Three Aging Mechanisms Fuel Neurodegeneration Together — A Unified Framework

Chronic neuroinflammation underlies virtually every major neurodegenerative disease, yet why it persists for years — even decades — has remained poorly explained. Current treatments largely target individual molecular pathways, with limited success. This review proposes a new explanatory framework that may reshape how researchers and clinicians think about brain aging and disease.

The authors synthesize evidence for what they term the 'Autophagy-Senescence-Inflammasome (ASI) axis' — a triad of interconnected biological processes that together create a self-sustaining cycle of neuroinflammation. Autophagy is the cell's housekeeping system, clearing damaged proteins and organelles. When it fails, dysfunctional mitochondria accumulate, generating oxidative stress and danger signals. These signals activate the NLRP3 inflammasome, an immune complex that triggers potent inflammatory responses.

Simultaneously, brain immune cells — astrocytes and microglia — enter a state called cellular senescence, where they stop dividing but release a damaging cocktail of inflammatory molecules known as the senescence-associated secretory phenotype (SASP). SASP amplifies inflammasome activation, while inflammasome activity further suppresses autophagy, closing a vicious loop. Mitochondrial dysfunction sits at the mechanistic center of all three processes.

The review maps this axis across six conditions: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain — demonstrating the framework's broad relevance. The authors critically evaluate existing therapeutic strategies targeting each pathway individually, noting their limited efficacy, and argue that multi-target interventions addressing the ASI axis simultaneously represent the most promising path forward.

Caveats include that this is a theoretical synthesis based on existing literature rather than new experimental data. The ASI axis as an integrated concept has not yet been directly tested in a clinical or preclinical model. Nonetheless, this framework offers a compelling organizational lens for understanding neuroinflammaging and may guide future combination therapy development.