美国哥伦比亚大学Emmanuelle Passegué团队的研究发现，自噬可减弱衰老造血干细胞（oHSC）中由炎症诱导的糖酵解损伤。2024年5月15日出版的《细胞-干细胞》杂志发表了这项成果。

研究人员证明自噬是衰老小鼠骨髓（BM）龛对慢性炎症的一种适应性细胞保护反应。研究发现，炎症会损害葡萄糖摄取，并通过Socs3介导的AKT/FoxO依赖性信号传导抑制oHSCs中的糖酵解，而炎症介导的自噬可使代谢适应糖酵解损伤，从而维持功能性静止。

此外，研究还发现，通过短期禁食/进食模式诱导自噬可使糖酵解通量恢复正常，并显著提高oHSC的再生潜力。该研究结果表明，炎症诱导的糖代谢减慢是造血干细胞随年龄增长而出现功能障碍的一个关键诱导因素，并确定自噬是影响oHSC再生能力的关键调控节点。

据了解，自噬是长寿信号程序和造血干细胞应对营养压力的机制。随着年龄的增长，一个造血干细胞亚群会通过增加自噬通量来保持再生能力，但在衰老造血干细胞中触发自噬和维持自噬激活的功能信号仍然未知。

附：英文原文

Title: Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells

Author: Paul V. Dellorusso, Melissa A. Proven, Fernando J. Calero-Nieto, Xiaonan Wang, Carl A. Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W. Swann, Theodore T. Ho, Zhiyu Zhao, Sean C. Bendall, Sean Morrison, Berthold Gttgens, Emmanuelle Passegué

Issue&Volume: 2024-05-15

Abstract: Autophagy is central to the benefits of longevity signaling programs and to hematopoieticstem cell (HSC) response to nutrient stress. With age, a subset of HSCs increasesautophagy flux and preserves regenerative capacity, but the signals triggering autophagyand maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown.Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronicinflammation in the aging murine bone marrow (BM) niche. We find that inflammationimpairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibitionof AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preservingfunctional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover,we show that transient autophagy induction via a short-term fasting/refeeding paradigmnormalizes glycolytic flux and significantly boosts oHSC regenerative potential. Ourresults identify inflammation-driven glucose hypometabolism as a key driver of HSCdysfunction with age and establish autophagy as a targetable node to reset oHSC regenerativecapacity.

DOI: 10.1016/j.stem.2024.04.020

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00174-7