title: A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans.
abstract: 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.
authors.affiliation: Molecular Aging Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 10067, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Chamoli
authors.forename: Anupama
authors.initials: A
authors.lastname: Singh
authors.forename: Yasir
authors.initials: Y
authors.lastname: Malik
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D001711:Biotransformation; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D031204:Caloric Restriction; D017124:Conserved Sequence; D042963:Electron Transport Complex II / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008658:Inactivation, Metabolic / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D009132:Muscles / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D040521:Subcutaneous Tissue / Q000201:enzymology; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D005227:Fatty Acids; D007328:Insulin; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015262:Xenobiotics; D042963:Electron Transport Complex II; D017346:Protein Serine-Threonine Kinases; C000596170:drl-1 protein, C elegans
keywords: Caenorhabditis elegans; beta-oxidation; dietary restriction; fat storage; lifespan; xenobiotic detoxification