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.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…NHR‐49 is a critical regulator of lipid metabolism and longevity (Burkewitz et al., 2015; Chamoli, Singh, Malik & Mukhopadhyay, 2014; Folick et al., 2015; Khan et al., 2013; Ratnappan et al., 2014; Seah et al., 2016), while related nuclear receptors, HNF4 and PPARα, are therapeutic targets that share at least some of these functions in mammals. Here, we show that NHR‐49 is also vital for an adaptive transcriptional response to the organic peroxide tBOOH.…”

“…Here, we report nhr‐49 ‐dependent expression of several fasting‐induced genes with pro‐survival/longevity functions that are not involved in lipid metabolism, including the glyoxylate cycle enzyme icl‐1 , the oxidoreductase sodh‐1 , and the flavin‐containing monooxygenase fmo‐2 . Consistent with these findings, nhr‐49 ‐dependent induction of predicted detoxification genes was observed in another long‐lived state (Chamoli et al., 2014). This was ascribed to NHR‐49‐driven lipid metabolic reprogramming, but our findings suggest that these genes may contribute to NHR‐49's stress‐protective function.…”

The red flour beetleTribolium castaneumallows for the convenient determination of fitness and survival as a measure of toxic effects of the food contaminant acrylamide

“…Interestingly these reactive oxygen species build the basis of the so-called mitohormesis, referring to downstream effects to ultimately induce endogenous defence mechanisms culminating in increased stress resistance and longevity (Schulz et al 2007;Ristow & Schmeisser 2011). In C. elegans ahr-1 mutants, longevity normally induced by a caloric restriction-like metabolic state was no longer visible (Chamoli et al 2014). Similar results were obtained in mutants for skn-1, the nrf-2 homologue in C. elegans, and in ABC-transporter mutants for pgp-3, suggesting that xenobiotic biotransformation gene expression is a key mediator for interventions which lead to a long and healthy life (Chamoli et al 2014).…”

“…In C. elegans ahr-1 mutants, longevity normally induced by a caloric restriction-like metabolic state was no longer visible (Chamoli et al 2014). Similar results were obtained in mutants for skn-1, the nrf-2 homologue in C. elegans, and in ABC-transporter mutants for pgp-3, suggesting that xenobiotic biotransformation gene expression is a key mediator for interventions which lead to a long and healthy life (Chamoli et al 2014).…”

“…It could be suggested that such AHR signalling is induced by a so far not identified acrylamide metabolite. Moreover, a very recent intriguing study in the nematode C. elegans revealed that a metabolic shift towards β-oxidation, as also observed under caloric restriction, increases the levels of reactive oxygen species and in turn induces the phase I and phase II detoxification genes (Chamoli et al 2014). Interestingly these reactive oxygen species build the basis of the so-called mitohormesis, referring to downstream effects to ultimately induce endogenous defence mechanisms culminating in increased stress resistance and longevity (Schulz et al 2007;Ristow & Schmeisser 2011).…”