Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.

衰老通常会使干细胞功能衰退，损害组织稳态。在这里，我们报告造血干细胞（HSC）获得了促进细胞存活的代谢弹性。高分辨率实时 ATP 分析以及葡萄糖追踪和代谢流分析表明，旧的 HSC 会重新编程其代谢以激活磷酸戊糖途径 (PPP)，从而对氧化应激具有更强的抵抗力，并且在稳定状态下更少依赖于糖酵解 ATP 的产生。因此，老HSC无需糖酵解即可存活，适应骨髓中的生理细胞因子环境。从机制上讲，旧的 HSC 在应激过程中增强线粒体复合物 II 的代谢，从而促进 ATP 的产生。此外，生理性低浓度血小板生成素 (TPO) 暴露诱导老 HSC 中琥珀酸脱氢酶组装因子 1 (SDHAF1) 的增加，使线粒体在代谢应激时能够快速产生 ATP，从而提高存活率。这项研究深入了解了通过老年造血干细胞的代谢重编程获得恢复能力及其改善与年龄相关的造血异常的分子基础。