Microglia, the resident immune cells in the brain, play a crucial role in brain development, maturation, and maintenance. This study investigates the consequences of permanent microglial deficiency on brain aging using a *Csf1r*^ΔFIRE/ΔFIRE^ mouse model. In juvenile mice, microglia are dispensable for the transcriptomic maturation of other brain cell types. However, with aging, pathologies accumulate in *Csf1r*^ΔFIRE/ΔFIRE^ brains, including progressive brain calcifications, macroglial reactivity, and white matter integrity decline. The thalamus is particularly sensitive to the absence of microglia, showing atrophy, neuron loss, vascular alterations, and severe tissue calcification. Transplanting wild-type microglia into *Csf1r*^ΔFIRE/ΔFIRE^ brains protects against these pathological changes, indicating that lifelong microglial absence results in an age-related neurodegenerative condition that can be counteracted by healthy microglial transplantation. These findings highlight the critical role of microglia in protecting against age-associated brain pathologies and provide insights into the pathogenesis of neurodegenerative diseases.Microglia, the resident immune cells in the brain, play a crucial role in brain development, maturation, and maintenance. This study investigates the consequences of permanent microglial deficiency on brain aging using a *Csf1r*^ΔFIRE/ΔFIRE^ mouse model. In juvenile mice, microglia are dispensable for the transcriptomic maturation of other brain cell types. However, with aging, pathologies accumulate in *Csf1r*^ΔFIRE/ΔFIRE^ brains, including progressive brain calcifications, macroglial reactivity, and white matter integrity decline. The thalamus is particularly sensitive to the absence of microglia, showing atrophy, neuron loss, vascular alterations, and severe tissue calcification. Transplanting wild-type microglia into *Csf1r*^ΔFIRE/ΔFIRE^ brains protects against these pathological changes, indicating that lifelong microglial absence results in an age-related neurodegenerative condition that can be counteracted by healthy microglial transplantation. These findings highlight the critical role of microglia in protecting against age-associated brain pathologies and provide insights into the pathogenesis of neurodegenerative diseases.