Abstract
Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.
Highlights
Reduced insulin/IGF-1 signaling increases the lifespan of nematodes, flies and rodents [1,2]
We show that down-regulation of Activin signaling in muscle, but not in adipose tissue, leads to extended lifespan
The muscle specific benefits of activated dFOXO are mediated through the control of autophagy by Smox, which we find to bind and transcriptionally repress Autophagy-specific gene 8a (Atg8a)/LC3, a reported longevity assurance gene of Drosophila [28]
Summary
Reduced insulin/IGF-1 signaling increases the lifespan of nematodes, flies and rodents [1,2]. It is reported that mice with mutation at the IGF-1 receptor (Igf1r) extend lifespan [7], as do mutants of the insulin receptor substrate (Irs2) [8] and of the insulin receptor within adipose tissues [9]. Reduced insulin results in FOXO nuclear translocation, which promotes or represses the transcription of FOXO target genes [11] (Figure S1A). In C. elegans lifespan extension of daf-2 and age-1(PI3 kinase) mutants requires daf-16, a FOXO homolog in worms [3]. Recent work likewise shows that FOXO is required for insulin-mediated lifespan extension in Drosophila [13,14]. Insulin signaling through its control of FOXO is a potentially conserved system to regulate aging but despite this emerging consensus, the proximal targets of insulin/FOXO signaling that orchestrate these mechanisms of longevity assurance are essentially unknown
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