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

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. [Display omitted] •Differences in autophagy levels in old HSCs are environmentally mediated•Autophagy is activated secondary to chronic inflammation-induced glycolysis suppression•Socs3 mediates metabolic suppression and autophagy adaptation in old HSCs•Fasting/refeeding restores the glycolytic state and regenerative capacity of old HSCs Dellorusso, Proven, et al. show that autophagy engagement in old murine HSCs compensates for metabolic deregulation induced by chronic inflammation of the aged bone marrow niche and that its transient modulation can reset the old HSC glycolytic state and regenerative capacity.