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October 29, 2010

NIA's ITP Confirms: Resveratrol Does Not Extend Lifespan; Limited Benefit to Rapamycin

SENS (Strategies for Engineered Negligible Senescence) reserachers reviewed the results of the serendipitous late-life lifespan study of rapamycin (sirolimus/Rapamune®), an inhibitor of the mammalian Target of Rapamycin (mTOR) pathway, through the NIA's Interventions Testing Program (ITP), "a multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction in mice." This study was hailed as a breakthrough, being the first robust demonstration of lifespan extension in mammals by a pharmacological agent, although as we reviewed, the absolute effect of rapamycin was limited, and in fact not entirely clear in males.

Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. ... Rapamycin was found to lead to improved survival in both males and females when pooling across test sites, and to significant effects at each test site considered separately. ... For males, rapamycin led to an increase of 10% in median age, averaged across the three sites, and an increase of 16% in the 90th percentile age [ie, by operational definition, maximum lifespan -MR]. For females, the corresponding values were 18% for median, and 13% for 90th percentile ages. ... Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice.

SENS researchers reviewed a long list of putative CR (Calorie restriction) mimetics that have failed in lifespan studies. Amongst these was the phytoalexin polyphenol resveratrol, famously found in trace amounts in wine and widely anticipated to be one of the first effective life-extending, youth-preserving compound, but found ineffective in testing in nonobese, longevous mice



These studies may reveal, even the most optimistic reading of these results and an assumption of perfect human translatability is still overshadowed by how limited the results are. Interventions such as rapamycin, which only retard the rate at which aging damage accumulates (or, perhaps, allows the organism to carry on functioning for a longer period of time under its accumulating burden), can only temporarily delay the onset of age-related ill-health, not arrest or reverse it -- and in the case of rapamycin, the first pharmacological agent to extend the lives of otherwise-healthy mammals, its ability to do even this has been found to be limited. Rejuvenation biotechnology offers an alternative approach, and the promise of a life of greatly-extended youthful functionality.

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