New Anti-Aging Drug: Drug Is Found to Extend Lives of Obese Mice
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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, say 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.
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.
The drug is one of a set of chemicals designed by Sirtris, a small pharmaceutical company in Cambridge, Mass., to mimic resveratrol - the trace ingredient of red wine thought to activate protective proteins called sirtuins.
The sirtuins help mediate 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 when extensive trials of resveratrol showed it did not prolong mice's lives, although it seemed to do them no harm. Another blow fell 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 new report, which did find benefits after following large groups of mice for more than three years, may do much to rescue SRT-1720 from this shadow. "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 David Sinclair of Harvard Medical School, an author of Dr. de Cabo's report and a co-chairman of Sirtris's scientific advisory board.
"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.
The researchers' findings would be even 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 are published early next year.
Some researchers feel 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 highly 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."
Fat Mice Live Longer With Novel Drug
By Todd Neale, Senior Staff Writer, MedPage Today
Published: August 18, 2011
An investigational compound extended survival in middle-age, obese male mice that were eating a high-fat diet, but researchers warned that it was too soon to say if the drug could do the same for humans.
Three groups of mice all gained a similar amount of weight during the study, but those that ate a low dose of SRT1720 lived 4% longer and those that ate a high dose lived 18% longer than their untreated counterparts (P<0.001), Rafael de Cabo, PhD, of the National Institute on Aging's Laboratory of Experimental Gerontology in Baltimore, and colleagues, wrote online in Scientific Reports.
Even so, a separate group of mice fed a standard diet without SRT1720 lived the longest -- a median of 125 weeks versus 94, 103, and 115 weeks in mice eating a high-fat diet with no SRT1720, a low dose, and a high dose, respectively.
Among the mice fed a high-fat diet, the extension in survival with the novel compound was accompanied by a variety of beneficial genetic and physiologic effects.
"What our data show conclusively is that long-term treatment of obese mice with SRT1720 allows them to live healthier, more vigorous lives, and the noteworthy significance of these findings is that potent molecules may one day be developed at the bench and translated to clinical practice for the promotion of healthspan and lifespan in humans," de Cabo and colleagues wrote in their paper.
But in a statement, de Cabo stressed the preliminary nature of the findings.
"It is too early to know whether these findings could be replicated in other animal models, much less humans," he said. "The bottom line is that we need much more research before considering SRT1720 or related compounds as a possible treatment for diseases of aging."
Accumulating evidence shows that obesity speeds the aging process, primarily through increased inflammation, according to the researchers. But another contributor is the suppression of longevity genes.
One such gene that gets suppressed -- Sirt1 -- codes for an enzyme that has been shown to extend the lifespan of lower organisms and improve metabolism and delay the onset of age-related diseases in mammals, de Cabo and colleagues explained.
SRT1720, a synthetic compound, activates the gene, offsetting the suppressive effects of the gene that occur with obesity.
To examine the agent's effects in vivo, de Cabo and colleagues randomized 56-week-old male mice to one of four groups, each containing 108 mice. The control group was fed a standard diet without SRT1720.
The other three groups were fed a high-fat diet. One did not receive SRT1720, one received a low dose of the compound (30 mg/kg), and one received a high dose (100 mg/kg).
The addition of SRT1720 alleviated many of the harmful effects of the high-fat diet. Among the findings:
· The high dose lessened the accumulation of fat in the liver, compared with untreated mice fed a high-fat diet. Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicated damage in the mice fed a high-fat diet, but SRT1720 reduced the impact and brought AST to levels seen in mice fed a standard diet.
· The high dose improved pancreas morphology among the mice fed a high-fat diet, although it was still abnormal compared with mice fed a standard diet.
· Among the mice fed a high-fat diet, heart and kidney mass increased only in those that did not receive SRT1720.
· SRT1720 normalized gene expression patterns away from those induced by a high-fat diet, suppressing markers of inflammation and apoptosis.
· The high dose brought levels of oxygen consumption and locomotor activity closer to those observed in the mice fed a standard diet.
All of those findings occurred in the absence of any signs of toxicity, even after more than 80 weeks of treatment, according to the researchers.
The study was conducted under a Cooperative Research and Development Agreement between Sirtris, a GlaxoSmithKline Company, and the National Institute on Aging (NIA). Funding was provided by the Intramural Research Program of the NIA/NIH, the Swiss National Science Foundation, and the ERC Ideas program.
De Cabo did not report any conflicts of interest. One of his co-authors consults for Sirtris, which has a commercial interest in developing SIRT1 activators. Four of the other study authors are employed by Sirtris.
Primary source: Scientific Reports
Minor R, et al "SRT1720 improves survival and healthspan of obese mice" Scientific Reports 2011; DOI: 10.1038/srep00070.
SRT-1720 is a drug developed by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuin subtype SIRT1. It has similar activity in the body to the known SIRT1 activator resveratrol, but is 1000x more potent. In animal studies it was found to improve insulin sensitivity and lower plasma glucose levels in fat, muscle and liver tissue, and increased mitochondrial and metabolic function. A study of SRT1720 conducted by the National Institute on Aging found that the drug may extend the lifespan of obese mice by 44% . Although SRT-1720 is not currently undergoing clinical development, a related compound, SRT-2104, is currently in clinical development for metabolic diseases.
Since the discovery of SRT-1720, the claim that this compound is a SIRT1 activator has been questioned and further defended.
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