Glial dynamics in brain aging: Cellular heterogeneity and regional vulnerability

Brain aging involves progressive structural, functional, and molecular changes that impair cognition and increase vulnerability to neurodegenerative diseases. While neurons have traditionally received primary research focus, recent advances in single-cell transcriptomics, spatial genomics, and functional imaging reveal that glial cells-microglia, astrocytes, and oligodendrocytes-undergo profound, heterogeneous alterations during aging that actively drive brain dysfunction. These changes include microglial transition from homeostatic surveillance to inflammatory, dystrophic states; astrocyte shift from metabolic support to atypical reactive phenotypes with impaired neurovascular coupling; and oligodendrocyte dysfunction causing progressive myelin degeneration. Critically, glial aging exhibits marked regional heterogeneity, with hippocampus and prefrontal cortex showing heightened vulnerability while cerebellum remains relatively preserved, patterns mirroring cognitive decline topography. At the molecular level, glial senescence involves interconnected mechanisms including cellular senescence with senescence-associated secretory phenotype (SASP), oxidative stress and mitochondrial dysfunction, impaired proteostasis and autophagy, epigenetic alterations favoring inflammatory gene expression, and dysregulated inflammatory signaling pathways. These changes propagate through complex glial-glial and neuron-glia interaction networks, amplifying dysfunction beyond individual cellular deficits. Importantly, glia retain plasticity enabling therapeutic intervention through diverse strategies: senolytic elimination of senescent cells, microglial phenotype modulation, remyelination enhancement, metabolic interventions, and lifestyle modifications including exercise and dietary approaches. This review synthesizes current understanding of glial heterogeneity, regional vulnerability patterns, underlying molecular mechanisms, and emerging therapeutic opportunities, providing an integrated framework for targeting glial dysfunction to promote healthy brain aging and prevent cognitive decline.