Brain Endothelial Cells are Exquisite Sensors of Age-Related Circulatory Cues

Brain endothelial cells (BECs) are key elements of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Because circulatory factors have prominent age-related effects on adult neurogenesis, microglia, neuronal activity, and learning and memory in mice the question arises how signals are relayed between the blood and brain. Using single cell RNA sequencing of hippocampal BECs we discovered that capillary BECs, compared with arterial and venous cells, exhibit the greatest transcriptional changes with aging, upregulating innate immunity, TGF-β signaling and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulated key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice had the opposite effect, essentially rejuvenating the BBB endothelial transcriptome. Interestingly, we find correlations between upregulated surface receptors on aging capillaries and the level of their ligands in aging mouse plasma. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.