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

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.