新たな研究でDr. de Cabo らは、毒性なく肥満マウスに利益をもたらすことを見つけた。人にも応用できるだろうという。しかしながら、正常なマウスより長生きできるわけではなかった。
Longer Lives for Obese Mice, With Hope for Humans of All Sizes
By NICHOLAS WADE
Published: August 18, 2011
Sustaining the flickering hope that human aging might somehow be decelerated, researchers have found they can substantially extend the average life span of obese mice with a specially designed drug.
The drug, SRT-1720, protects the mice from the usual diseases of obesity by reducing the amount of fat in the liver and increasing sensitivity to insulin. These and other positive health effects enable the obese mice to live 44 percent longer, on average, than obese mice that did not receive the drug, according to a team of researchers led by Rafael de Cabo, a gerontologist at the National Institute on Aging.
Drugs closely related to SRT-1720 are now undergoing clinical trials in humans.
The findings “demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals,” Dr. de Cabo and colleagues write in Thursday’s issue of the new journal Scientific Reports. Their conclusion supports claims that had been thrown in doubt by an earlier study that was critical of SRT-1720.
A drug that makes it cost-free to be obese may seem more a moral hazard than an incentive to good health. But the rationale behind the research is somewhat different: the researchers are trying to capture the benefits that allow mice on very low-calorie diets to live longer. It just so happens that such benefits are much easier to demonstrate in mice under physiological stress like obesity than in normal mice.
“The drugs could be used as a preventative to stave off diseases, but I don’t think they will ever be an excuse to abuse your body,” said David Sinclair, a biologist at Harvard Medical School and co-chairman of the scientific advisory board of Sirtris, which developed SRT-1720.
The company, a small pharmaceutical concern in Cambridge, Mass., designed SRT-1720 and a set of similar drugs to mimic resveratrol ― the trace ingredient of red wine that is thought to activate protective proteins called sirtuins.
The sirtuins help bring about the 30 percent extension of life span enjoyed by mice and rats that are kept on very low-calorie diets. Since few people can keep to such an unappetizing diet, researchers hoped that doses of resveratrol might secure a painless path to significantly greater health and longevity.
But large doses of resveratrol are required to show any effect, so chemical mimics like SRT-1720 were developed to activate sirtuin at much lower doses.
Sirtuins have proved to be highly interesting proteins, but the goal of extending life span was set back last year when extensive trials of resveratrol showed it did not prolong mice’s lives, although it seemed to do them no harm. Another blow came in 2009, when biologists at Pfizer reported that SRT-1720 and other resveratrol mimics did not activate sirtuins and did not have any beneficial effects in fat mice.
The report by Dr. de Cabo and his colleagues may do much to rescue SRT-1720 from this shadow. They found that SRT-1720 offered substantial benefits to the fat mice, with no signs of toxicity. Unlike the Pfizer study, which was short term, they followed large groups of mice for over three years.
“This is good evidence that this compound has a positive effect on the physiology of the obese animal, and that is definitely promising for humans,” said Jan Vijg, an expert on aging at the Albert Einstein College of Medicine in the Bronx.
Dr. de Cabo and his team “make a reasonable case” that the compound works by activating sirtuins, although they have not proved it, Dr. Vijg said.
In one sense it does not much matter how the drug obtains its effects, as long as it works. But the credibility of SRT-1720 and its cousins also rests on their design as sirtuin activators.
Despite the positive new results with SRT-1720, Sirtris is not putting it into clinical trials because the company believes another of its resveratrol mimics, SRT-2104, is more promising. That drug “is more suitable for human consumption,” said Dr. Sinclair, a co-author of Dr. de Cabo’s report.
“Questions were raised about the molecules and if they are working the way we said they were,” Dr. Sinclair said. “But with this paper, the weight of evidence is shifting back in favor of the premise that we can tweak the aging pathway with drugs.”
Obese mice are a standard research tool, but experts differ as to how relevant they are to humans. “They’ve poisoned the mice with this high-fat diet that makes them very sick indeed, and with SRT-1720 they can reverse some portion of that illness,” said Dr. Richard A. Miller, an expert on aging mice at the University of Michigan.
Dr. Miller said the finding “looks like something people should pay a lot of attention to,” but added that the study would have been even more interesting if it had shown an effect on normal mice.
Dr. de Cabo and his team included normal, untreated lean mice in their study as a control group for the treated and untreated fat mice. The treated fat mice lived longer than the untreated ones, but died long before the normal mice. Although the treated fat mice lived significantly longer on average, there was little difference between their maximum life span and that of the untreated mice. The drug, in other words, helped the fat mice enjoy more of their available life span without increasing the span itself.
The researchers’ findings would be more significant if they had showed that SRT-1720 prolonged the lives of normal mice. Dr. Sinclair said that this leg of the study had been started at the same time, but that the treated normal mice were taking longer to die and could not be reported with the others. Dr. de Cabo said the results were “encouraging” but could not be discussed until they were published early next year. But Dr. Vijg noted that since the drug did not extend the maximum life span of fat mice, it would be surprising if it did so with lean mice.
Some researchers say that too much attention has been given to resveratrol and its sirtuin-activating mimics, and that other compounds like the antibiotic rapamycin may be even more promising. But the sirtuins “are worth a lot of attention even though some of the early claims have proved hard to reproduce,” Dr. Miller said.
Because of the uncertainty about several earlier findings, the sirtuin field has become polarized. “Some people are strongly in support, and others are convinced there’s nothing there,” said Brian Kennedy, president of the Buck Institute for Research on Aging. He described himself as standing in the middle, but hopeful that the sirtuins would turn out to be “key modulators of aging.”
SRT1720 improves survival and healthspan of obese mice
Robin K. Minor,
Joseph A. Baur,
Ana P. Gomes,
Theresa M. Ward,
Evi M. Mercken,
Pablo M. Irusta,
Basil P. Hubbard,
Alexa A. White,
Nathan L. Price,
William R. Swindell,
Kevin J. Pearson
Received 18 July 2011
Accepted 29 July 2011
Published 18 August 2011
Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals.
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