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
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Mentions: Downregulation of IIS can extend life span in diverse organisms (Piper et al., 2008). Because of the many potential interactions between the TOR pathway and IIS, we investigated whether rapamycin treatment could further increase the life span of long-lived IIS mutants. Rapamycin treatment of flies heterozygous for chico1, a mutation in the gene encoding the single Drosophila IRS homolog, extended life span beyond that induced by rapamycin treatment of controls (Figure 6A). However, rapamycin treatment of chico1 homozygotes, which have more strongly reduced IIS and longer life span than heterozygotes (Figure 6A), shortened life span to levels comparable with non-rapamycin-treated controls (Figure 6A). Rapamycin treatment was biochemically effective in chico1 homozygotes, because phosphorylation of S6K was similarly downregulated by rapamycin (Figure S4). Rapamycin treatment of flies with reduced levels of Drosophila insulin-like peptides (DILPs) due to the partial ablation of the DILP-producing median neurosecretory cells (mNSC) (Broughton et al., 2005) did not further increase life span in these long-lived flies (Figure 6B). Taken together, these data suggest that, when life span by rapamycin treatment is maximized, weak downregulation of IIS, as in chico1 heterozygotes, can further extend life span, showing that IIS extends life span by mechanisms additional to those affected by rapamycin. However, stronger downregulation of IIS, which alone extends life span, can be deleterious in the presence of rapamycin, through as-yet-unidentified mechanisms.
Affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, UK.