Chromosomal instability (CIN) refers to the rate at which cells are unable to properly segregate whole chromosomes, leading to aneuploidy. Besides its prevalence in cancer cells and postulated implications in promoting tumorigenesis, studies in aneuploidy-prone mouse models uncovered an unanticipated link between CIN and aging. Using young to old-aged human dermal fibroblasts, we observed a dysfunction of the mitotic machinery arising with age that mildly perturbs chromosome segregation fidelity and contributes to the generation of fully senescent cells. Here, we investigated mitotic mechanisms that contribute to age-associated CIN. We found that elderly cells have an increased number of stable kinetochore-microtubule (k-MT) attachments and decreased efficiency in the correction of improper k-MT interactions. Chromosome mis-segregation rates in old-aged cells decreased upon both genetic and small-molecule enhancement of MT-depolymerizing kinesin-13 activity. Notably, restored chromosome segregation accuracy inhibited the phenotypes of cellular senescence. Therefore, we provide mechanistic insight into age-associated CIN and disclose a strategy for the use of a small-molecule to inhibit age-associated CIN and to delay the cellular hallmarks of aging.

中文翻译：

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小分子抑制衰老相关的染色体不稳定性延迟了细胞的衰老。

染色体不稳定性（CIN）是指细胞无法正确分离完整染色体从而导致非整倍性的速率。除了其在癌细胞中的流行以及在促进肿瘤发生中的假定影响外，对非整倍体倾向小鼠模型的研究还发现了CIN与衰老之间的意外联系。使用年轻到老年的人类真皮成纤维细胞，我们观察到随着年龄增长而产生的有丝分裂机能障碍，会轻度干扰染色体分离的保真度并有助于生成完全衰老的细胞。在这里，我们调查了与年龄相关的CIN的有丝分裂机制。我们发现老年细胞具有增加的稳定的线粒体-微管（k-MT）附件的数量，并降低了纠正不正确的k-MT相互作用的效率。遗传和小分子增强MT解聚驱动蛋白13活性的同时，老年细胞中的染色体错误分离率降低。值得注意的是，恢复的染色体分离精度抑制了细胞衰老的表型。因此，我们提供了与年龄相关的CIN的机制洞察力，并公开了使用小分子抑制与年龄相关的CIN并延缓衰老的细胞标志的策略。