Molecular and cellular neurosciencesOct 5, 2026

Calorie restriction-like treatments adjust key cell signals to restore protein cleanup in the aging brain

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 6, 2026

Abstract

Caloric restriction mimetics (CRMs) activate AMPK and suppress mTORC1, potentially enhancing autophagic processes linked to neurodegeneration.

Brain aging may result from the failure of neuronal protein maintenance, leading to toxic protein buildup associated with neurodegenerative diseases.
The AMPK-mTOR-autophagy signaling pathway is crucial for regulating cellular energy and protein clearance.
CRMs, such as rapamycin, metformin, resveratrol, and spermidine, activate AMPK and inhibit mTORC1, promoting processes that enhance protein clearance.
These molecular actions could improve the removal of toxic proteins like amyloid-β, tau, and α-synuclein in preclinical models.
Challenges in clinical application include limited effectiveness in the central nervous system, variable autophagic responses, and lack of reliable biomarkers for monitoring treatment effects.

Simplified

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.

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Calorie restriction-like treatments adjust key cell signals to restore protein cleanup in the aging brain

Abstract

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