Age-Associated Changes in the Immune System and Blood⁻Brain Barrier Functions

Abstract

Age is associated with altered immune functions that may affect the brain. Brain barriers, including the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are important interfaces for neuroimmune communication, and are affected by aging. In this review, we explore novel mechanisms by which the aging immune system alters central nervous system functions and neuroimmune responses, with a focus on brain barriers. Specific emphasis will be on recent works that have identified novel mechanisms by which BBB/BCSFB functions change with age, interactions of the BBB with age-associated immune factors, and contributions of the BBB to age-associated neurological disorders. Understanding how age alters BBB functions and responses to pathological insults could provide important insight on the role of the BBB in the progression of cognitive decline and neurodegenerative disease.

Keywords: aging; blood–brain barrier; inflammation.

Figure 1

Changes in vascular blood–brain barrier (BBB) function that may lead to brain pathology with age. The upper panel depicts physiological functions of the BBB such as glucose transport, expression of intact tight junction complexes and suppression of vesicular processes that prevent the paracellular or transcellular leakage of blood proteins into the brain, intact functions of the efflux transporter P-gp, which contributes to barrier function by limiting diffusion of its substrates into the brain, and in concert with lipoprotein receptor-related protein 1 (LRP-1), facilitates amyloid beta (Aβ) clearance from the brain. Additionally, entry of insulin into the brain supports neuronal functions and contributes to learning and memory, and brain entry of circulating compounds with high-capacity transporters such as CCL11 is limited by low circulatory concentrations. The lower panel depicts aspects of BBB dysfunction that are either supported or suggested to occur with aging. Transparent appearance of transporters (GLUT1, LRP-1, and P-gp) indicates reduced protein expression levels at the BBB, and the interdictory circles over transporters indicate known functional impairments which may occur in the presence or absence of expression changes. The question mark on the insulin receptor suggests a possible mechanism by which aging influences brain insulin through altered function of the insulin transporter, which has not yet been definitively determined.