UCSF

Aging is the greatest risk factor for a wide range of diseases, including cardiovascular diseases, cancers, neurodegenerative disorders, and diabetes. Yet why this is happening mechanistically remains largely unknown. Stem cells are responsible for the lifelong generation, maintenance, and repair of tissue and organ systems, and are therefore are both useful models to study cellular aging and attractive candidates for causing tissue and organismal aging. While stem cell aging has not been definitively linked to organismal aging, a decline in tissue function with age often correlates with a decline in stem cell function. Aging is also often accompanied by a decline in stem cell function, often correlating with degenerative diseases. In particular, during aging, hematopoietic stem cells (HSCs) lose their ability to regenerate the blood system, and promote disease development. Autophagy is critical for protecting HSCs from metabolic stress and has long been associated with health and longevity. 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.