Extended Data Fig. 10. Model for the role of autophagy in HSC function and HSC aging.

HSC activation is accompanied by mitochondria activation and a shift in metabolic activity from glycolysis to OXPHOS, which provides energy and increases the production of mitochondrial metabolites such as α-ketoglutarate (α-KG) that act as substrates/co-factors for epigenetic enzymes. Metabolically activated HSCs are poised to undergo lineage priming and produce differentiated progeny to regenerate the blood system. However, activated HSCs must also return to quiescence to maintain the stem cell pool. In this context, autophagy plays an essential role by clearing activate mitochondria to allow OXPHOS-driven HSCs to efficiently revert to a mostly glycolysis-based metabolic quiescence. Without autophagy, HSCs display an overactive OXPHOS-driven metabolism that promotes myeloid-biased differentiation and loss of stemness as a consequence of epigenetic reprogramming. Other mechanisms of mitochondria elimination likely allow some autophagy-deficient HSCs to return to quiescence during homeostasis, but they do not substitute for autophagy in maintaining HSC function in conditions of intense regeneration stress like transplantation. This role of autophagy becomes even more important with age as the inability of ~ 2/3 of oHSCs to activate autophagy results in an overactive OXPHOS metabolism that impairs self-renewal, promotes proliferation and myeloid differentiation, and contributes to replication stress. These unhealthy oHSCs drive most of the aging blood phenotypes. In contrast, ~ 1/3 of oHSCs activate autophagy, control their metabolic activity, and are the fittest old stem cells that retain functional abilities in an adverse aging BM microenvironment. As all oHSCs remain competent for autophagy induction, it will be exciting to test whether rejuvenation interventions aimed at activating autophagy in unhealthy autophagy-inactivated oHSCs will improve the health of the aging blood system.