Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice

Abstract

Inhibition of the mTOR (mechanistic target of rapamycin) signaling pathway by the FDA-approved drug rapamycin promotes life span in numerous model organisms and delays age-related disease in mice. However, the utilization of rapamycin as a therapy for age-related diseases will likely prove challenging due to the serious metabolic and immunological side effects of rapamycin in humans. We recently identified an intermittent rapamycin treatment regimen-2mg/kg administered every 5 days-with a reduced impact on glucose homeostasis and the immune system as compared with chronic treatment; however, the ability of this regimen to extend life span has not been determined. Here, we report for the first time that an intermittent rapamycin treatment regimen starting as late as 20 months of age can extend the life span of female C57BL/6J mice. Our work demonstrates that the anti-aging potential of rapamycin is separable from many of its negative side effects and suggests that carefully designed dosing regimens may permit the safer use of rapamycin and its analogs for the treatment of age-related diseases in humans.

Keywords: Anti-aging; Life span; Mice; Rapamycin; mTOR.

Figure 1.

Intermittent administration of rapamycin extends life span. (A) Kaplan–Meier plot showing life span of C57BL/6J.Nia female mice administered rapamycin (2mg/kg) or vehicle once every 5 days (n = 20 vehicle-treated mice, 14 rapamycin-treated mice; p = .002, one-tailed log-rank test). Mean, median, and maximum (75th percentile, p = .005, one-tailed Boschloo exact test) life span are shown; this analysis excludes six rapamycin-treated mice that developed dermatitis. (B) Life span analysis excluding only three rapamycin-treated mice euthanized due to dermatitis (n = 20 vehicle-treated mice, 17 rapamycin-treated mice; p = .011, one-tailed log-rank test; 75th percentile life span p = .01, one-tailed Boschloo exact test). (C) Life span analysis inclusive of every mouse that received vehicle or rapamycin, included those euthanized because of dermatitis (n = 20 vehicle-treated mice, 20 rapamycin-treated mice; p = .035, one-tailed log-rank test; 75th percentile life span p = .02, one-tailed Boschloo exact test).

Figure 2.

Intermittent administration of rapamycin does not impair glucose or insulin tolerance. (A) Glucose and (B) insulin tolerance test on female C57BL/6J.Nia mice treated with either vehicle or rapamycin (2mg/kg) once every 5 days for 8 weeks (n = 7–10 vehicle, n = 10 rapamycin, two-tailed t test). Tests were performed 5 days after the last administration of either vehicle or rapamycin, at the conclusion of an overnight fast. Error bars represent standard error.

Figure 3.

Intermittent administration of rapamycin impacts body weight and composition. (A) Weight tracking of mice receiving vehicle or rapamycin (2mg/kg) once every 5 days (starting n = 10 vehicle-treated mice, 10 rapamycin-treated mice at 615 days of age). (B, C) Changes in weight and body composition after 5 months of intermittent administration of either vehicle or rapamycin (n = 15 vehicle-treated mice, 13 rapamycin-treated mice; p value shown for values between 0.05 and 0.1, two-tailed t test). Error bars represent standard error.

Figure 4.

Intermittent administration of rapamycin alters food consumption, spontaneous activity, and respiratory exchange ratio (RER). Metabolic chambers were used to assess (A) food consumption, (B) spontaneous activity, (C) RER, and (D) calculated energy expenditure in mice administered either vehicle or rapamycin intermittently for 5 months. (n = 15 vehicle-treated mice, 12 rapamycin-treated mice; *p < .05, p value shown for values between 0.05 and 0.1, two-tailed t test). Error bars represent standard error.