Brain Aging and Cellular Senescence Trigger Neuroimmunological Dysregulation and Neurodegeneration

Abstract

Cellular senescence during brain aging is a complex biological phenomenon triggered by age-related and external factors, leading to epigenetic and genetic alterations that impair cellular replication, cause mitochondrial dysfunction, and activate the senescence-associated secretory phenotype (SASP). This activation initiates proinflammatory signaling cascades and impairs inflammation-resolution mechanisms, facilitating the accumulation of immunosenescent cells and proinflammatory mediators and promoting the chronic, age-associated inflammation known as “inflammaging.” Although immunosenescence and inflammaging are distinct mechanisms, they are not independent. Both can contribute to the development and progression of neurodegenerative disorders by maintaining a chronic systemic proinflammatory state mediated by dysfunction of signaling pathways involved in lipid metabolism and inflammation resolution, as well as by disrupting the blood–brain barrier, which facilitates neuroinflammation within the brain parenchyma. Furthermore, dysfunction in bidirectional communication pathways between the immune system and the central nervous system, driven by immunosenescence in neural cells, including glial cells and neurons, which are postmitotic cells that can acquire phenotypic traits associated with senescence, facilitates SASP activation, leading to neuroinflammation and neurodegeneration. This review examines the mechanisms underlying brain aging and SASP activation, as well as the signaling pathways involved in inflammaging and its links to immunosenescence, blood–brain barrier damage, and neurodegeneration, which together facilitate the development and progression of neurodegenerative diseases and pathological aging.