Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies
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 simu...
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MDPI AG
2025-06-01
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| author | Bogdan Cordos Amelia Tero-Vescan Ian N. Hampson Anthony W. Oliver Mark Slevin |
| author_facet | Bogdan Cordos Amelia Tero-Vescan Ian N. Hampson Anthony W. Oliver Mark Slevin |
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| description | 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. |
| format | Article |
| id | doaj-art-b3b77924a9b94997ba92e1e4d452c728 |
| institution | DOAJ |
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| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-b3b77924a9b94997ba92e1e4d452c7282025-08-20T03:16:35ZengMDPI AGPharmaceuticals1424-82472025-06-0118682910.3390/ph18060829Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic StrategiesBogdan Cordos0Amelia Tero-Vescan1Ian N. Hampson2Anthony W. Oliver3Mark Slevin4Center of Experimental and Imaging Studies, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 38th Gh. Marinescu Street, 540139 Târgu Mureş, RomaniaDepartment of Biochemistry, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 38th Gh. Marinescu Street, 540139 Târgu Mureş, RomaniaDivision of Cancer Sciences, University of Manchester, Oxford Rd, Manchester M13 9WL, UKRavan Bio Ltd., Unit 7A Kilburn House, Lloyd Street N, Manchester M15 6SE, UKCenter for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 38th Gh. Marinescu Street, 540139 Târgu Mureş, RomaniaBrain 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.https://www.mdpi.com/1424-8247/18/6/829Alzheimer’s diseaseautophagyneurodegenerationmetforminbenzimidazoleacetylsalicylic acid |
| spellingShingle | Bogdan Cordos Amelia Tero-Vescan Ian N. Hampson Anthony W. Oliver Mark Slevin Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies Pharmaceuticals Alzheimer’s disease autophagy neurodegeneration metformin benzimidazole acetylsalicylic acid |
| title | Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies |
| title_full | Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies |
| title_fullStr | Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies |
| title_full_unstemmed | Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies |
| title_short | Synergistic Autophagy-Related Mechanisms of Protection Against Brain Aging and AD: Cellular Pathways and Therapeutic Strategies |
| title_sort | synergistic autophagy related mechanisms of protection against brain aging and ad cellular pathways and therapeutic strategies |
| topic | Alzheimer’s disease autophagy neurodegeneration metformin benzimidazole acetylsalicylic acid |
| url | https://www.mdpi.com/1424-8247/18/6/829 |
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