Fig. 1. The regulation of autophagy by SIRT1 under calorie restriction.

The level of nutrients (e.g., glucose, lipids, and amino acids) is detected by energy sensors, namely, AMPK, SIRT1, or mTOR^17,97,104. Calorie restriction activates AMPK or SIRT1 but inhibits mTOR activity. AMPK and SIRT1 upregulate the expression of Atgs through the activation of forkhead box transcription factors (FOXOs)^97,105. In addition, SIRT1 also forms a molecular complex with Atg proteins, including Atg7 and Atg8 (LC3). SIRT1 deacetylates the core autophagy machinery in nutrient restricted conditions and thereby increases autophagy. Calorie restriction also potentiates the expression of SIRT1 and increases its deacetylase activity^17,18. SIRT1 deacetylates p53¹⁸, which downregulates p53 and increases autophagy^19,20. However, another well-known negative regulator of autophagy, mTOR, is downregulated under low nutrient conditions