Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as CDKN1A, CDKN2A in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors’ fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS.

衰老影响中枢神经系统中的所有细胞类型，并在中枢神经系统疾病中发挥重要作用。然而，人们对驱动这些与年龄相关的变化的潜在分子机制及其对疾病的贡献知之甚少。衰老大脑以及多发性硬化症等疾病中的白质的特点是髓鞘和旁节的细微异常，这表明少突胶质细胞（中枢神经系统的髓磷脂维持细胞）失去了保存适当髓磷脂结构的能力并可能在年龄和某些疾病中发挥作用。在这里，我们利用来自年轻、成人和老年人类捐赠者的直接转化的少突胶质细胞 (dchiOL) 来研究与年龄相关的变化。来自所有三个年龄组的 dchiOL 以类似的方式分化为 O4 + 未成熟少突胶质细胞，但 MBP + 成熟 dchiOL 的比例随着供体年龄的增加而下降。这与旧 dchiOL 中 ROS 产生的增加和细胞衰老标记物（例如CDKN1A、CDKN2A）的上调有关。比较成年和老年供体的 dchiOL 转录组图谱揭示了 1324 个差异调节基因，与供体成纤维细胞的转录组图谱或直接转化的人类神经元或原代啮齿动物少突胶质细胞谱系细胞的已发表数据集有有限的重叠。对 dchiOL 和人类白质组织样本的甲基化分析表明，中枢神经系统白质和 dchiOL 中的实际年龄和表观遗传年龄相关，并导致了年龄特异性表观遗传特征的鉴定。此外，我们观察到，与健康个体相比，多发性硬化症 (MS) 患者的有髓鞘、外观正常的白质的表观遗传老化加速。 使用促炎性小胶质细胞的上清液可以在体外诱导年轻 dchiOL 的分化受损和细胞衰老标记物的上调。总之，我们的数据表明，生理衰老以及炎症诱导的细胞衰老有助于多发性硬化症等炎症性脱髓鞘疾病中的少突胶质细胞病理学。