Work

Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies

Year: 2025

Type: review

Abstract: Brain aging is driven by interconnected processes, including impaired autophagy, chronic inflammation, mitochondrial dysfunction, and cellular senescence, all of which contribute to neurovascular decline and neurodegenerative diseases such as Alzheimer's disease (AD). Targeting these mechanisms simultaneously offers a promising therapeutic approach. This review explores the rationale for combining metformin, benzimidazole derivatives, phosphodiesterase-5 (PDE5), and acetylsalicylic acid (ASA) as a multi-targeted strategy to restore proteostasis, reduce senescence-associated secretory phenotype (SASP) factors, and enhance mitochondrial and lysosomal function. Metformin activates AMP-activated protein kinase (AMPK) and promotes autophagy initiation and chaperone-mediated autophagy, whilst benzimidazole derivatives enhance lysosomal fusion through JIP4-TRPML1 pathways independently of mTOR signaling; and ASA augments autophagic flux while suppressing NF-κB-driven inflammation and promoting specialized pro-resolving mediator pathways. This combinatorial approach targets both upstream autophagy initiation and downstream autophagosome-lysosome fusion, while concurrently attenuating inflammation and cellular senescence. Patient stratification based on the biomarkers of autophagy impairment, inflammation, and metabolic dysfunction could optimize therapeutic responses. While this strategy shows strong preclinical promise, careful attention to timing, dosing, and cell-specific responses is crucial to maximize benefits and avoid adverse effects. Future studies integrating biomarker-guided precision medicine frameworks are essential to validate the potential of this therapeutic combination in preventing or slowing cognitive decline and promoting healthy brain aging.

Source: Pharmaceuticals

DOI: 10.3390/ph18060829

Authors: Bogdan Cordos, Amelia Tero-Vescan, Ian N. Hampson, Anthony W. Oliver, Mark Slevin

Institutions: Universitatea de Medicină, Farmacie, Științe și Tehnologie „George Emil Palade” din Târgu Mureș, University of Manchester

Language: English

Topic: Autophagy in Disease and Therapy

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499