(i) Aging is associated with tissue-specific increases in proinflammatory protein expression, resulting in greater levels of inflammatory mediators (cytokines and chemokines) in peripheral circulation (blood). (ii) Inflammatory cytokines in blood signal cytokine receptors expressed in brain endothelial cells. This results in increased blood-brain barrier permeability and an upregulation of cellular adhesion molecules such as VCAM1. (iii) Inflammatory cytokines signal cytokine receptors on the luminal side of brain endothelial cells, leading to proinflammatory activation and leukocyte adhesion to vascular adhesion molecules, both of which promote proinflammatory endothelial activation. Together, these processes lead to an increased expression of inflammatory proteins in the brain parenchyma. (iv) Inflammatory proteins in the brain parenchyma can influence microglia and astrocyte phenotypes. For example, initial exposure of microglia to inflammatory mediators causes a transition from a surveilling homeostatic phenotype to an intermediate or activated phenotype. (v) Prolonged exposure to inflammatory signaling is believed to cause long-term microglial priming, characterized by exaggerated cytokine expression, reduced chemotaxis, and deficient phagocytosis. Primed microglia are more prone to aberrant expression in the context of disease. (vi) DNA damage, mitochondrial dysfunction, exposure to proteinaceous aggregates, and other forms of cellular stress can promote senescence of cells within the central nervous system, including brain endothelial cells and microglia. GFAP, glial fibrillary acidic protein; ICAM1, intercellular adhesion molecule 1; IL-1R1, IL-1 receptor type 1.