Pamela V. Martino-Adami, PhD., Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne. Kerpener Str. 62, 50937 Cologne, Germany, E-mail:
J Prev Alzheimers Dis. 2022;9(3):523-531. doi: 10.14283/jpad.2022.42.
The underlying processes occurring in aging are complex, involving numerous biological changes that result in chronic cellular stress and sterile inflammation. One of the main hallmarks of aging is senescence. While originally the term senescence was defined in the field of oncology, further research has established that also microglia, astrocytes and neurons become senescent. Since age is the main risk factor for neurodegenerative diseases, it is reasonable to argue that cellular senescence might play a major role in Alzheimer's disease. Specific cellular changes seen during Alzheimer's disease are similar to those observed during senescence across all resident brain cell types. Furthermore, increased levels of senescence-associated secretory phenotype proteins such as IL-6, IGFBP, TGF-β and MMP-10 have been found in both CSF and plasma samples from Alzheimer's disease patients. In addition, genome-wide association studies have identified that individuals with Alzheimer's disease carry a high burden of genetic risk variants in genes known to be involved in senescence, including ADAM10, ADAMTS4, and BIN1. Thus, cellular senescence is emerging as a potential underlying disease process operating in Alzheimer's disease. This has also attracted more attention to exploiting cellular senescence as a therapeutic target. Several senolytic compounds with the capability to eliminate senescent cells have been examined in vivo and in vitro with notable results, suggesting they may provide a novel therapeutic avenue. Here, we reviewed the current knowledge of cellular senescence and discussed the evidence of senescence in various brain cell types and its putative role in inflammaging and neurodegenerative processes.
衰老过程中发生的潜在过程很复杂，涉及许多生物变化，导致慢性细胞应激和无菌性炎症。衰老的主要标志之一是衰老。虽然衰老这个术语最初是在肿瘤学领域定义的，但进一步的研究已经确定，小胶质细胞、星形胶质细胞和神经元也会衰老。由于年龄是神经退行性疾病的主要危险因素，因此有理由认为细胞衰老可能在阿尔茨海默病中起主要作用。在阿尔茨海默病中观察到的特定细胞变化与在所有驻留脑细胞类型中观察到的衰老过程中的变化相似。此外，在阿尔茨海默病患者的 CSF 和血浆样本中发现了衰老相关分泌表型蛋白（如 IL-6、IGFBP、TGF-β和 MMP-10）水平升高。此外，全基因组关联研究表明，阿尔茨海默病患者携带与衰老相关的基因（包括 ADAM10、ADAMTS4 和 BIN1）中已知的遗传风险变异的高负担。因此，细胞衰老正在成为阿尔茨海默病的潜在疾病过程。这也引起了更多的关注，即将细胞衰老作为一种治疗靶点。已经在体内和体外检查了几种具有消除衰老细胞能力的衰老细胞溶解化合物，并取得了显著的结果，表明它们可能为提供一种新的治疗途径。在这里，我们回顾了细胞衰老的现有知识，并讨论了衰老在各种脑细胞类型中的证据及其在炎症和神经退行性过程中的潜在作用。
