title: Autophagy maintains the metabolism and function of young and old stem cells.
abstract: 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.
authors.affiliation: Department of Medicine, Hem/Onc Division, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Theodore T
authors.initials: TT
authors.lastname: Ho
authors.affiliation: Department of Medicine, Hem/Onc Division, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Warr
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
authors.forename: Emmalee R
authors.initials: ER
authors.lastname: Adelman
authors.affiliation: Department of Medicine, Hem/Onc Division, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Lansinger
authors.affiliation: Department of Medicine, Hem/Onc Division, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Flach
authors.affiliation: Department of Medicine, Hem/Onc Division, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Evgenia V
authors.initials: EV
authors.lastname: Verovskaya
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.affiliation: Department of Medicine, Hem/Onc Division, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism