This review synthesizes evidence that immunosenescence and chronic inflammaging drive neurodegeneration by disrupting microglial and astrocyte homeostasis, mitochondrial and barrier function, and protein-aggregate clearance, and it surveys actionable therapeutic strategies—senolytics,…

Directly relevant to Parkinson's therapeutic discovery because it links immune-aging mechanisms (senescent glia, systemic inflammation, BBB dysfunction) to impaired clearance of protein aggregates (e.g., α‑synuclein) and prioritizes clinically translatable interventions and delivery approaches that…

Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.