A single-cell transcriptome atlas of cell diversity in human prefrontal cortex across the postnatal lifespan

Brain aging is a major risk factor for numerous diseases, including cerebrovascular diseases and neurodegenerative disorders, posing a significant threat to human health. Currently, the continuous changes of different cell types in human brain tissue throughout an individual's life course have not been fully elucidated. Here we describe the continuous changes in the transcriptomes of different cell types and their subpopulations in the prefrontal cortex (PFC) across the postnatal lifespan. We integrated single-nucleus RNA sequencing (snRNA-seq) data of the PFC from 158 healthy individuals aged 19–101 years across 15 datasets and constructed a PFC aging atlas of 587,878 nuclei. We found that the ages of 30s and 50s are the two most significant periods of brain transcriptome changes in adulthood. Synaptic development, integration, and transmission are generally downregulated during aging. Different subpopulations of various cell types undergo age-related transitions and participate in the brain aging process at different time points. The increase in apoptotic signals and the production of inflammatory factors in astrocytes of elderly individuals accelerate brain aging. Microglia are mainly in a homeostatic state in the early stage, which is beneficial to the normal function of the CNS, and mainly in an activated state in the later stage, showing an increase in the release of inflammatory factors and chemotaxis. The activation of microglia may be related to the abnormal development of synapses and dendritic spines, as well as the abnormal myelination. Abnormally activated microglia are involved in the occurrence and development of Alzheimer's disease (AD) and multiple sclerosis (MS) in elderly individuals. The function of trans-blood-brain-barrier transport in endothelial cells is significantly downregulated with age. Based on aging-related plasma proteomics data, FUT9 was identified as a plasma biomarker related to brain aging. Our study clarifies the temporal differences and potential connections in the aging of different cell types in the PFC, providing a reference for the selection of specific cell types and time windows for future anti-CNS aging interventions.