Metformin extends C. elegans lifespan through lysosomal pathway

Elife. 2017 Oct 13;6:e31268. doi: 10.7554/eLife.31268.

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.

Keywords: AMPK; C. elegans; cell biology; mTOR; metformin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / physiology*
  • Hypoglycemic Agents / metabolism*
  • Longevity / drug effects
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Metformin / metabolism*

Substances

  • Hypoglycemic Agents
  • Metformin
  • Mechanistic Target of Rapamycin Complex 1
  • AMP-Activated Protein Kinases

Grant support

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