Abstract
Mutations of the insulin/IGF signaling (IIS) pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1). Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP) is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP). Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP.
Highlights
Mutations of the insulin/IGF-signaling (IIS) pathway in Drosophila and C. elegans slow aging when measured by adult survival and by the decline of age-associated traits [1,2,3,4,5,6,7]
Genetic epistasis studies in worm and fly have examined whether the FOXO transcription factor is required for reduced IIS signaling to extend lifespan
Neither chico genotype decreases the phosphorylation of 4E binding protein (4E-BP). This observation contrasts with results for how insulin/IGF signaling impacts target of rapamycin (TOR) in cell culture [19,46] but not with in vivo analyses of Drosophila somatic tissue of chico homozygotes [45,47,48,49]
Summary
Mutations of the insulin/IGF-signaling (IIS) pathway in Drosophila and C. elegans slow aging when measured by adult survival and by the decline of age-associated traits [1,2,3,4,5,6,7]. Slow Aging through IRS Requires 4E-BP signaling through phosphatidylinositol-3-OH kinase PI(3)K which regulates effector pathways including PKB/ AKT, Tsc, PRAS40 and GSK [11,12,13]. Genetic epistasis studies in worm and fly have examined whether the FOXO transcription factor is required for reduced IIS signaling to extend lifespan. In C. elegans, longevity assurance conferred by mutations of daf-2, the Insulin/IGF receptor ortholog, requires FOXO encoding daf-16 to extend lifespan [3,14,15]. Null mutations of dfoxo in Drosophila only partially restore lifespan of IIS mutants toward wildtype. These observations suggest that IIS potentially signals through additional, unexplored factors to control aging
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