Dietary Restriction and Glycolytic Inhibition Reduce Proteotoxicity and Extend Lifespan via NHR-49

Mechanisms mediating protective effects of dietary restriction during aging are of great interest since activating such mechanisms protect against a wide range of age-related diseases. In mammals key metabolic responses to nutritional deprivation are mediated by the transcription factor PPAR-alpha, which is activated by free fatty acids and promotes lipid metabolism while inhibiting glucose metabolism. The C. elegans gene nhr-49 appears to function similarly in C. elegans. Here we report that protective effects of dietary restriction and inhibition of glucose metabolism to increase lifespan wild-type C. elegans and reduce toxicity in a polyQ model of Huntington's disease in C. elegans are dependent on NHR-49 and its co-activator CREB-Binding Protein (CBP). We have previously demonstrated that inhibition of cbp blocks protective effects of dietary restriction and blocks the molecular switch from glucose metabolism to alternative substrates. Conversely, increased glucose concentration and inhibition of cbp reduce lifespan and increase proteotoxicity. Lactate and inhibition of ETC complex II mimicked toxic effects of glucose on proteotoxicity whereas pyruvate and inhibition of ETC complex I protected against glucose-enhanced proteotoxicity. These results support that PPAR-alpha-like activity mediates protective effects of dietary restriction by reducing glucose metabolism via reducing production of NADH, and corroborate and extend recent studies demonstrating that PPPAR-alpha agonists increase lifespan in C. elegans dependent on NHR-49.