Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex

We performed Visium spatial transcriptomics (ST) and single-nucleus RNA sequencing (snRNA-seq) on a cohort of nonpathological human tissues to uncover signatures of aging and senescence in the dorsolateral prefrontal cortex (dlPFC). In doing so, we identified gene expression changes characteristic of aged cortical layers. The cellular composition of the dlPFC also changed with age, with increased homeostatic astrocyte abundance and with decreased somatostatin (SST) inhibitory neurons. Nuclei from dlPFC cell types displayed a strong decline in oxidative phosphorylation- and cytoplasmic translation-related genes with age. Additionally, oligodendrocytes showed several hallmarks of senescence and a linear increase in CDKN2A expression with age. Combined analysis of ST and snRNA-seq datasets revealed astrocyte- and vascular cell-related gene expression programs in the white matter and layer 1 that were strongly enriched with age and for senescence-associated genes. These findings will help facilitate future studies exploring the role of senescent cell subpopulations in the aging brain.