health (write that down!).
Resveratrol, the Only Universal Longevity Molecule . . .
Surely you noticed that we said “one” key to longevity, not “the” key. There are more, and they’re all interrelated (a few are discussed in the sidebar). One of them, it now seems clear, is resveratrol, an antioxidant polyphenol found in grapes and red wine, as well as in raisins, purple grape juice, peanuts, mulberries, eucalyptus trees, and the root of the Japanese knotweed (Polygonum cuspidatum).
The Gene Connection to Caloric Restriction
Despite the constancy of maximum human lifespan throughout recorded history, the average lifespan continues to increase, as it has been doing for centuries. This trend is now threatened, however, by the pandemic of obesity in the Western world, the effects of which could halt or even reverse it. Indeed, a recent study in the United Kingdom forecast that men would live 5 years less by 2050 if the pandemic were not brought under control.
Although it will probably never happen, obesity could be abolished—and longevity attained—through caloric restriction, a concept familiar to those who are interested in antiaging research. The idea is simple: just consume about 30–40% fewer calories daily, all your life, than in a normal, healthy diet. In a wide variety of experimental animals (including primates, our closest relatives), the proven result of this regimen is longevity—but not the “ordinary” longevity associated with long-term good health (and some good luck). That kind of longevity merely allows one to live long by the normal standards of the species, but still within the maximum lifespan.
Caloric restriction (CR), by contrast, produces extraordinary longevity, i.e., living beyond the normal maximum lifespan for the species (up to 50% longer in mice), and enjoying generally excellent health in the process.* With CR, then, you could expect to live a very long time, perhaps well beyond the roughly 120-year limit that has prevailed, to this day, throughout mankind’s recorded history. Because the CR regimen is so austere, though, your life would probably seem longer than it really was. Not surprisingly, there are about as many voluntary practitioners of caloric restriction as there are pork-averse members of Congress.
There have been many hypotheses on how CR works to prolong lifespan, including the simple one that reduced caloric intake means reduced production of free radicals, owing to reduced rates of cellular energy metabolism. The damaging attacks by free radicals on cellular constituents are believed to be a key factor in the development of the chronic degenerative diseases of aging, and thus of aging itself.
There is no doubt that free radicals are harmful and contribute significantly to the aging process, or that
antioxidant protection against their destructive effects is beneficial and can extend average lifespan substantially in experimental animals. Nonetheless, it does not appear that CR’s longevity effects are due primarily to a reduced production of free radicals.
Instead, evidence obtained since 2000 points strongly to a more complicated mechanism involving a mammalian gene called SIRT1, which is one of a family of seven genes that code for proteins called sirtuins (sir·TWO·ins). Sirtuins are found in virtually all known organisms (all have genes similar to SIRT1), and they are believed to act similarly in all of them.
Caloric restriction upregulates the SIRT1 gene (and its homologs in other species), thereby stimulating the activation of sirtuins—and it’s the sirtuins’ physiological actions in our cells that are believed to promote increased longevity. Thus, any chemical compound that could similarly upregulate SIRT1 could, theoretically, promote increased longevity as well. There is now much evidence to suggest that that is what resveratrol does. Coincidentally (or perhaps not—who knows?), resveratrol is also a potent antioxidant that helps scavenge free radicals.
In terms of efficacy in human beings, caloric restriction would probably be the best strategy for longevity. Realistically, however, general good health is probably more attainable—especially if it’s given a big boost by resveratrol, as may turn out to be possible.
- Ross-Thomas E. Obesity could hit economies as hard as malnutrition. Reuters Health, Nov. 15, 2006.
Resveratrol is the only chemical compound known to increase longevity in a wide variety of experimental organisms, from lowly brewer’s yeast (Saccharomyces cerevisiae) to a roundworm (Caenorhabditis elegans) to a fruit fly (Drosophila melanogaster) to the turquoise killifish (Nothobranchius furzeri) to—trumpet fanfare, please—the common mouse (Mus musculus)—a mammal!
. . . Is Probably the Holy Grail of Antiaging Research
The publication in November 2006 of a research paper describing resveratrol’s ability to extend the longevity of mice—obese mice, no less—generated media hoopla and made resveratrol a household word, despite its awkward pronunciation (rez·VEER·ah·troll). Journalists fell all over themselves (and often tripped on the facts) in their haste to hype resveratrol as a kind of Fountain of Youth compound.
Readers of Life Enhancement have, of course, been familiar with resveratrol for years, especially since the November 2003 article entitled
“Resveratrol May Be a Longevity Molecule,” which posed the question: Is resveratrol the Holy Grail of antiaging research? In other words, is resveratrol a chemical compound that can extend maximum human lifespan beyond the age-old (so to speak) limit of about 120 years? In subsequent articles chronicling further discoveries regarding the myriad health benefits and antiaging properties of this remarkable compound, the answer has become ever clearer: yes, resveratrol probably is the Holy Grail—at least until something better comes along.*
David Sinclair’s Path to Fame and Fortune
The pioneer on the road to this conclusion has been David Sinclair, an associate professor of pathology at Harvard Medical School and director of its Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. A native of Australia, Sinclair is a former MIT postdoctoral student of Leonard Guarente, another pioneer in the molecular biology of aging.
Having learned well from the master, the student started his own research group at Harvard to compete with him in the race for the Holy Grail. Both scientists have also started high-tech companies with major funding from venture capitalists, to, uh, capitalize on their discoveries and become so wealthy that the Nobel Prize money they may one day share will seem like chump change.
The fundamental importance of the new discovery by Sinclair and his 26 colleagues (including some from Australia and Spain) is twofold:
- It demonstrates enhanced longevity in mammals, i.e., creatures that are genetically very similar to humans, with essentially the same kind of metabolism and general physiology.
- It demonstrates enhanced health and longevity in obese mammals, which would ordinarily be expected to develop chronic degenerative diseases—especially type 2 diabetes—and, therefore, to die sooner rather than later.
Is Resveratrol an Antidiabetic Agent?
Let’s see what prompted the study, and what was found. Sinclair and his colleagues had been searching for a chemical compound that would upregulate the SIRT1 gene (in laboratory experiments), thereby stimulating the activation of sirtuins (for an explanation, see the sidebar above). Of the over 20,000 compounds they screened, about 25 filled the bill, and of these, resveratrol was the most potent, as they discovered in 2003. Subsequent studies (none, thus far, in humans, however) indicated that resveratrol had remarkable abilities to prevent or treat chronic degenerative diseases, such as cardiovascular disease, cancer, arthritis, and neurodegenerative diseases; most significantly—indeed, spectacularly—it extended lifespan in every experimental organism in which it was tested.
In their new study, Sinclair and his colleagues were motivated not by longevity considerations but rather by resveratrol’s potential benefits as an antidiabetic agent—hence the focus on obese mice, which are prone to diabetes. The researchers divided 170 52-week-old (middle-aged) male mice into three groups with different diets: (1) a standard diet of mouse chow; (2) a high-calorie diet (60% from fat); and (3) the same high-calorie diet supplemented with either 5.2 or 22.4 mg of resveratrol per kilogram of body weight, per day.* No toxic effects of these dosages were observed in the mice, nor have any been observed in humans taking supplemental resveratrol.
Yes—And Much More
The published results of the study focused on the higher of the two doses, which was found to be more effective than the lower one. Actually, the study is not yet complete, but the paper was submitted for publication after 114 weeks, when the mice that had not yet died were 166 weeks, or 3.2 years, old (their normal lifespan is about 2.5 years). The final results will be published later, when all the mice have died.
At the time the current paper was submitted, the following results had become clear:
- Obesity – At about 8 weeks into the trial, all the mice on the high-calorie diets (with or without resveratrol) started to become obese, to about the same degree. The mice on the standard diet did not.
- Longer survival – At about 18 weeks into the trial, the untreated high-calorie (HC) mice began to die at a significantly greater rate than the resveratrol-treated high-calorie (HCR) mice, and they continued to do so for the duration (see the graph below). By contrast, the HCR mice, despite their obesity, died off at essentially the same rate as the standard-diet (SD) mice. Although the final results are not yet known, a statistical analysis of the data projects that resveratrol reduced the risk of obesity-related death by 31%. “There is no question that we are seeing increased longevity,” says Sinclair. The overall life extension is about 15–20%.
- Better physical condition – Tests of balance and motor function showed that the HCR mice were significantly more robust than the HC mice, with physical abilities comparable to those of the SD mice.
- Resistance to diabetes – Compared with the HC mice, the HCR mice showed significantly higher insulin sensitivity and lower plasma levels of glucose, insulin, and insulinlike growth factor-1 (IGF-1), again paralleling the SD mice. Despite their obesity, in other words, they showed no significant propensity to insulin resistance or type 2 diabetes; the latter is a major risk factor for cardiovascular and neurodegenerative diseases.
- Protection from liver and heart damage – The HC mice showed typical evidence of fatty liver disease due to obesity, with greatly increased size and weight of their livers. In the HCR mice, by contrast, there were no such effects—their livers were normal. Similar results were also seen in heart tissue, which resveratrol protected from the harm normally caused by excessive fat.
Individually and collectively, these
results are breathtaking. They suggest
a powerful effect of resveratrol in
improving both the health and the
longevity of obese mice.
- More mitochondria – The livers of the HCR mice had considerably more mitochondria than those of the HC mice and were comparable in this regard to those of the SD mice. Mitochondria are the cellular organelles where energy metabolism takes place to power life processes.
Favorable physiology shift – Sophisticated molecular genetic analyses indicated that resveratrol substantially shifted the physiology of the HCR mice toward that of the SD mice, i.e., toward normal, thus counteracting the pathologies associated with obesity. Specifically, of 153 biochemical pathways that were significantly altered in the HC mice, resveratrol opposed the effects of high caloric intake in 144 of them (94%).
11 on a Scale of 10
Individually and collectively, these results are breathtaking. They suggest a powerful effect of resveratrol in improving both the health and the longevity of obese mice, in defiance of the normal consequences of obesity, and without any dietary restrictions! Sinclair and his colleagues believe they have confirmed what had long been suspected—that resveratrol mimics the effects of caloric restriction by activating sirtuins, without the burden of having to eat less food. (Curiously, the obese mice showed virtually all the benefits of CR except one: they did not lose weight.)
Survival rates of lean and obese mice. Note that resveratrol protects obese mice from premature mortality. The overall life extension in the resveratrol-supplemented mice is about 15–20%. Adapted from Ref. 1.
Not all experts in the field agree, however. There is legitimate controversy regarding the proper interpretation of the results and the speculations as to where they might lead. There is no doubt whatever, though, as to their fundamental importance. In commenting on the study, Dr. Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, said, “The significance of the study on a scale of 10 is 11 in the aging and longevity field.”
A Big Question Looms, While Others Are Answered
He also pointed out, however, that it’s still not clear whether the obese mice in this study lived longer because resveratrol slowed their aging or because it prevented obesity-related diseases. Nor did the study show whether or not resveratrol can increase longevity in normal mice—that question is currently being investigated in Sinclair’s laboratory. Meanwhile, the authors of the current study concluded,
Taken together, the findings in this study 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-1α activity, and mitochondrial number. Notably, all these changes occurred without a significant reduction in body weight. . . . this study 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.
Five Keys to Longevity
In this article, we have seen that there are at least five interrelated keys to longevity. Not in any presumed order of efficacy, they are:
- General good health – This can usually be achieved with some combination of disciplined effort (healthy diet and regular exercise) and good luck (including a favorable genetic makeup).
Antioxidant protection – Suppressing free radicals can be achieved through good nutrition, including nutritional supplements.
Maartje van Caspel
- Caloric restriction – This can be achieved with supernatural willpower and sacrifice.
- Upregulation of SIRT1 gene – This activates the sirtuins; it can be achieved through caloric restriction and, apparently, by taking resveratrol.
- Taking resveratrol – This ties everything together by conferring numerous health benefits (1) that reduce the likelihood of death from chronic degenerative diseases; by acting as an antioxidant (2); and by mimicking caloric restriction (3) through its activation of SIRT1 and the sirtuins (4).
To date, there have been no studies on the efficacy of resveratrol in human beings, so it’s still too early to judge what its effects on human health and longevity will be. All we can say for sure at this point is that resveratrol shows tremendous promise, in ways that no other substance ever has—an 11 on a scale of 10, remember?
- Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK,
de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006 [online preprint; doi 10.1038/nature05354].
- 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.
- Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo
evidence. Nature Rev Drug Disc 2006;5(6):493-506.
- Wade N. Aging drugs: hardest test is still ahead. The New York Times, Nov. 7, 2006.
- Kaeberlein M, Rabinovitch PS. Grapes versus gluttony. Nature 2006
[online preprint; doi 10.1038/nature05308].
- Anon. Small molecule increases lifespan and “healthspan” of obese mice. Harvard Medical School press release, Nov. 1, 2006.
- Stipp D. Substance in red wine appears to let mice live longer. The Wall Street Journal, Nov. 2, 2006.
Will Block is the publisher and editorial director of Life Enhancement magazine.