A SINGLE-CELL SPATIAL ATLAS REVEALS CELLULAR AND REGIONAL PROGRAMS OF BRAIN AGING

Aging is the dominant risk factor for cognitive decline, yet the cellular and spatial organization of brain aging remains incompletely understood. Here, we generated a single-cell spatial transcriptomic atlas of the mouse brain spanning postnatal development to late adulthood, profiling 13 ages from 2 months to 27 months. This atlas provides a comprehensive spatiotemporal map of cellular composition and gene expression dynamics across the aging brain. By integrating this atlas with genome-wide association studies of the brain age gap (BAG), we performed genetically informed spatial mapping of complex traits (gsMap) to identify cell types and regions driving accelerated brain aging. We uncovered strong and spatially restricted associations with oligodendrocytes in the corpus callosum and epithelial cells in the choroid plexus. These results were independently validated using MAGMA analysis of human single-cell transcriptomic data, which consistently implicated oligodendrocytes and committed oligodendrocyte precursor cells as key contributors to genetic risk for accelerated brain aging. Furthermore, we constructed a single-cell spatial aging clock to quantify local aging acceleration and revealed that senescence-associated secretory phenotype (SASP) genes and other secretory proteins exert non–cell-autonomous effects on neighboring cells. Together, our study establishes a spatiotemporal transcriptomic framework for brain aging, spatially resolves genetically vulnerable cell populations, and provides mechanistic insights into cell–cell interactions that may drive regional aging and represent potential targets for intervention.