Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):E2501-9. doi: 10.1073/pnas.1321776111. Epub 2014 Jun 2.


The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Dehydrogenase / metabolism
  • Amino Acids, Branched-Chain / chemistry
  • Animals
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / physiology*
  • Gene Expression Regulation
  • Green Fluorescent Proteins / chemistry
  • Hormesis / drug effects*
  • Hot Temperature
  • Hydrogen Peroxide / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Longevity / drug effects*
  • Metformin / pharmacology*
  • Mitochondria / enzymology
  • Models, Animal
  • Oxidative Stress
  • Oxygen Consumption
  • Peroxiredoxins / physiology*
  • Protein Unfolding
  • Proteomics
  • Reactive Oxygen Species
  • Rotenone / chemistry
  • Signal Transduction
  • Time Factors


  • Amino Acids, Branched-Chain
  • Caenorhabditis elegans Proteins
  • Hypoglycemic Agents
  • Reactive Oxygen Species
  • Rotenone
  • Green Fluorescent Proteins
  • Metformin
  • Hydrogen Peroxide
  • PRDX-2 protein, C elegans
  • Peroxiredoxins
  • Acyl-CoA Dehydrogenase