title: Influence of steroid hormone signaling on life span control by Caenorhabditis elegans insulin-like signaling.
abstract: Sterol-sensing nuclear receptors and insulin-like growth factor signaling play evolutionarily conserved roles in the control of aging. In the nematode Caenorhabditis elegans, bile acid-like steroid hormones known as dafachronic acids (DAs) influence longevity by binding to and regulating the activity of the conserved nuclear receptor DAF-12, and the insulin receptor (InsR) ortholog DAF-2 controls life span by inhibiting the FoxO transcription factor DAF-16. How the DA/DAF-12 pathway interacts with DAF-2/InsR signaling to control life span is poorly understood. Here we specifically investigated the roles of liganded and unliganded DAF-12 in life span control in the context of reduced DAF-2/InsR signaling. In animals with reduced daf-2/InsR activity, mutations that either reduce DA biosynthesis or fully abrogate DAF-12 activity shorten life span, suggesting that liganded DAF-12 promotes longevity. In animals with reduced DAF-2/InsR activity induced by daf-2/InsR RNAi, both liganded and unliganded DAF-12 promote longevity. However, in daf-2/InsR mutants, liganded and unliganded DAF-12 act in opposition to control life span. Thus, multiple DAF-12 activities influence life span in distinct ways in contexts of reduced DAF-2/InsR signaling. Our findings establish new roles for a conserved steroid signaling pathway in life span control and elucidate interactions among DA biosynthetic pathways, DAF-12, and DAF-2/InsR signaling in aging.
authors.affiliation: Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Dumas
authors.forename: Chunfang
authors.initials: C
authors.lastname: Guo
authors.forename: Hung-Jen
authors.initials: HJ
authors.lastname: Shih
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hu
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002782:Cholestenes / Q000378:metabolism; D017238:Genes, Helminth; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D008024:Ligands; D008136:Longevity / Q000187:drug effects*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013256:Steroids / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; D006728:Hormones; D007328:Insulin; D008024:Ligands; D013256:Steroids; C533800:dafachronic acid; D011972:Receptor, Insulin
keywords: Caenorhabditis elegans; aging; insulin signaling; longevity; steroid hormones
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