SIRT1 Is Downregulated by Autophagy in Senescence and Ageing

Abstract

SIRT1 is an NAD+-dependent deacetylase that plays critical roles in a broad range of biological events, including metabolism, immune response, and aging. While there is strong interest in stimulating SIRT1 catalytic activity, the homeostasis of SIRT1 at the protein level is poorly understood. Here, we report that macroautophagy (hereafter referred as autophagy), a catabolic membrane trafficking pathway that degrades cellular components through autophagosomes and lysosomes, mediates downregulation of mammalian SIRT1 protein during senescence and in vivo aging. In senescence, nuclear SIRT1 is recognized as an autophagy substrate and is subjected to cytoplasmic autophagosome-lysosome degradation, via the autophagy protein LC3. Importantly, the autophagy-lysosome pathway contributes to loss of SIRT1 during aging of several tissues related to the immune and hematopoietic system, including spleen, thymus, hematopoietic stem and progenitor cells from aged mice, and CD8+CD28- T cells from aged human donors. Our study reveals a mechanism in regulating the protein homeostasis of SIRT1, and suggests a potential strategy to stabilize SIRT1 to promote productive aging.