Extended Data Figure 10: Model for the role of autophagy in HSC function and HSC ageing.

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 (αKG) that act as substrates/co-factors for epigenetic enzymes. Metabolically, aHSCs are poised to undergo lineage priming and produce differentiated progeny to regenerate the blood system. However, aHSCs must also return to quiescence to maintain the stem cell pool. In this context, autophagy plays an essential role by clearing active 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 probably 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 such as transplantation. This role of autophagy becomes even more important with age as the inability of about two-thirds 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 ageing blood phenotypes. In contrast, about one-third of oHSCs activate autophagy, control their metabolic activity, and are the fittest old stem cells that retain functional abilities in an adverse ageing bone marrow 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 ageing blood system.