title: Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2.
abstract: 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.
authors.affiliation: Laboratory for Functional Genomics and Proteomics and.
authors.forename: Wouter
authors.initials: W
authors.lastname: De Haes
authors.affiliation: Laboratory for Functional Genomics and Proteomics and.
authors.forename: Lotte
authors.initials: L
authors.lastname: Frooninckx
authors.affiliation: Laboratory for Functional Genomics and Proteomics and.
authors.forename: Roel
authors.initials: R
authors.lastname: Van Assche
authors.affiliation: Laboratory for Aging Physiology and Molecular Evolution, Department of Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Arne
authors.initials: A
authors.lastname: Smolders
authors.affiliation: Laboratory for Functional Genomics and Proteomics and.
authors.forename: Geert
authors.initials: G
authors.lastname: Depuydt
authors.affiliation: Laboratory of Socioecology and Social Evolution, Department of Biology, KU Leuven, 3000 Leuven, Belgium; and.
authors.forename: Johan
authors.initials: J
authors.lastname: Billen
authors.affiliation: Laboratory for Aging Physiology and Molecular Evolution, Department of Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Braeckman
authors.affiliation: Laboratory for Functional Genomics and Proteomics and Liliane.Schoofs@bio.kuleuven.be.
authors.forename: Liliane
authors.initials: L
authors.lastname: Schoofs
authors.affiliation: Laboratory for Functional Genomics and Proteomics and.
authors.forename: Liesbet
authors.initials: L
authors.lastname: Temmerman
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000737:chemistry; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000737:chemistry; D059165:Hormesis / Q000187:drug effects*; D006358:Hot Temperature; D006861:Hydrogen Peroxide / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology; D023421:Models, Animal; D018384:Oxidative Stress; D010101:Oxygen Consumption; D054464:Peroxiredoxins / Q000502:physiology*; D058767:Protein Unfolding; D040901:Proteomics; D017382:Reactive Oxygen Species; D012402:Rotenone / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000597:Amino Acids, Branched-Chain; D029742:Caenorhabditis elegans Proteins; D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; D012402:Rotenone; D049452:Green Fluorescent Proteins; D008687:Metformin; D006861:Hydrogen Peroxide; C534226:PRDX-2 protein, C elegans; D054464:Peroxiredoxins; D042964:Acyl-CoA Dehydrogenase