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

Luis E D Gimenez, Parakashtha Ghildyal, Kathleen E. Fischer, Hongxiang Hu, William W. Ja, Benjamin A Eaton, Yimin Wu, Steven N. Austad, Ravi Ranjan

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)121-129
Number of pages9
JournalAging Cell
Volume12
Issue number1
DOIs
StatePublished - Feb 2013

Fingerprint

Drosophila
Oxidative Stress
Insulin
Arrestin
Diptera
Neurosecretion
Phenotype
G-Protein-Coupled Receptors
Psychological Stress
GTP-Binding Proteins
Brain

Keywords

  • Aging
  • Drosophila
  • Endocrinology
  • Genetics
  • Insulin/IGF-1signaling
  • Longevity
  • Neuroscience
  • Signaling

ASJC Scopus subject areas

  • Cell Biology
  • Aging

Cite this

Gimenez, L. E. D., Ghildyal, P., Fischer, K. E., Hu, H., Ja, W. W., Eaton, B. A., ... Ranjan, R. (2013). Modulation of methuselah expression targeted to Drosophila insulin-producing cells extends life and enhances oxidative stress resistance. Aging Cell, 12(1), 121-129. https://doi.org/10.1111/acel.12027

Modulation of methuselah expression targeted to Drosophila insulin-producing cells extends life and enhances oxidative stress resistance. / Gimenez, Luis E D; Ghildyal, Parakashtha; Fischer, Kathleen E.; Hu, Hongxiang; Ja, William W.; Eaton, Benjamin A; Wu, Yimin; Austad, Steven N.; Ranjan, Ravi.

In: Aging Cell, Vol. 12, No. 1, 02.2013, p. 121-129.

Research output: Contribution to journalArticle

Gimenez, LED, Ghildyal, P, Fischer, KE, Hu, H, Ja, WW, Eaton, BA, Wu, Y, Austad, SN & Ranjan, R 2013, 'Modulation of methuselah expression targeted to Drosophila insulin-producing cells extends life and enhances oxidative stress resistance', Aging Cell, vol. 12, no. 1, pp. 121-129. https://doi.org/10.1111/acel.12027
Gimenez, Luis E D ; Ghildyal, Parakashtha ; Fischer, Kathleen E. ; Hu, Hongxiang ; Ja, William W. ; Eaton, Benjamin A ; Wu, Yimin ; Austad, Steven N. ; Ranjan, Ravi. / Modulation of methuselah expression targeted to Drosophila insulin-producing cells extends life and enhances oxidative stress resistance. In: Aging Cell. 2013 ; Vol. 12, No. 1. pp. 121-129.
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