Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

Abstract

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.

Figures

Figure 1

Survival plots for male (left) and female (right) mice, comparing control mice to those fed rapamycin in the diet starting at 600 days of age, pooling across the three test sites. P-values were calculated by the log-rank test. 4% of the control mice, and 3% of rapamycin-assigned mice were removed from the experiment for technical reasons. Only 5 animals (3 controls, 2 rapamycin) were removed after the start of rapamycin treatment at 600 days. Thus there were no significant differences between groups in censoring.

Figure 2

Survival of control and rapamycin-treated mice for males (top) and females (bottom) for each of the three test sites separately. P-values represent results of log-rank calculations. Vertical lines at age 600 days indicate the age at which the mice were first exposed to rapamycin.

Figure 3

A. Survival plots for male (left) and female (right) mice, comparing control mice to rapamycin-treated mice of a separate (“Cohort 2006”) population, in which mice were treated with rapamycin from 270 days of age. Because at the time of the interim analysis all live mice were between 800 and 995 days of age, we have only limited information about the shape of the survival curve at ages above 900 days, and the apparent change in slope at the oldest ages (> 990 days) reflects this experimental uncertainty. P-values calculated by the log-rank test. B. Effects of dietary rapamycin on an mTORC1 effector in the visceral fat pads from 750- to 880-day-old male and female mice. Ribosomal subunit protein S6 (rpS6) and its phosphorylation status (P-rpS6 - double arrow) were immunoassayed in tissue lysates prepared from mice consuming microencapsulated rapamycin-containing (Rapa) or control diets. Antibodies used are shown to the left. The ratio of intensity values for P-rpS6: rpS6 are shown in the graphs for females and males. Pan-actin was also immunoassayed in the blots to provide an indication of protein loading for each lane. C. Whole blood rapamycin content in 750- to 880-day-old male and female mice.