The regenerative potential of neural stem cells (NSCs) declines during aging, leading to cognitive dysfunctions. This decline involves up-regulation of senescence-associated genes, but inactivation of such genes failed to reverse aging of hippocampal NSCs. Because many genes are up-regulated or down-regulated during aging, manipulation of single genes would be insufficient to reverse aging. Here we searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. We found that a combination of inducing the zinc finger transcription factor gene Plagl2 and inhibiting Dyrk1a, a gene associated with Down syndrome (a genetic disorder known to accelerate aging), rejuvenated aged hippocampal NSCs, which already lost proliferative and neurogenic potential. Such rejuvenated NSCs proliferated and produced new neurons continuously at the level observed in juvenile hippocampi, leading to improved cognition. Epigenome, transcriptome, and live-imaging analyses indicated that this gene combination induces up-regulation of embryo-associated genes and down-regulation of age-associated genes by changing their chromatin accessibility, thereby rejuvenating aged dormant NSCs to function like juvenile active NSCs. Thus, aging of NSCs can be reversed to induce functional neurogenesis continuously, offering a way to treat age-related neurological disorders.

中文翻译：

---

Plagl2 和抗 Dyrk1a 活性对衰老神经干细胞的功能复兴

神经干细胞 (NSC) 的再生潜能在衰老过程中下降，导致认知功能障碍。这种下降涉及衰老相关基因的上调，但这些基因的失活未能逆转海马神经干细胞的衰老。由于许多基因在衰老过程中上调或下调，因此对单个基因的操纵不足以逆转衰老。在这里，我们从胚胎和成人 NSC 及其调节剂之间差异表达的核因子中寻找可以使老年小鼠大脑中的 NSC 恢复活力的基因组合。我们发现诱导锌指转录因子基因Plagl2和抑制Dyrk1a的组合，一种与唐氏综合症（一种已知会加速衰老的遗传疾病）相关的基因，使老化的海马神经干细胞恢复活力，这些神经干细胞已经失去了增殖和神经源性的潜力。这种再生的神经干细胞以在幼年海马中观察到的水平不断增殖并产生新的神经元，从而改善认知。表观基因组、转录组和实时成像分析表明，这种基因组合通过改变其染色质可及性诱导胚胎相关基因上调和年龄相关基因下调，从而使老化的休眠 NSC 恢复活力，使其像幼年活跃的 NSC 一样发挥作用。因此，可以逆转 NSC 的衰老以持续诱导功能性神经发生，从而提供一种治疗与年龄相关的神经系统疾病的方法。