Microglia aging in the hippocampus advances through intermediate states that drive inflammatory activation and cognitive decline

During aging, microglia – the resident macrophages of the brain – exhibit dystrophic phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia dystrophy have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFβ1 and translational states using pharmacological approachesin vitroto reveal their modulation of the progression to an inflammatory state. Furthermore, we utilized single-cell RNA-Seq in conjunction with anin vivoadult microglia-specificTgfb1conditional genetic knockout mouse model, to demonstrate that microglia advancement through intermediate aging states drives inflammatory activation and associated hippocampal-dependent cognitive decline.