Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications

Highlights What are the main findings? Aging-associated immunosenescence and inflammaging drive neurodegeneration by impairing microglial and astrocyte function and disrupting systemic-CNS immune crosstalk. Both innate and adaptive immune compartments contribute to sustained neuroinflammation, synaptic dysfunction, and neuronal loss. What are the implications of the main findings? Targeting senescent cells, restoring immune balance, and modulating inflammation may offer therapeutic avenues for neurodegenerative diseases. Early intervention in immune aging could enhance brain resilience and slow disease progression.Highlights What are the main findings? Aging-associated immunosenescence and inflammaging drive neurodegeneration by impairing microglial and astrocyte function and disrupting systemic-CNS immune crosstalk. Both innate and adaptive immune compartments contribute to sustained neuroinflammation, synaptic dysfunction, and neuronal loss. What are the implications of the main findings? Targeting senescent cells, restoring immune balance, and modulating inflammation may offer therapeutic avenues for neurodegenerative diseases. Early intervention in immune aging could enhance brain resilience and slow disease progression.Abstract 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.