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Autophagy maintains the metabolism and function of young and old stem cells
Open accessAbstract
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.
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“During ageing, tissue regenerative functions decline, in part due to stem cell-intrinsic accumulation of damage (for example, DNA damage, loss of proteostasis and oxidative damage), functional decay of niche cells and increased inflammation (inflammageing)4–9 through uncharacterized mechanisms.”
From Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredIn the citing paper
“the functional heterogeneity of the HSC population increases with age.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [33]
In the citing paper
“individual HSCs behave very differently.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [33]
In the citing paper
“in aged mice that display an overall increase in HSC pool size”
From Aging of hematopoietic stem cells (2018) · cites this paper as [33]
In the citing paper
“A large fraction of aged HSCs show impaired levels of autophagy.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [33]
In the citing paper
“Autophagy, which helps degrade large aggregates or damaged organelles, is critical to maintain HSCs during ageing106.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [106]
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Metadata
- Authors
- Ho, T. T., Warr, M. R., Adelman, E. R., Lansinger, O. M., Flach, J., Verovskaya, E. V., Figueroa, M. E., & Passegué, E.
- Affiliations
- University of California, San Francisco (US)
- University of Michigan (US)
- ORCID
- Venue
- Nature
- Published
- 2017-03
- Volume
- 543
- Issue
- 7644
- Pages
- 205-210
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5344718
- OpenAlex
- W2592615787
- Cited by
- 896
- References
- 42
- Citations by year
- 2026: 58 · 2025: 67 · 2024: 95 · 2023: 103 · 2022: 107 · 2021: 124 · 2020: 118 · 2019: 93 · 2018: 90 · 2017: 40
- FWCI
- 71.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (T32AG000114)
- National Heart, Lung, and Blood Institute (R01HL126947)
- National Cancer Institute (R01CA184014)
- National Institute of General Medical Sciences (T32GM008284)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063720)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- autophagy, hematopoietic stem cells, cellular aging, stem cell self-renewal, mitochondrial accumulation, myeloid differentiation, epigenetic regulation, metabolic stress, regenerative capacity, stem cell quiescence
- MeSH terms
- Cell Self Renewal, Animals, Autophagy, Female, Hematopoiesis, Hematopoietic Stem Cells, Male, Mitochondria, Cellular Senescence, Myeloid Cells, Epigenesis, Genetic, Mice
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