Advanced single-cell analysis reveals that glial cells—microglia, astrocytes, and oligodendrocytes—undergo dramatic cellular transitions during brain aging that actively drive cognitive decline. Microglia shift from protective surveillance to inflammatory states, astrocytes lose their metabolic support functions, and oligodendrocytes fail to maintain myelin integrity. These changes show striking regional patterns, with the hippocampus and prefrontal cortex experiencing severe glial dysfunction while the cerebellum remains relatively protected—matching the geography of age-related memory and executive function decline. The molecular drivers include senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and dysregulated inflammatory signaling that propagates through interconnected glial networks. This represents a fundamental shift from viewing brain aging as primarily neuronal loss to recognizing glial dysfunction as an active driver of cognitive impairment. The therapeutic implications are profound: unlike neurons, glial cells retain plasticity throughout life, making them viable targets for intervention. Senolytic drugs that eliminate dysfunctional cells, along with exercise and dietary approaches that modulate glial phenotypes, offer promising avenues for preserving cognitive function. This framework positions glial health as a cornerstone of successful brain aging strategies.