Abstract
Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair‐deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair‐deficient Ercc1 ∆/− mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair‐deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action.
Highlights
Caloric or dietary restriction (CR/Dietary restriction (DR); reduced total dietary intake without malnutrition) is the best documented intervention that compresses morbidity and extends life span (Fontana et al, 2010; Speakman & Mitchell, 2011)
To obtain a more mechanistic understanding of the large difference in effects of rapamycin treatment vs DR on survival of Ercc1∆/− mice, we examined the effect of 14 ppm rapamycin on the liver full genome transcriptome of Ercc1∆/− mice versus WT controls and compared it to simultaneously re-analyzed changes induced by DR
We found that rapamycin did not increase life span of Ercc1∆/− mice, a progeroid DNA repair deficiency mouse model that mimics numerous aspects of aging and responds well to DR (Vermeij, Dollé, et al, 2016)
Summary
Caloric or dietary restriction (CR/DR; reduced total dietary intake without malnutrition) is the best documented intervention that compresses morbidity and extends life span (Fontana et al, 2010; Speakman & Mitchell, 2011). Human DR studies have shown beneficial health effects (Kraus et al, 2019; van de Rest et al, 2016) but controlled studies on long-term consequences of DR in humans are lacking It remains to be seen how humans would react to an extended period of DR in terms of compliance and potential side effects of DR (Dirks & Leeuwenburgh, 2006; Most et al, 2017). Applying DR to these and other progeroid DNA repair mutant mice, dramatically extended life span, improved overall health and delayed numerous aspects of aging, including neurodegeneration. It reduced the endogenous DNA damage load and transcription stress, lowering one of the causal hallmarks of aging (Vermeij, Dollé, et al, 2016; Vermeij, Hoeijmakers, et al, 2016). Progeroid DNA repair mutant mice appear a well-suited model for examining potential DR mimetics like rapamycin (Ingram & Roth, 2015)
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