July 08, 2009

Rapamycin, an immunosuppressant, Enables Elderly Mice to live 9-13% Longer

P values were calculated by the log-rank test. Four per cent of the control mice and three per cent of rapamycin-assigned mice were removed from the experiment for technical reasons. Only five animals (three controls, two rapamycin) were removed after the start of rapamycin treatment at 600 days. Thus, there were no significant differences between groups in censoring.

MIT Technology Review reports of the first drug proven to extend the life of mammals.

Prior to this research, the only ways to increase rodents' life span were via genetic engineering or caloric restriction--a nutritionally complete but very low-calorie diet.

Rapamycin is an antifungal compound already approved by the FDA as an immunosuppressive therapy to help prevent organ rejection in transplant patients. It is currently being tested in clinical trials for potential anticancer effects.

researchers found that rapamycin given to mice as a food supplement starting at 20 months of age--the equivalent of 60 years in humans--extended average life span by 9 percent in males and 13 percent in females. "It's particularly exciting because it works so late in life to extend life span," says Sinclair. "The fact that you can give a drug after 20 months of age in a mouse and still see a life-span extension is striking."

The results were pooled from three independent studies--at Jackson Laboratory, in Bar Harbor, ME; the University of Texas Health Science Center, in San Antonio; and the University of Michigan, in Ann Arbor--and coordinated by the National Institute of Aging's Interventions Testing Program (ITP). Rapamycin is the first success story to emerge from the ITP, which systematically evaluates anti-aging drug candidates for effectiveness in mice.

The Journal nature has the original research.

Abstract: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

A 10 page pdf with supplemental information

The authors caution that it's still not clear whether rapamycin will have similar life-span-enhancing effects in humans, and that because of its known toxicities, such as fungal infections and pneumonia, the drug should not be taken by the general population as a kind of universal fountain of youth.

A more realistic goal, says Kaeberlein, is to investigate whether it can treat specific age-related disorders--as in the several ongoing cancer trials, for example. Studies have also suggested that interfering with the TOR signaling pathway could slow the progression of Huntington's disease, Alzheimer's disease, and diabetes. "Realistically," says Kaeberlein, "I think what most of us are hoping for, and are somewhat optimistic about, is the idea that you may be able to get an extra decade--possibly an extra two decades--of relatively good health."

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