Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts

Aging is a major risk factor in many forms of late-onset neurodegenerative disorders. The ability to recapitulate age-related characteristics of human neurons in culture will offer unprecedented opportunities to study the biological processes underlying neuronal aging. Here, we show that using a recently demonstrated microRNA-based cellular reprogramming approach, human fibroblasts from postnatal to near centenarian donors can be efficiently converted into neurons that maintain multiple age-associated signatures. Application of an epigenetic biomarker of aging (referred to as epigenetic clock) to DNA methylation data revealed that the epigenetic ages of fibroblasts were highly correlated with corresponding age estimates of reprogrammed neurons. Transcriptome and microRNA profiles reveal genes differentially expressed between young and old neurons. Further analyses of oxidative stress, DNA damage and telomere length exhibit the retention of age-associated cellular properties in converted...衰老是多种迟发性神经退行性疾病的主要风险因素。在体外培养体系中复现人类神经元的年龄相关特征，将为研究神经元衰老背后的生物学过程提供前所未有的机遇。本研究证实，借助近期报道的基于微RNA (microRNA) 的细胞重编程方法，可将出生后至近百岁供体来源的人类成纤维细胞高效转化为神经元，且该类神经元保留多种衰老相关特征。对DNA甲基化数据应用衰老表观遗传生物标志物（表观遗传时钟 (epigenetic clock)）进行分析后发现，成纤维细胞的表观遗传年龄与重编程神经元的年龄预测值高度相关。转录组与微RNA表达谱分析揭示了年轻与衰老神经元之间差异表达的基因。进一步针对氧化应激、DNA损伤及端粒长度的分析显示，转化得到的神经元保留了衰老相关的细胞特性……