Autophagy maintains the metabolism and function of young and old (hematopoietic) stem cells

With age, hematopoietic stem cells (HSCs) lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting HSCs from metabolic stress. Here, we show that loss of autophagy in HSCs causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs HSC self-renewal activity and regenerative potential. Strikingly, the majority of HSCs in aged mice share these altered metabolic and functional features. However, ~ 1/3 of aged HSCs exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young HSCs. Our results demonstrate that autophagy actively suppresses HSC metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old HSCs.