The Aging Brain: Mechanistic Insights into BBB Dysfunction, Neuroinflammation, and Immune Exhaustion in Cognitive Decline

Aging is a multifaceted process that profoundly affects the central nervous system, contributing to cognitive decline and heightened susceptibility to neurodegenerative diseases. This review explores the intricate interplay between age-related changes in the blood-brain barrier (BBB), immune dysfunction, and neuroinflammation. Age-associated deterioration of the BBB compromises its integrity, facilitating the infiltration of neurotoxic substances and immune cells into the brain, thereby exacerbating neural damage. Simultaneously, microglial dysfunction and chronic systemic inflammation amplify the neurodegenerative cascade, with emerging evidence linking these processes to cognitive decline. T cell exhaustion, a hallmark of aging, further compounds neuroinflammation by impairing immune surveillance and regulatory T cell function, promoting a permissive environment for neuronal damage. Emerging therapies targeting T cell rejuvenation offer promising avenues for mitigating age-related neurodegenerative processes. This review also delves into the mechanistic pathways, including NF-κB and JAK-STAT, which serve as critical mediators connecting BBB dysfunction, immune dysregulation, and chronic inflammation. By elucidating the interconnected mechanisms underlying aging and neurodegeneration, this paper highlights potential therapeutic strategies aimed at preserving cognitive function and mitigating the impact of aging on the brain.