Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

Abstract

The antitumour drug rapamycin targets TOR, a kinase that is part of the PI3K–AKT–mTOR cascade, involved in regulating protein translation, cell growth and autophagy. Reducing TOR function is known to extend the life of yeast, worms and flies. Now experiments replicated in three different laboratories demonstrate that rapamycin, fed to male and female mice in a dose that substantially inhibits TOR signalling, can extend their median and maximal lifespan by up to 14%. This life extension was observed in mice fed rapamycin from 270 days of age and also at a late stage in their life, from age 600 days. These findings point to the TOR pathway as a critical point in the control of ageing in mammals and in the pathogenesis of late-life illnesses. Although inhibition of the TOR signalling pathway extends lifespan in invertebrates, it was unknown whether mTOR signalling inhibition has similar effects in mammalian species. Here, feeding mice the drug rapamycin — an inhibitor of the mTOR pathway — late in life is shown to extend lifespan by 9–14%; currently, the only way to extend lifespan in rodents is by severe dietary restriction. Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies1,2,3,4,5; 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.