Abstract

Microglia, the resident immune cells of the central nervous system (CNS), play critical roles in maintaining brain homeostasis and regulating immune responses. However, as these cells age, they undergo significant functional changes, including impaired phagocytosis, increased production of proinflammatory cytokines, and heightened oxidative stress. These age-related changes contribute to the progression of various neurodegenerative diseases, including multiple sclerosis (MS). This chapter explores the mechanistic underpinnings of microglial aging and its involvement in the pathogenesis of MS, particularly during the progressive stages of the disease. It discusses how aging microglia fail to clear myelin debris effectively, inhibiting remyelination processes and exacerbating axonal degeneration. Furthermore, the molecular mechanisms driving microglial senescence, such as mitochondrial dysfunction, iron overload, epigenetic alterations, and chronic, low-grade oxidative stress leading to inflammaging, are examined in detail. Recent research suggests that these age-related changes in microglia foster a chronic inflammatory environment that accelerates neurodegeneration and impairs CNS repair mechanisms. In addition, the chapter highlights potential therapeutic strategies targeting microglial aging, including antiinflammatory therapies, mitochondrial support, and epigenetic modulation, which hold promise for slowing disease progression in MS. All in all, this chapter provides a comprehensive overview of the evolving understanding of microglial aging and its impact on neurodegenerative diseases, with a particular focus on MS. More specifically, it emphasizes how these interconnected mechanisms create a self-reinforcing cycle of chronic microglial “activation“ that links aging, microglial dysfunction, and MS progression.