Caloric restriction mimetics rewire the AMPK-mTOR-ULK1 signaling nexus to restore autophagic proteostasis in the aging brain.

Abstract

Brain aging is driven by progressive failure of neuronal proteostasis, culminating in the accumulation of toxic protein aggregates characteristic of Alzheimer's, Parkinson's, and Huntington's diseases. The AMPK-mTOR-autophagy signaling hub integrates cellular energy status with protein clearance machinery, making it a critical therapeutic node. Caloric restriction mimetics (CRMs), including rapamycin, metformin, resveratrol, and spermidine, exploit this axis by activating AMPK via AMP/ATP modulation and simultaneously suppressing mTORC1 kinase activity. This dual action relieves mTORC1-mediated inhibition of the ULK1 complex, triggering autophagosome nucleation, while sustained mTORC1 suppression promotes TFEB-driven lysosomal biogenesis, collectively restoring autophagic flux. Preclinically, these molecular events enhance clearance of amyloid-β, tau, α-synuclein, and mutant huntingtin and improve mitochondrial quality control via mitophagy. Despite robust mechanistic evidence, clinical translation remains constrained by poor CNS bioavailability, context-dependent autophagic outcomes, and the absence of validated pharmacodynamic biomarkers (e.g., LC3-II turnover, p62 flux) to confirm neuronal target engagement in humans. This review integrates CRM action on the AMPK/mTOR/autophagy axis with both the hallmarks of neuronal aging and disease-specific pathology, providing a molecular framework to guide the rational design of CNS-penetrant formulations, combination strategies, and personalized approaches to modify neurodegeneration.