Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

Abstract

Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding raga-1 (RagA) or rsks-1 (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of raga-1 mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.

Data availability

Sequencing data have been deposited in GEO under accession code GSE132794

The following data sets were generated

Article and author information

Author details

  1. Yue Zhang

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anne Lanjuin

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Suvagata Roy Chowdhury

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Meeta Mistry

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Carlos G Silva-García

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Heather J Weir

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Chia-Lin Lee

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Caroline C Escoubas

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Emina Tabakovic

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. William Mair

    Department of Genetics and Complex Diseases, Harvard T H Chan School of Public Health, Boston, United States
    For correspondence
    wmair@hsph.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0661-1342

Funding

National Institute for Aging (1R01AG044346)

  • William Mair

National Institute for Aging (1R01AG059595)

  • William Mair

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Matt Kaeberlein, University of Washington, United States

Version history

  1. Received: June 7, 2019
  2. Accepted: August 11, 2019
  3. Accepted Manuscript published: August 14, 2019 (version 1)
  4. Version of Record published: August 28, 2019 (version 2)

Copyright

© 2019, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yue Zhang
  2. Anne Lanjuin
  3. Suvagata Roy Chowdhury
  4. Meeta Mistry
  5. Carlos G Silva-García
  6. Heather J Weir
  7. Chia-Lin Lee
  8. Caroline C Escoubas
  9. Emina Tabakovic
  10. William Mair
(2019)
Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans
eLife 8:e49158.
https://doi.org/10.7554/eLife.49158

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https://doi.org/10.7554/eLife.49158

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