Nat Commun. 2026 Jan 22.
Lexus Tatge,
Juhee Kim,
Rene Solano Fonseca,
Kyle Feola,
Jordan M Wall,
Gupse Otuzoglu,
Ann C Johnson,
Kielen R Zuurbier,
Jaeyoung Oh,
Shaghayegh T Beheshti,
Victor A Lopez,
Anthony J Daley,
Emma G Werner,
Patrick Metang,
Sonja L B Arneaud,
Abigail Watterson,
Jeffrey G McDonald,
Vincent S Tagliabracci,
Michael E French,
Peter M Douglas.
Oscillations between lipid anabolism and catabolism are essential for maintaining cellular health during metabolic fluctuations. Fasting, a conserved determinant of aging, improves disease outcomes and extends lifespan, yet the relative contributions of lipid catabolism versus its attenuation to fasting-induced longevity remain unresolved. The metabolic flexibility of C. elegans under variable nutrient availability provides a powerful system to address this question. We show that lifespan extension from fasting depends not on sustained activation of lipid catabolism, but on its silencing upon nutrient replenishment. The fasting-responsive nuclear hormone receptor NHR-49 activates β-oxidation; however, unlike classical ligand-regulated receptors, NHR-49 is regulated through ligand-independent mechanisms involving cofactor-mediated transcriptional attenuation and protein turnover. We identify casein kinase 1 alpha 1 (KIN-19) as a key regulator of metabolic plasticity and fasting-induced longevity that silences β-oxidation via primed phosphorylation of NHR-49. Thus, cooperative ligand-independent silencing of this conserved nuclear hormone receptor promotes fasting-associated longevity.