From Neuron-Centric to Glia-Centric: How Aging Glial Networks Drive Neurodegenerative Disease.

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The traditional neuron-centric view of neurodegeneration is being replaced by a glial network-based framework. This shift recognizes that age-related dysfunction in non-neuronal cells critically shapes neuronal vulnerability and circuit resilience. Aging, the major risk factor for neurodegenerative diseases, is increasingly associated with the accumulation of senescent glial cells, particularly astrocytes, which emerge as early and active drivers of central nervous system decline. This review highlights astrocytic senescence as a key mechanism linking brain aging to neurodegeneration. Senescent astrocytes exhibit hallmark features including stable cell cycle arrest, mitochondrial dysfunction, and the acquisition of a senescence-associated secretory phenotype (SASP), which disrupts synaptic integrity, impairs proteostasis, and sustains chronic neuroinflammation. These alterations often precede overt neuronal loss in disorders such as Alzheimer's and Parkinson's disease. We discuss core hallmarks and biomarkers of glial senescence, emphasizing integrative strategies combining functional assays and molecular markers. We further highlight circulating SASP-related factors and extracellular vesicles as translational indicators of systemic senescence. Finally, we examine emerging senotherapeutic approaches aimed at restoring glial homeostasis, including senolytics, senomorphics, and CAR-T-based immunotherapies. Targeting glial senescence and interglial communication therefore represents a promising, though complex, paradigm-shifting avenue for delaying brain aging and mitigating neurodegenerative progression.

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