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Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis
Seungyeon Yang1,2,3 (Graduate student), Subin Moon1,2,3 (Graduate student), Soojung Claire Hur4 (Professor), Seung Min Jeong 1,2,3,* (Professor)
1Department of Biochemistry and 2Institute for Aging and Metabolic Diseases and 3Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea,
4Department of Mechanical Engineering, Johns Hopkins University
Senescence, a cellular process through which damaged or dysfunctional cells suppress their cell cycle, contributes to aging or age-related functional declines. Cell metabolism has been closely correlated with aging processes and it is widely recognized that metabolic changes underlie cellular alterations with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We find that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, the increased formation of autophagosome following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we find that the inhibition of autophagy or the enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence.
Abstract, Accepted Manuscript(in press) [Submitted on May 13, 2023, Accepted on September 7, 2023]
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