Silencing lipid catabolism determines longevity in response to fasting

Oscillations between lipid anabolism and catabolism allow for long-term preservation of cellular health amid systemic metabolic fluctuations. As a conserved aging determinant, fasting can improve disease outcomes and extend lifespan. Yet, the relative importance of activating lipid catabolism versus its attenuation in fasting-induced longevity remains unclear. The robust adaptability of the soil-dwelling worms, C. elegans, to variable nutrient availability provides an excellent means to better understand how metabolic transitions alter aging trajectories. Here, we show that, rather than activation, the silencing of lipid catabolism upon nutrient replenishment is essential for lifespan extension through fasting. The fasting-responsive nuclear hormone receptor, NHR-49, is pivotal in activating lipid catabolism through ß-oxidation. Unlike traditional ligand-regulated nuclear hormone receptors, NHR-49 employs a unique regulatory mechanism that bypasses ligand binding, instead relying on cofactors to mediate its transcriptional attenuation and turnover during times of nutrient stress. Here, we identify casein kinase 1 alpha 1 (KIN-19) as a central regulator of metabolic plasticity and fasting-induced longevity, which attenuates ß-oxidation via primed phosphorylation of NHR-49. Overall, cooperative, ligand-independent silencing of this conserved nuclear hormone receptor promotes longevity associated with fasting. Overall design: RNAseq profiling of N2 C.elegans were collected at Day 1 under empty vector control RNAi or kin-19 RNAi