Oral rapamycin does not mimic caloric restriction in mice

Abstract

Rapamycin, an inhibitor of target of rapamycin (TOR), is the only known dietary additive that increases lifespan to the same extent as caloric restriction (CR). While mechanisms for lifespan extension remain unknown, both rapamycin and CR treatments influence signaling pathways that converge on TOR, an important regulator of growth and energy balance. We tested the hypothesis that similarities in lifespan extension of oral rapamycin and a 70% CR diet in mice would extend to physiological variables potentially important for the extension of life, including resting metabolic rate (RMR), heart rate (HR) and body temperature (Tb). C57BL/6J mice housed at 22°C were implanted with EKG telemeters, fed a control, rapamycin, or CR diet for 8 weeks, and then assessed for RMR via indirect calorimetry as well as HR and Tb via telemetry. CR mice, as compared to controls, showed dramatic reductions in minimal RMR (0.14±0.01 vs. 0.92±0.05 mL O2/min), HR (135±11 vs. 420±16 bpm) and Tb (25.7±0.2°C vs. 35.2 vs. 0.3°C). Rapamycin, however, had no significant impact on minimal RMR (0.85±0.07 mL O2/min), HR (405±17 bpm) or Tb (35.0±0.2°C) when compared to controls. These findings suggest that lifespan extension in rapamycin‐fed mice is not due to reductions in RMR, HR or Tb. Instead, it is likely that CR and rapamycin extend life though different mechanisms or that the treatments extend life via a mechanism that does not influence RMR, HR or Tb.