Core activation program and selective regional responsiveness of microglia during aging and parabiosis.

Aging is associated with immune dysregulation in the brain and is the greatest risk factor for many neurodegenerative diseases. Rejuvenation interventions can mediate beneficial effects. Microglia are major contributors to neurodegenerative disease progression; however, the molecular changes underlying brain aging and rejuvenation remain poorly understood at the single-cell level. We identified and benchmarked several reproducible microglial states and a core set of genes that drive microglial activation in the mouse brain. We investigated microglial heterogeneity and examined the impact of aging and parabiosis-mediated exposure to young and old blood on microglial subpopulations across four brain regions: the cerebellum, cortex, hippocampus, and striatum. We revealed region-specific differences in microglial composition and age-related changes. The cerebellum consistently emerged as the most responsive region, whereas the striatum showed minimal responsiveness to parabiosis interventions. These findings highlight regional vulnerability and inform microglia-targeted strategies to modulate brain aging.