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<p>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 <i>C. elegans</i> 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.</p>

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Silencing lipid catabolism determines longevity in response to fasting

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月22日

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  • 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

摘要

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.