Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated β-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of β-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate β-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1β secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.

Andalusian Research Institute in Data Science and Computational Intelligence University of Granada Granada Spain

Biomedical Research Center University Hospital Hradec Kralove 500 05 Hradec Kralove Czech Republic

College of Life Science Yangtze University Jingzhou 434025 China

College of Physical Education and Health Chongqing College of International Business and Economics Chongqing 401520 China

Department of Chemistry and Biochemistry Mendel University in Brno 613 00 Brno Czech Republic

Department of Chemistry Faculty of Natural Sciences Constantine the Philosopher University in Nitra 949 74 Nitra Slovakia

Department of Chemistry Faculty of Science University of Hradec Králové 500 03 Hradec Králové Czech Republic

Faculty of Chemical and Food Technology Slovak University of Technology 812 37 Bratislava Slovakia

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