Lonidamine extends lifespan of adult Caenorhabditis elegans by increasing the formation of mitochondrial reactive oxygen species

Horm Metab Res. 2011 Sep;43(10):687-92. doi: 10.1055/s-0031-1286308. Epub 2011 Sep 19.

Abstract

Compounds that delay aging in model organisms may be of significant interest to antiaging medicine, since these substances potentially provide pharmaceutical approaches to promote healthy lifespan in humans. The aim of the study was to test whether pharmaceutical concentrations of the glycolytic inhibitor lonidamine are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. Several hundreds of adult C. elegans roundworms were maintained on agar plates and fed E. coli strain OP50 bacteria. Lonidamine was applied to test whether it may promote longevity by quantifying survival in the presence and absence of the compound. In addition, several biochemical and metabolic assays were performed with nematodes exposed to lonidamine. Lonidamine significantly extends both median and maximum lifespan of C. elegans when applied at a concentration of 5 micromolar by 8% each. Moreover, the compound increases paraquat stress resistance, and promotes mitochondrial respiration, culminating in increased formation of reactive oxygen species (ROS). Extension of lifespan requires activation of pmk-1, an orthologue of p38 MAP kinase, and is abolished by co-application of an antioxidant, indicating that increased ROS formation is required for the extension of lifespan by lonidamine. Consistent with the concept of mitohormesis, lonidamine is capable of promoting longevity in a pmk-1 sensitive manner by increasing formation of ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / metabolism
  • Cell Respiration / drug effects
  • Enzyme Activation / drug effects
  • Hep G2 Cells
  • Humans
  • Indazoles / pharmacology*
  • Longevity / drug effects*
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Oxygen Consumption / drug effects
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects
  • Stress, Physiological / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Indazoles
  • Reactive Oxygen Species
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinases
  • Pmk-1 protein, C elegans
  • p38 Mitogen-Activated Protein Kinases
  • lonidamine