Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity.

中文翻译：

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自噬对抗衰老造血干细胞中炎症驱动的糖酵解损伤


自噬对于长寿信号传导程序的益处以及造血干细胞 (HSC) 对营养应激的反应至关重要。随着年龄的增长，HSC 的一部分会增加自噬通量并保留再生能力，但触发自噬和维持自噬激活的旧 HSC (oHSC) 功能的信号仍然未知。在这里，我们证明自噬是对衰老小鼠骨髓（BM）生态位中慢性炎症的适应性细胞保护反应。我们发现炎症通过 Socs3 介导的 AKT/FoxO 依赖性信号传导抑制来损害葡萄糖摄取并抑制 oHSC 中的糖酵解，而炎症介导的自噬参与通过使代谢适应糖酵解损伤来保持功能静止。此外，我们表明，通过短期禁食/再进食范式诱导瞬时自噬可使糖酵解通量正常化，并显着增强 oH​​SC 的再生潜力。我们的结果确定炎症驱动的葡萄糖代谢低下是 HSC 随着年龄增长而功能障碍的关键驱动因素，并将自噬确立为重置 oHSC 再生能力的目标节点。