Open AccessModulation of methuselah expression targeted to D rosophila insulin‐producing cells extends life and enhances oxidative stress resistance
Author(s) -
Gimenez Luis E. D.,
Ghildyal Parakashtha,
Fischer Kathleen E.,
Hu Hongxiang,
Ja William W.,
Eaton Benjamin A.,
Wu Yimin,
Austad Steven N.,
Ranjan Ravi
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12027
Subject(s) - biology , longevity , phenotype , microbiology and biotechnology , insulin receptor , insulin resistance , oxidative stress , g protein coupled receptor , signal transduction , receptor , insulin , gene , genetics , endocrinology
Summary 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 signalling in specific tissues remains unknown. We determined that reduced expression of mth targeted to the insulin‐producing cells ( IPC s) 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 β‐arrestin, which uncouples GPCR s from their G‐proteins. We confirmed the functional relationship between MTH and β‐arrestin by finding that IPC ‐targeted overexpression of β‐arrestin alone mimics the longevity phenotype of reduced MTH signaling. As reduced MTH signaling also inhibits insulin secretion from the IPC s, the most parsimonious mechanistic explanation of 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.