Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis
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Senescence, a cellular process through which damaged or dysfunctionalcells suppress the cell cycle, contributes to aging orage-related functional decline. Cell metabolism has been closelycorrelated with aging processes, and it has been widely recognizedthat metabolic changes underlie the cellular alterationsthat occur with aging. Here, we report that fatty acidoxidation (FAO) serves as a critical regulator of cellular senescenceand uncover the underlying mechanism by which FAOinhibition induces senescence. Pharmacological or genetic ablationof FAO results in a p53-dependent induction of cellularsenescence in human fibroblasts, whereas enhancing FAO suppressesreplicative senescence. We found that FAO inhibitionpromotes cellular senescence through acetyl-CoA, independentof energy depletion. Mechanistically, increased formation ofautophagosomes following FAO inhibition leads to a reductionin SIRT1 protein levels, thereby contributing to senescence induction. Finally, we found that inhibition of autophagy or enforcedexpression of SIRT1 can rescue the induction of senescenceas a result of FAO inhibition. Collectively, our study revealsa distinctive role for the FAO-autophagy-SIRT1 axis in theregulation of cellular senescence.
Abstract
Senescence, a cellular process through which damaged or dysfunctionalcells suppress the cell cycle, contributes to aging orage-related functional decline. Cell metabolism has been closelycorrelated with aging processes, and it has been widely recognizedthat metabolic changes underlie the cellular alterationsthat occur with aging. Here, we report that fatty acidoxidation (FAO) serves as a critical regulator of cellular senescenceand uncover the underlying mechanism by which FAOinhibition induces senescence. Pharmacological or genetic ablationof FAO results in a p53-dependent induction of cellularsenescence in human fibroblasts, whereas enhancing FAO suppressesreplicative senescence. We found that FAO inhibitionpromotes cellular senescence through acetyl-CoA, independentof energy depletion. Mechanistically, increased formation ofautophagosomes following FAO inhibition leads to a reductionin SIRT1 protein levels, thereby contributing to senescence induction. Finally, we found that inhibition of autophagy or enforcedexpression of SIRT1 can rescue the induction of senescenceas a result of FAO inhibition. Collectively, our study revealsa distinctive role for the FAO-autophagy-SIRT1 axis in theregulation of cellular senescence.
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