Article

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

Although different tissues undergo distinct alterations with age, one overarching hallmark of aging is reduced stem cell function in regenerative tissues.¹ The composition of the blood system evolves with age alongside well-characterized changes in hematopoietic stem cell (HSC) activity, including an age-dependent expansion of the HSC pool with decreased regenerative potential in transplantation assays, a skewed differentiation toward myeloid cell production at the expense of lymphopoiesis and erythropoiesis, and a perturbed state of quiescence characterized by increased stress-response signaling.² In addition, aging remodels the bone marrow (BM) niche and increases both systemic and microenvironmental inflammation that directly contribute to impaired blood production.^3,4,5 Together, these changes promote the onset of blood cancers, increase susceptibility to infections, and drive chronic inflammatory disorders and systemic tissue degeneration in the elderly.^2,5,6

HSCs are tightly regulated by their metabolic status, which underlies their sensitivity to metabolic deregulation in aging.^7,8 Quiescent HSCs predominantly utilize glycolysis and limit mitochondrial glucose oxidation, whereas activated HSCs increase glucose consumption and link glycolysis with mitochondrial metabolism in order to meet proliferative requirements.^8,9 Genetic loss of glycolysis-promoting regulators, or downstream effectors, and aberrant activation of oxidative phosphorylation (OXPHOS) prevent maintenance of HSC quiescence and promote stem cell exhaustion.^10,11 Fatty acid (FA) oxidation and lipid metabolism are also linked to maintenance of mitochondrial activity and function in quiescent HSCs.¹² These metabolic states are closely associated with the regulation of nutrient-sensing signaling pathways and the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/forkhead transcription factors (FoxO) signaling cascade in HSCs.^13,14,15 They are also regulated by fundamental proteostasis mechanisms, particularly macro-autophagy (hereafter called autophagy) that is engaged in HSCs through a FoxO-mediated pathway to withstand starvation¹⁶ and is used at steady state to recycle activated mitochondria, maintain lysosomal function, and terminate OXPHOS-mediated pro-differentiation signaling.^9,17 Additionally, asymmetric inheritance of lysosomes and autophagosomes predicts HSC activation state,¹⁸ and the activity of chaperone-mediated autophagy, a selective form of lysosomal protein degradation that is essential to sustain HSC activation in young mice, decreases over time in old mice.¹⁹ By contrast, old HSCs (oHSCs) remain competent for autophagy induction in stress conditions and, in contrast to many other aging cells and tissues, show increased activation of autophagy with age.¹⁶ Strikingly, autophagy-activated oHSCs have higher regeneration potential than oHSCs that do not engage autophagy and maintain a more youthful metabolism compared with autophagy-inactivated oHSCs that display an overactive oxidative metabolism.¹⁷ However, which signals promote autophagy engagement in the aged HSC compartment and why autophagy activation increases the regenerative potential of oHSCs remain unknown. Understanding these connections has direct translational implications for restoring oHSC function.