title: Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP.
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.
authors.affiliation: Department of Ecology and Evolutionary Biology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Ecology and Evolutionary Biology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Post
authors.affiliation: Department of Ecology and Evolutionary Biology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Kang
authors.affiliation: Department of Ecology and Evolutionary Biology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Tatar
mesh_terms: D000818:Animals; D049628:Body Size / Q000187:drug effects; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005838:Genotype; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009154:Mutation / Q000235:genetics; D010063:Ovum / Q000187:drug effects / Q000378:metabolism; D010269:Paraquat / Q000633:toxicity; D010448:Peptide Initiation Factors / Q000378:metabolism*; D016016:Proportional Hazards Models; D012098:Reproduction / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D029721:Drosophila Proteins; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; C410006:Thor protein, Drosophila; C120233:chico protein, Drosophila; D010269:Paraquat