A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans

Aging Cell. 2014 Aug;13(4):641-55. doi: 10.1111/acel.12218. Epub 2014 Mar 21.


Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading to lower food intake or by feeding diluted bacterial food to the worms. In this study, we show that knocking down a mammalian MEKK3-like kinase gene, mekk-3 in C. elegans, initiates a process similar to DR without compromising food intake. This DR-like state results in upregulation of beta-oxidation genes through the nuclear hormone receptor NHR-49, a HNF-4 homolog, resulting in depletion of stored fat. This metabolic shift leads to low levels of reactive oxygen species (ROS), potent oxidizing agents that damage macromolecules. Increased beta-oxidation, in turn, induces the phase I and II xenobiotic detoxification genes, through PHA-4/FOXA, NHR-8 and aryl hydrocarbon receptor AHR-1, possibly to purge lipophilic endotoxins generated during fatty acid catabolism. The coupling of a metabolic shift with endotoxin detoxification results in extreme longevity following mekk-3 knock-down. Thus, MEKK-3 may function as an important nutrient sensor and signalling component within the organism that controls metabolism. Knocking down mekk-3 may signal an imminent nutrient crisis that results in initiation of a DR-like state, even when food is plentiful.

Keywords: Caenorhabditis elegans; beta-oxidation; dietary restriction; fat storage; lifespan; xenobiotic detoxification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biotransformation
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Caloric Restriction*
  • Conserved Sequence
  • Electron Transport Complex II / metabolism
  • Fatty Acids / metabolism
  • Gene Knockdown Techniques
  • Inactivation, Metabolic / genetics
  • Insulin / metabolism
  • Longevity / physiology*
  • Muscles / enzymology
  • Oligonucleotide Array Sequence Analysis
  • Oxidation-Reduction
  • Protein Serine-Threonine Kinases / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Subcutaneous Tissue / enzymology
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation
  • Xenobiotics / metabolism


  • Caenorhabditis elegans Proteins
  • Fatty Acids
  • Insulin
  • Reactive Oxygen Species
  • Transcription Factors
  • Transforming Growth Factor beta
  • Xenobiotics
  • Electron Transport Complex II
  • Protein Serine-Threonine Kinases
  • drl-1 protein, C elegans