DECODING MICROGLIAL HETEROGENEITY AND STATE TRANSITIONS IN THE AGING BRAIN

Microglia, the resident immune cells of the brain, undergo profound functional and phenotypic alterations during aging, contributing to chronic neuroinflammation. These cells are increasingly recognized as key drivers of age-related cognitive decline. However, the cellular heterogeneity and state transitions of microglia across the lifespan remain incompletely understood at the single-cell level. Here, we performed single-cell RNA-sequencing on FACS-isolated microglia from young and aged mouse brains to comprehensively characterize the transcriptional landscape of microglial aging. Our analysis revealed multiple transcriptionally distinct age-associated microglial subpopulations, including previously uncharacterized inflammatory, phagocytic, and metabolically dysfunctional states that emerge specifically in the aged brain. Through trajectory analysis, we delineated a continuous progression of microglial states during aging, uncovering dynamic gene expression programs that orchestrate the transition from homeostatic to age-associated phenotypes. Furthermore, we identified unique molecular signatures and key regulatory pathways defining each microglial state, revealing potential targets for modulating neuroinflammation and brain aging. Collectively, our study elucidates the complex heterogeneity and dynamic nature of microglial aging, establishing a molecular framework for understanding microglia-mediated brain aging and providing therapeutic strategies for preserving cognitive function during aging.