Substance Found That Can Prolong Healthy Life in Mice

November 03, 2006

November 3, 2006 (New York, NY) - Resveratrol, a natural compound found in red wine, grapes, and nuts, has been shown to prevent many adverse metabolic effects of a high-fat diet and to increase survival in mice in a new study, raising the possibility that this agent or something similar could become the much-sought-after elixir for a long and healthy life [ 1].

The study, published online in Nature on November 1, 2006, was conducted by a team led by Drs Joseph Baur (Harvard Medical School, Boston, MA) and Kevin Pearson (National Institute on Aging, Baltimore, MD). They conclude: “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."

But the current study used much higher doses of the compound than could be gleaned from drinking red wine, and although senior author Dr David Sinclair (Harvard Medical School), is already taking supplements of resveratrol, another member of the research team told heart wire that he did not recommend this as an antiaging strategy at present, as no human data were yet available. Dr Rafael de Cabo (National Institute on Aging) said: “What we have shown in mice is very exciting, but it is too soon to rush out and start consuming large quantities of this compound, as there is no evidence that it works in humans as yet and very little is known about possible side effects. Yes, David is taking it, but that is his personal decision, but I will not start taking it until we have more data. We don’t know enough about it yet. It could be risky.”

First study in mammals

Resveratrol has already been shown to extend the life span of diverse species, including certain yeast cells, fruit flies, roundworms, and fish. The current study in mice is the first study to investigate its antiaging effects in mammals.

From previous laboratory studies, the authors hypothesized that resveratrol might prevent the adverse metabolic consequences of a high-calorie diet, which might result in prolonged survival. They studied middle-aged (one-year-old) male mice that were fed either a standard diet or a high-calorie diet (60% of calories from fat) for the remainder of their lives. Two other groups of mice were given the same diets, but with resveratrol added. When the paper was written, at which time the colony of mice would have been 114 weeks old, 58% of the high-calorie-diet control animals had died, compared with 42% of the mice receiving the high-calorie diet and resveratrol. Thus, resveratrol was associated with a 31% reduction in the risk of death in the high-calorie-diet group, reducing their risk to a level similar to the control mice fed a standard diet.

In addition to extending their lives, resveratrol also kept the mice fit and healthy in their old age. In a study of motor function, in which the mice ran on top of a rotating rod, the animals given the high-calorie diet fell off much sooner than those on the standard diet, but those given a high-calorie diet plus resveratrol steadily improved their motor skills as they aged, to the point where they were indistinguishable from the standard-diet group. “This is important, as it suggests that this compound may not just extend life but may also enable individuals to lead healthy and functional lives for longer," de Cabo commented to heart wire .

Resveratrol was also associated with improved glucose tolerance and prevented the detrimental effects of the high-calorie diet on the liver. De Cabo told heart wire that, for him, the effects of resveratrol on the liver were particularly exciting. “I was not a believer until I did the autopsies in the mice and I saw the pathologies of the liver. I was blinded to which group was which, but there were clear differences between those on resveratrol and those not. I was floored by some of these effects."

Cardiovascular benefits

In terms of cardiovascular effects, the researchers found that mice given resveratrol along with a high-fat diet had less damage to cardiac muscle and healthier aortic tissue than those given a high-fat diet without resveratrol. De Cabo noted that this may explain some of the cardiovascular benefits that have been associated with drinking red wine, but he cautioned that this was just speculation. “The amount of resveratrol that we gave the mice was the equivalent of drinking 100 bottles of wine each day--you’re not going to get the effect from a couple of glasses. But it is interesting that red wine has been shown to have beneficial cardiovascular effects--there could be a link here."

Anticancer effects too

He pointed out that resveratrol is also being studied as an anticancer agent, with potent anticancer activity having been shown in vitro and in animal studies, and it is now starting in clinical trials for this indication. “Its anticancer action may be related to its antiaging effects, but it has many other actions as well that may be more relevant to the antiaging observations," de Cabo said. “Its mechanism of action is not well understood--it is a broad acting molecule targeting many different things within the cell, so we don’t really know how it is bringing about its antiaging effects." But it has very potent beneficial effects on the liver and on glucose metabolism that are probably at least partly responsible. “It has multiple effects, including anti-inflammatory and antioxidant effects--indeed, 93% of the metabolic pathways induced by a high-fat diet were reversed by this substance," he added.

What next?

The researchers are now planning further studies of the compound in mice to see whether it can reverse the effects of a high-fat diet when given later--ie, whether it can undo the bad that has already been done. They are also planning a pilot study in nonhuman primates, with a design similar to the current study in mice, and if that shows good results, they would then start clinical trials.

Mimics calorie restriction

De Cabo explained that the possibility that resveratrol may have antiaging effects was first discovered when Sinclair and colleagues were doing research on the well-known observation that calorie restriction can prolong life. It has long been known that reducing caloric intake by about 40% of normal can delay age-related diseases and extend life span in mammals. A gene known as SIRT1, which regulates such processes as glucose and insulin production, fat metabolism, and cell survival, has been implicated in this process, and while Sinclair’s team were screening compounds to find ones that activated SIRT1, they found resveratrol showed such activity. Sinclair has now formed a company --Sirtris Pharmaceuticals--to develop drugs based on resveratrol.

But de Cabo said that while this may be how resveratrol works, it is by no means certain. “It does activate the SIRT1 gene in vitro, but this does not mean that this is definitely the mechanism of action of its antiaging effect in mice. The link between resveratrol and SIRT1 is far from proven. Yes, resveratrol does seem to be doing something good in mice. It is very promising and exciting, but we need more studies and we want to investigate how it is working. We certainly don’t want to give out the message that it is okay to gorge at McDonald's then drink large quantities of wine or take resveratrol to negate the effect. Maybe one day this may be possible, but we don’t know that yet," he cautioned.

Media go to town

Not surprisingly, the Nature paper attracted a lot of attention from the mainstream media and was the focus of long articles in both the Wall Street Journal and the New York Times [ 2, 3].

The New York Times article, by Michael Mason, quotes Dr Leonard P Guarente (Massachusetts Institute of Technology, Cambridge) as saying: “In mice, calorie restriction doesn’t just extend life span, it mitigates many diseases of aging: cancer, cardiovascular disease, neurodegenerative disease. The gain is just enormous.” Sinclair adds: “The goal is not just to make people live longer. It’s to see eventually that an 80-year-old feels like a 50-year-old does today. It’s just a big waste of talent and wisdom to have people die in their 60s and 70s.” But Mason notes that that there are conflicting views on how much calorie restriction could increase life span in humans, with some suggesting that a pill mimicking the effects of calorie restriction might enable people to live to 112, with some even reaching 140, but other groups estimating that the maximum life span gain from calorie restriction for humans would be just 2% to 7%. “Calorie restriction is doomed to fail and will make people miserable in the process of attempting it,” Dr Jay Phelan (University of California, Los Angeles) is reported as saying.

The Times article also notes that researchers at Washington University in St Louis, MO have reported that people following such calorie-restricted diets have better-functioning hearts and fewer signs of inflammation than similar subjects on regular diets. It quotes one scientist as saying: “Calorie restriction has a powerful, protective effect against diseases associated with aging. We don’t know how long each individual will end up living, but they certainly have a longer life expectancy than average.” But other experts are not convinced, noting that exceptional thinness, a logical consequence of calorie restriction, is actually associated with an increased risk of death.

In the Wall Street Journal piece, reporter David Stipp notes that Sinclair’s company, Sirtris, has raised $82 million from venture capitalists and has begun testing a resveratrol-based drug in diabetic patients. Other companies also working on finding drugs that may mimic the calorie-restriction approach to slow aging are said to be Elixir Pharmaceuticals (founded by Sinclair’s former mentor Guarente), BioMarker Pharmaceuticals, and LifeGen Technologies.

The article also notes that while Sinclair has focused on the SIRT1 gene as the switch to activate the calorie-restriction antiaging effect, other scientists have published work suggesting that calorie restriction can exert antiaging effects independently of the SIRT gene and that other genes may be more relevant.

  1. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; DOI:10.1038/nature05354. Available at: http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05354.html.

  2. Stipp D. Researchers seek key to antiaging in calorie cutback. Wall Street Journal, October 30, 2006. Available at: http://www.wsj.com.

  3. Mason M. One for the ages: a prescription that may extend life. New York Times, October 31, 2006. Available at: http://www.nytimes.com.

The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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