Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA; Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA, USA; Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
Cell Metab. 2023 Mar 7;35(3):472-486.e6. doi: 10.1016/j.cmet.2023.02.001. Epub 2023 Feb 27.
With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we combined multiomics, single-cell measurements, and functional testing of MuSCs from young and old mice. The multiomics approach allowed us to assess which changes are causal, which are compensatory, and which are simply correlative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs, with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibit a population dichotomy composed of GSH cells (comparable with young MuSCs) and GSH cells with impaired functionality. Mechanistically, we show that antagonism between NRF2 and NF-κB maintains this bimodality. Experimental manipulation of GSH levels altered the functional dichotomy of aged MuSCs. These findings identify a novel mechanism of stem cell aging and highlight glutathione metabolism as an accessible target for reversing MuSC aging.
随着年龄的增长，骨骼肌干细胞（MuSCs）从静止状态中更缓慢地激活，并且死亡增加，导致肌肉修复缺陷。为了探索这些缺陷的分子基础，我们结合了多组学、单细胞测量和来自年轻和老年小鼠的 MuSCs 的功能测试。多组学方法使我们能够评估哪些变化是因果关系，哪些是代偿性的，哪些仅仅是相关的。我们发现，在老年 MuSCs 中，谷胱甘肽（GSH）代谢受到干扰，既有因果关系，也有代偿性。与年轻的 MuSCs 不同，老年 MuSCs 表现出一种由 GSH 细胞（与年轻的 MuSCs 相当）和功能受损的 GSH 细胞组成的群体二分法。从机制上讲，我们表明 NRF2 和 NF-κB 之间的拮抗作用维持了这种双峰性。GSH 水平的实验操纵改变了老年 MuSCs 的功能二分法。这些发现确定了干细胞衰老的新机制，并强调了谷胱甘肽代谢作为逆转 MuSC 衰老的一个可及的靶点。
