Early Stem Cell Aging in the Mature Brain.

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to enhance stem cell function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term (ST-NSC) and long-term NSCs (LT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC pro-aging factor. Treatment with the Abl-inhibitor Imatinib increased NSC proliferation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable to cellular aging, yet NSC function can be partially restored. Attached are supplementary figures 4-7. S4 is RNA-Seq mapping efficiency summary. S5 are the expression matrices. S6 is differential expression. S7 is associated GO term enrichment.干细胞功能异常是诸多年龄相关性疾病的核心致病驱动因素。探明早期即损害干细胞功能的调控机制，可为生命后期增强干细胞功能提供关键干预靶点。本研究精准定位了成年海马体中多种可扰乱神经干细胞（Neural Stem Cell, NSC）功能的调控因子。克隆追踪分析显示，神经干细胞呈现异步耗竭特征，研究人员据此鉴定出短期神经干细胞（Short-term Neural Stem Cell, ST-NSC）与长期神经干细胞（Long-term Neural Stem Cell, LT-NSCs）两个亚群。短期神经干细胞（ST-NSC）增殖速率较快，可分化为神经元，并在年轻大脑中逐渐耗竭。与此同时，具备多向分化潜能的长期神经干细胞（LT-NSCs）可存活数月，但因静息期延长而偏离稳态平衡。对深度静息状态下的神经干细胞进行单细胞转录组分析，揭示了成熟大脑中分子衰老的多项标志性特征，并鉴定出酪氨酸蛋白激酶Abl1为神经干细胞的促衰老因子。使用Abl抑制剂伊马替尼（Imatinib）进行干预，可提升中年大脑内神经干细胞的增殖能力，且不会损害其稳态维持功能。本研究表明，海马体神经干细胞对细胞衰老尤为易感，但此类干细胞的功能可得到部分恢复。附件包含补充图4至7：补充图S4为RNA-Seq比对效率汇总结果；补充图S5为基因表达矩阵；补充图S6为差异表达分析结果；补充图S7为相关基因本体（Gene Ontology, GO）富集分析结果。