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Modulation of methuselah expression targeted to Drosophila insulin-producing cells extends life and enhances oxidative stress resistance.

Authors
  • Gimenez, Luis E D
  • Ghildyal, Parakashtha
  • Fischer, Kathleen E
  • Hu, Hongxiang
  • Ja, William W
  • Eaton, Benjamin A
  • Wu, Yimin
  • Austad, Steven N
  • Ranjan, Ravi
Type
Published Article
Journal
Aging cell
Publication Date
Feb 01, 2013
Volume
12
Issue
1
Pages
121–129
Identifiers
DOI: 10.1111/acel.12027
PMID: 23121290
Source
Medline
License
Unknown

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 signalling in specific tissues remains unknown. We determined that reduced expression of mth targeted 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 β-arrestin, which uncouples GPCRs 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 IPCs, 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.

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