Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.
Bottom Line: Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat.Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation.Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms.
Affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, UK.Show MeSH
Mentions: We measured phosphorylation of S6K, a well-described downstream target of TORC1, as an indicator of rapamycin efficacy, by western blot analysis using a phospho-Thr398-dependent S6K antibody. We observed a significant dose-dependent reduction in phospho-T398-S6K levels after rapamycin treatment for 1–3 days, confirming that rapamycin reduced TOR signaling in vivo (Figure 1A). To determine bioavailability of rapamycin throughout the fly, we measured S6K phosphorylation in different regions of the fly body. Phospho-T398-S6K levels were decreased to similar levels in heads, thoraces, and abdomens (Figure 1B), suggesting that TOR signaling is ubiquitously downregulated in adult flies upon rapamycin treatment.
Affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, UK.