Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

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 com-bined 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 dichot-omy composed of GSHhigh cells (comparable with young MuSCs) and GSHlow cells with impaired function-ality. Mechanistically, we show that antagonism between NRF2 and NF-KB maintains this bimodality. Exper-imental 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.

Automated summary

With age, skeletal muscle stem cells (MuSCs) exhibit slower activation and increased death, resulting in defective muscle repair. Through multiomics, single-cell measurements, and functional testing, researchers have identified perturbed glutathione (GSH) metabolism as a mechanism of MuSC aging. This perturbed metabolism leads to a dichotomy in the aged MuSC population, with some cells maintaining functionality and others having impaired functionality due to reduced GSH levels. Manipulating GSH levels can alter the functional dichotomy and potentially reverse MuSC aging.