Autophagy maintains the metabolism and function of young and old stem cells

With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells. Loss of autophagy increases the accumulation of mitochondria and the respiration status of haematopoietic stem cells, which perturbs their self-renewal and regeneration activities, and promotes cellular aging. Ageing haematopoietic stem cells (HSCs) are not able to regenerate blood cells as well as their younger counterparts, and show bias towards particular lineages. But autophagy has previously been shown to protect HSCs from the effects of metabolic stress. Here Emmanuelle Passegué and colleagues find that loss of autophagy in HSCs increases the accumulation of mitochondria and raises the metabolic state of HSCs, disturbing their abilities for self-renewal and regeneration. This behaviour is similar to that observed in old HSCs, although about one-third of old HSCs still have a high level of autophagy and a low metabolic state to help them maintain their regenerative capacity.