Aging of the Blood-Brain Barrier and Altered Permeability to Peripheral Immune Cells: Implications for Central Nervous System Disorders.

The blood-brain barrier (BBB), built by endothelial tight junctions, transporters, and the endothelial-pericyte-astrocyte unit, maintains a tightly regulated the central nervous system (CNS) milieu and permits selective immune cell entry. With age, tight junction downregulation, transport and metabolic imbalance, pericyte loss, basement membrane and glycocalyx remodeling, and reactive astrocytosis erode BBB integrity. These shifts reset leukocyte-trafficking thresholds and routes, producing either excessive admission or inadequate entry of peripheral immune cells. The resulting dysregulated immune surveillance activates microglia, amplifies neuroinflammation, disrupts myelin and synaptic homeostasis, and contributes to Alzheimer's and Parkinson's diseases, vascular dementia, and other neuroinflammatory conditions. This review synthesizes cellular and molecular mechanisms of BBB aging, outlines pathways and phenotypes of immune translocation, and proposes a cascade linking permeability imbalance to immune mismatch, driving neurodegeneration and injury. We discuss interventions focused on barrier repair and immune recalibration, including the reinforcement of tight junctions, restoration of pericyte homeostasis, and modulation of endothelial transport and chemokine axes. By implementing these strategies within stage- and time-specific therapeutic windows, this framework informs earlier diagnosis, biomarker development, and disease-modifying strategies for CNS disorders.