Autophagy and Hematopoietic Stem Cell Potential During Aging

Aging of the hematopoietic system promotes various immune and systemic disorders and is driven in-part by dysfunction of life-long self-renewing hematopoietic stem cells (HSC). Autophagy is required for the benefit associated with activation of conserved longevity signaling programs and is essential for HSC function in response to various stressors. With age, some HSCs basally increase autophagy flux and maintain inert metabolic activity. This autophagy-activated subset is responsible for the residual regenerative capacity of old stem cells, but the mechanisms promoting autophagy activation in HSC aging remain unknown. Here, we demonstrate that autophagy is a response to chronic inflammation in the aging HSC niche. Chronic inflammation impairs glucose metabolism in young and old HSCs (oHSC) by impeding AKT-FOXO intracellular signaling networks. We find that autophagy enables metabolic adaptation of oHSCs to non-glucose energy substrates for functional maintenance. Notably, water-only fasting transiently further activates autophagy in oHSCs, and upon refeeding normalizes glucose uptake and glycolytic flux as well as regenerative output. Our results demonstrate that inflammation-driven glucose hypometabolism impairs oHSC regenerative capacity, that autophagy activation metabolically adapts oHSCs to an inflamed niche, and that autophagy is a modulable node to restore glycolytic and regenerative capacity during stem cell aging.