Cellular Senescence in Neurodegeneration: From Cell Types to Therapeutic Opportunities

Neurodegenerative diseases of the central nervous system, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, represent a growing health challenge in ageing populations. Among the mechanisms underlying these disorders, increasing attention has been directed toward the role of cellular senescence. This process, triggered by chronic cellular and oxidative stress as well as DNA damage, leads to irreversible cell-cycle arrest and the development of the senescence-associated secretory phenotype (SASP). Within the central nervous system, the accumulation of senescent cells induces chronic inflammation, blood-brain barrier disruption, and progression of neurodegenerative processes. In this review, we present current evidence regarding the mechanisms of cellular senescence in the central nervous system, with particular emphasis on the role of SASP in neuroinflammation, vascular dysfunction, and neural tissue damage. Experimental and clinical data supporting the involvement of cellular senescence in the pathogenesis of Alzheimer's disease, Parkinson's disease, and multiple sclerosis are discussed. The review also covers methods for identifying senescent cells in the brain, including molecular marker-based approaches and machine learning-based tools. Importantly, we discuss the methodological limitations of commonly used senescence markers, such as their limited specificity and the risk of false-positive detection, particularly in the heterogeneous cellular environment of the central nervous system. Strategies to improve detection reliability discussed in this review include the use of multimarker signatures, analysis of SASP components using qRT-PCR and ELISA, as well as transcriptomic approaches such as RNA sequencing and single-cell RNA sequencing. Furthermore, we analyze therapeutic strategies targeting senescent cells-senolytics, senomorphics, and SASP modulation-together with their limitations and associated clinical challenges. The collected evidence indicates that precise characterization of senescent cell populations in the brain is essential for the development of disease-modifying therapies for neurodegenerative disorders.