Metformin extends C. elegans lifespan through lysosomal pathway

Abstract

Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin. Elucidating the molecular mechanism of metformin regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.

Article and author information

Author details

  1. Jie Chen

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yuhui Ou

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yi Li

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Shumei Hu

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Li-Wa Shao

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Ying Liu

    Institute of Molecular Medicine, Peking University, Beijing, China
    For correspondence
    ying.liu@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3328-026X

Funding

National Natural Science Foundation of China (31422033)

  • Ying Liu

Ministry of Science and Technology of the People's Republic of China (2013CB910104)

  • Ying Liu

National Natural Science Foundation of China (31471381)

  • Ying Liu

Young thousand Talents Program of China

  • Ying Liu

Peking-Tsinghua Center for Life Sciences

  • Ying Liu

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

Reviewing Editor

  1. Hong Zhang, Institute of Biophysics, Chinese Academy of Sciences, China

Version history

  1. Received: August 15, 2017
  2. Accepted: October 11, 2017
  3. Accepted Manuscript published: October 13, 2017 (version 1)
  4. Version of Record published: November 14, 2017 (version 2)

Copyright

© 2017, Chen 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. Jie Chen
  2. Yuhui Ou
  3. Yi Li
  4. Shumei Hu
  5. Li-Wa Shao
  6. Ying Liu
(2017)
Metformin extends C. elegans lifespan through lysosomal pathway
eLife 6:e31268.
https://doi.org/10.7554/eLife.31268

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https://doi.org/10.7554/eLife.31268

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