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Cited by 434Hematopoietic Stem Cell TransplantationMesenchymal stem cell researchTelomeres, Telomerase, and Senescence

Aging of hematopoietic stem cells

Open access
de Haan, Gerald, Lazare, Seka Simone·2018·Blood
DOI 10.1182/blood-2017-06-746412
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Abstract

Hematopoietic stem cells (HSCs) ensure a balanced production of all blood cells throughout life. As they age, HSCs gradually lose their self-renewal and regenerative potential, whereas the occurrence of cellular derailment strongly increases. Here we review our current understanding of the molecular mechanisms that contribute to HSC aging. We argue that most of the causes that underlie HSC aging result from cell-intrinsic pathways, and reflect on which aspects of the aging process may be reversible. Because many hematological pathologies are strongly age-associated, strategies to intervene in aspects of the stem cell aging process may have significant clinical relevance.

Verified 2026-10-06 · 7 references not checked yet

Integrity signals

Registry

Crossref · 10.1182/blood-2017-06-746412

Cites

101 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 101 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Young bone marrow cells engraft less well in aged recipients than in young recipients.

    “young bone marrow cells, when transplanted into aged recipients, engraft worse than when transplanted into young recipients.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Rossi, 2005, Cell intrinsic alterations underlie hematopoietic stem cell aging, Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [43] Ergen, 2012, Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing, Blood source

      Not checked in the free run.

  • Premisecitation

    The functional heterogeneity of the HSC population rises with age.

    “the functional heterogeneity of the HSC population increases with age.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [10] Dykstra, 2011, Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells, J Exp Med source

      Not checked in the free run.

    • cites [13] Sudo, 2000, Age-associated characteristics of murine hematopoietic stem cells, J Exp Med source

      Not checked in the free run.

    • cites [17] Beerman, 2010, Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion, Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [32] Cho, 2008, A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells, Blood source

      Not checked in the free run.

    • cites [33] Ho, 2017, Autophagy maintains the metabolism and function of young and old stem cells, Nature source

      Not checked in the free run.

  • Premisecitation

    Aging of the hematopoietic system differs at least qualitatively among mouse strains.

    “aging (also of the hematopoietic system) is at least qualitatively different in distinct strains of mice.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] De Haan, 1999, Genetic analysis of hemopoietic cell cycling in mice suggests its involvement in organismal life span, FASEB J source

      Not checked in the free run.

    • cites [31] de Haan, 1997, Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene, J Exp Med source

      Not checked in the free run.

  • Premisecitation

    A defective bone marrow environment can give rise to hematological malignancies.

    “hematological malignancies can result from a defective bone marrow environment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Zambetti, 2016, Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia, Cell Stem Cell source

      Not checked in the free run.

  • Interpretationreasoning

    Most of the proliferative burden is carried by committed progenitors.

    “most of the proliferative burden resides with committed progenitors”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 4
  • May combine two claims. 14

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The number of stem cells with reduced potential rises with age to offset the loss of function of individual stem cells.

    “the pool of stem cells with reduced potential increases to compensate for loss of function of individual stem cells”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Telomere shortening contributes to the functional decline of HSCs, and this is especially evident in humans.

    “the involvement of telomere shortening in the functional decline of HSC is particularly evident in human”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Aubert, 2008, Telomeres and aging, Physiol Rev source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Some cell-intrinsic causes of HSC aging are probably irreversible, while several others may be amenable to pharmacological intervention.

    “Although some of these cell-intrinsic causes of aging are unlikely to be reversible, several others might allow interventions and thus could potentially be explored for pharmacological targeting”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In humans, an age-dependent rise in putative stem cell frequency coincides with impaired function and reduced lymphoid potential.

    “an age-dependent increase in the frequency of putative stem cells, coinciding with impaired functionality and reduced lymphoid potential, has also been in the human system.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Kuranda, 2011, Age-related changes in human hematopoietic stem/progenitor cells, Aging Cell source

      Not checked in the free run.

    • cites [28] Pang, 2011, Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age, Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [29] Rundberg Nilsson, 2016, Human and murine hematopoietic stem cell aging is associated with functional impairments and intrinsic megakaryocytic/erythroid bias, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Telomeres shorten progressively in human HSCs from fetal liver, cord blood, or adult bone marrow, and this is linked to a strongly reduced proliferative potential.

    “telomeres progressively shorten in human HSCs isolated from fetal liver, cord blood, or adult bone marrow, which is associated with a strongly reduced proliferative potential.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Vaziri, 1994, Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Each time an HSC divides, its capacity to contribute to blood cell production falls.

    “with each cell division, the potential of a HSC to contribute to blood cell production declines”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    During steady-state hematopoiesis, the most primitive HSCs are largely inactive and divide rarely.

    “during steady-state hematopoiesis the most primitive stem cells are largely inactive.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [18] Van Zant, 1984, Studies of hematopoietic stem cells spared by 5-fluorouracil, J Exp Med source

      Not checked in the free run.

    • cites [19] Bradford, 1997, Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment, Exp Hematol

      Not checked in the free run.

    • cites [20] Cheshier, 1999, In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells, Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [21] Dykstra, 2007, Long-term propagation of distinct hematopoietic differentiation programs in vivo, Cell Stem Cell source

      Not checked in the free run.

    • cites [22] Morita, 2010, Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment, J Exp Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The cell-intrinsic aging pathways are probably highly interdependent and interconnected.

    “in effect they are likely to be highly interdependent and interconnected.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Interpretationnone given

    The accumulation of random DNA damage is the least reversible cause of HSC aging.

    “The most irreversible cause of HSC aging relates to the accumulation of random DNA damage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In otherwise healthy people, clonal hematopoiesis raises the risk of leukemia and cardiovascular disease and is linked to higher mortality.

    “clonal hematopoiesis in otherwise healthy individuals increases the risk to develop leukemia, and, interestingly, cardiovascular disease, and thus is associated with increased mortality.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [74] Zink, 2017, Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly, Blood source

      Not checked in the free run.

    • cites [75] Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med source

      Not checked in the free run.

    • cites [76] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Clonal hematopoiesis is linked to a higher incidence of atherosclerotic cardiovascular disease, which suggests that monocytic cells derived from these aged stem cell clones function poorly.

    “clonal hematopoiesis has been associated with increased incidence of atherosclerotic cardiovascular disease, suggesting that the function of monocytic cells derived from these aged stem cell clones is impaired.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [83] Fuster, 2017, Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice, Science source

      Not checked in the free run.

    • cites [84] Jaiswal, 2017, Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High levels of mitochondrial reactive oxygen species build up in aged HSCs and impair their function.

    “high levels of reactive oxygen species, generated by mitochondria, accumulate in aged HSCs and compromise their functioning.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells, Nat Med source

      Not checked in the free run.

    • cites [62] Mohrin, 2015, Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged red cells and aged platelets function poorly.

    “aged red cells and aged platelets display impaired functioning”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Hoehn, 2015, Molecular mechanisms of erythrocyte aging, Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Removing senescent cells in mice improves regenerative capacity and prolongs life span.

    “The genetic or pharmacological depletion of senescent cells in mice has been shown to enhance regenerative potential and extend life span.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Baker, 2016, Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan, Nature source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Impaired autophagy in aged HSCs leads to mitochondrial accumulation, which causes metabolic stress.

    “impaired autophagy in aged HSCs appears to specifically result in the accumulation of mitochondria, which in turn induces metabolic stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Pharmacological interventions in these signaling pathways are feasible and may restore function in aged HSCs.

    “pharmacological interventions in these signaling pathways are feasible and may be exploited to restore function in aged HSCs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mutations in genes encoding epigenetic enzymes occur in elderly people with oligoclonal hematopoiesis and in patients with myelodysplastic syndromes or acute myeloid leukemia.

    “mutations in genes encoding for epigenetic enzymes have been found in either elderly people whose hematopoietic system has become oligoclonal, or in patients with myelodysplastic syndromes or acute myeloid leukemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Steensma, 2015, Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial dysfunction from accumulating mitochondrial DNA mutations causes several hematopoietic defects typical of the elderly, but HSCs themselves seem relatively resistant.

    “Mitochondrial dysfunctioning caused by accumulating mitochondrial DNA mutations has been shown to cause multiple hematopoietic defects that are typically seen in the elderly, but HSCs themselves appear to relatively resistant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Norddahl, 2011, Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging, Cell Stem Cell source

      Not checked in the free run.

18 of 18

  • The paper relies on this without support.

    The formation of blood cells in mice and humans is conceptually identical.

    “decades of research have shown that, conceptually, the formation of blood cells in mouse and human is identical”

  • The paper relies on this without support.

    Many hematological conditions are strongly age-dependent.

    “many hematological conditions are strongly age-dependent.”

  • The paper relies on this without support.

    The purity of HSCs in transplantation experiments is never more than 50%.

    “the purity of HSCs, at least when assayed in transplantation experiments, is never more than 50%.”

  • The paper relies on this without support.

    Even after the most stringent enrichment protocols, many non-HSCs remain.

    “even after the most stringent enrichment protocols, many non-HSCs (mostly progenitors) remain.”

  • The paper relies on this without support.

    Genetic disparities are likely to be prominent in humans.

    “These genetic disparities are also likely to be prominent in human.”

  • The paper relies on this without support.

    During steady-state in vivo hematopoiesis, no conversion of hematopoietic progenitors into stem cells has been reported.

    “but in the hematopoietic system such progenitor-to-stem cell conversions have never been described, at least not during steadystate in vivo hematopoiesis.”

  • The authors state this as an assumption.

    Human HSC aging is not fundamentally different from mouse HSC aging.

    “Assuming that in human HSC aging is not fundamentally different than in mice”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Aged HSCs have lower regenerative potential and skewed differentiation toward the myeloid lineage instead of the lymphoid lineage.

    “Furthermore, aged HSCs have been shown to have lower regenerative potential and skewed differentiation toward the myeloid lineage instead of the lymphoid lineage [88].”

    From Osteoimmunology of Fracture Healing. (2024) · cites this paper as [88]

Cites

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Related

Authors
de Haan, G., & Lazare, S. S.
Affiliations
  • European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  • University Medical Center Groningen (NL)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2018-02-01
Volume
131
Issue
5
Pages
479-487
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2017-06-746412
OpenAlex
W2768409010
Semantic Scholar
767a7a803b0d377cfb03d909da859be3e4df29bc
Cited by
432
References
107
Citations by year
2026: 41 · 2025: 46 · 2024: 68 · 2023: 62 · 2022: 55 · 2021: 67 · 2020: 51 · 2019: 27 · 2018: 15
FWCI
4.01
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Funders
  • European Commission (316964)
  • ZonMw
  • KWF Kankerbestrijding (2014-7178, RUG 2014-7178)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
hematopoietic stem cells, stem cell aging, cellular senescence, self-renewal, regenerative capacity, molecular mechanisms of aging
MeSH terms
Aging, Animals, Autophagy, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mitochondria, Cellular Senescence, Epigenesis, Genetic

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