Fig. 1: Age-related changes in the vasculature.

[1] Senescent immune cells secrete reactive oxygen species (ROS) that [2] activates the NF-kB pathway in cerebral endothelial cells (CECs). Then, CECs adopt a senescent-associated secretory phenotype (SASP) and [3] secrete MMP that degrade the extracellular matrix. Other SASP components secreted by senescent CECs can also promote fibrosis and collagen deposition. [4] Senescent CECs secrete pro-inflammatory substances (IL-1, IL-6, IL-8) into the vasculature lumen that impair tight junctions between CEC, and [5] facilitate the infiltration of immune cells and monocytes through the CEC layer. [6] Infiltrating monocytes reach the internal elastic lamina and change their phenotype to macrophages, [7] which phagocytize oxidized lipoproteins. In the internal elastic lamina, [8] reactive macrophages and infiltrating immune cells secrete pro-inflammatory cytokines that exacerbate inflammatory responses, and [9] contribute to the deposition of cellular debris, fatty substances, migrated vascular smooth muscle cells, and lipid-laden macrophages (foam cells) that lead to the formation of atherosclerotic plaques. Figure made with Biorender.com.