Sirt1, an NAD-dependent deacetylase, plays a critical role in regulating autophagy. Overexpression of Sirt1 increases basal autophagy, while its absence in mouse embryonic fibroblasts (MEFs) impairs autophagy under starvation conditions. Reintroducing wild-type Sirt1 restores autophagy, indicating its essential function. Sirt1 forms complexes with key autophagy proteins, including Atg5, Atg7, and Atg8, and directly deacetylates these proteins in an NAD-dependent manner. Sirt1 deficiency leads to increased acetylation of autophagy-related proteins in cultured cells and tissues. Sirt1 knockout mice exhibit features similar to Atg5 knockout mice, including mitochondrial dysfunction, energy homeostasis disruption, and early perinatal mortality. In utero delivery of pyruvate extends the survival of Sirt1 knockout pups, suggesting that pyruvate may mitigate the energy deficit caused by impaired autophagy. These findings highlight Sirt1 as a key regulator of autophagy and link sirtuin function to cellular responses to nutrient limitation. Sirt1's role in autophagy is further supported by its interaction with PGC-1α, a mitochondrial biogenesis regulator, and its potential to clear damaged mitochondria. Sirt1's regulation of autophagy may have therapeutic implications for age-related diseases and neurodegenerative disorders.Sirt1, an NAD-dependent deacetylase, plays a critical role in regulating autophagy. Overexpression of Sirt1 increases basal autophagy, while its absence in mouse embryonic fibroblasts (MEFs) impairs autophagy under starvation conditions. Reintroducing wild-type Sirt1 restores autophagy, indicating its essential function. Sirt1 forms complexes with key autophagy proteins, including Atg5, Atg7, and Atg8, and directly deacetylates these proteins in an NAD-dependent manner. Sirt1 deficiency leads to increased acetylation of autophagy-related proteins in cultured cells and tissues. Sirt1 knockout mice exhibit features similar to Atg5 knockout mice, including mitochondrial dysfunction, energy homeostasis disruption, and early perinatal mortality. In utero delivery of pyruvate extends the survival of Sirt1 knockout pups, suggesting that pyruvate may mitigate the energy deficit caused by impaired autophagy. These findings highlight Sirt1 as a key regulator of autophagy and link sirtuin function to cellular responses to nutrient limitation. Sirt1's role in autophagy is further supported by its interaction with PGC-1α, a mitochondrial biogenesis regulator, and its potential to clear damaged mitochondria. Sirt1's regulation of autophagy may have therapeutic implications for age-related diseases and neurodegenerative disorders.