• Open Access

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

Authors

  • Luis E. D. Gimenez,

    1. Department of Pharmacology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
    Current affiliation:
    1. Current address, Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
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    • These authors contributed equally.
  • Parakashtha Ghildyal,

    1. Department of Pharmacology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
    Current affiliation:
    1. Department of Anatomy, University of Oslo, Oslo, Norway
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  • Kathleen E. Fischer,

    1. Department of Physiology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
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  • Hongxiang Hu,

    1. Department of Pharmacology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
    Current affiliation:
    1. Department of Integrative Biology & Pharmacology, University of Texas Health Science Center Houston, Houston, TX, USA
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  • William W. Ja,

    1. Department of Metabolism & Aging, The Scripps Research Institute, Jupiter, FL, USA
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  • Benjamin A. Eaton,

    1. Department of Physiology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
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  • Yimin Wu,

    1. Department of Physiology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
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  • Steven N. Austad,

    1. Department of Cellular & Structural Biology and Department of Molecular Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
    2. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
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  • Ravi Ranjan

    Corresponding author
    1. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
    • Department of Pharmacology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
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    • These authors contributed equally.

Correspondence

Ravi Ranjan, Department of Pharmacology, University of Texas Health Science Center San Antonio, San Antonio, TX 78245, USA. Tel.: 210-562-5093; fax: 210-380-2637; e-mail: ranjan@uthscsa.edu

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 (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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