Modulation of Methuselah Expression Targeted to Drosophila Insulin-producing Cells Extends Life and Enhances Oxidative Stress Resistance.
Authors: Gimenez LE; Ghildyal P; Fischer KE; Hu H; Ja WW; Eaton BA; Wu Y; Austad SN; Ranjan R Year: 2012 Journal: Aging cell Abstract: Ubiquitously reduced signaling via Methuselah (MTH), a G-protein coupled receptor (GPCR) required for neurosecretion, has previously been reported to extend life and enhance stress resistance in flies. Whether these effects are due to reduced MTH signaling only in specific tissue(s) and through with signaling effects reduced MTH might produce these phenotypes remains unknown. We determined that reduced expression of mth targeted only to the insulin-producing cells (IPCs) of the fly brain was sufficient to extend life and enhance oxidative stress resistance. Paradoxically, we discovered that overexpression of mth targeted to the same cells has similar phenotypic effects to reduced expression due to MTH's interaction with beta-arrestin, which uncouples GPCRs from their G-proteins. We confirmed the functional relationship between MTH and beta-arrestin by finding that IPC-targeted overexpression of beta-arrestin alone mimics the longevity phenotype of reduced MTH signaling. As reduced MTH signaling also inhibits insulin secretion from the IPCs, the most parsimonious mechanistic explanation for its longevity and stress resistance enhancement might be through reduced insulin/IGF signaling (IIS). However, examination of phenotypic features of long-lived IPC-mth modulated flies as well as several downstream IIS targets implicates enhanced activity of the JNK stress resistance pathway more directly than insulin signaling in the longevity and stress resistance phenotypes. (c)2012 The Authors Aging Cell (c) 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland. Reference
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