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Cited by 407Genetics, Aging, and Longevity in Model OrganismsHematopoietic Stem Cell TransplantationMesenchymal stem cell research

Ageing and rejuvenation of tissue stem cells and their niches

Open access
Brunet, Anne, Goodell, Margaret A., Rando, Thomas A.·2023·Nature Reviews Molecular Cell Biology
DOI 10.1038/s41580-022-00510-wPMC PMC9879573
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Abstract

Most adult organs contain regenerative stem cells, often organized in specific niches. Stem cell function is critical for tissue homeostasis and repair upon injury, and it is dependent on interactions with the niche. During ageing, stem cells decline in their regenerative potential and ability to give rise to differentiated cells in the tissue, which is associated with a deterioration of tissue integrity and health. Ageing-associated changes in regenerative tissue regions include defects in maintenance of stem cell quiescence, differentiation ability and bias, clonal expansion and infiltration of immune cells in the niche. In this Review, we discuss cellular and molecular mechanisms underlying ageing in the regenerative regions of different tissues as well as potential rejuvenation strategies. We focus primarily on brain, muscle and blood tissues, but also provide examples from other tissues, such as skin and intestine. We describe the complex interactions between different cell types, non-cell-autonomous mechanisms between ageing niches and stem cells, and the influence of systemic factors. We also compare different interventions for the rejuvenation of old regenerative regions. Future outlooks in the field of stem cell ageing are discussed, including strategies to counter ageing and age-dependent disease. Stem cell function declines during ageing, resulting in the loss of tissue integrity and health deterioration. Ageing is associated with defects in the maintenance of stem cell quiescence and cell differentiation ability, clonal expansion and infiltration of immune cells in the niche. This Review discusses the mechanisms underlying ageing in stem cells and their niches, and potential rejuvenation strategies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes how mammalian tissue stem cells and their niches deteriorate with age, focusing on brain, muscle and blood, and discusses rejuvenation strategies. It argues that stem cell ageing is driven by cell-intrinsic changes plus non-cell-autonomous niche, immune and systemic factors, with interventions such as parabiosis, exercise, dietary restriction and partial reprogramming showing promise but unresolved safety and durability questions.

Key findings

  • Most somatic stem cells decline in number and function with age, but HSCs are an exception: phenotypically defined HSC numbers increase while function decreases, and old HSCs produce fewer lymphoid cells and are skewed towards the myeloid lineage.
  • Ageing niches show immune-cell infiltration, inflammation, altered soluble factors and increased stiffness; in the SVZ neurogenic niche, RNA-seq uncovered 11 cell types, and ageing is accompanied by clonally expanded cytotoxic CD8+ T cells.
  • Clonal haematopoiesis is ubiquitous in aged humans and is associated with a tenfold increased risk of malignancy; it often involves somatic mutations in epigenetic regulators such as DNMT3A.
  • Rejuvenation strategies including heterochronic parabiosis, exercise, dietary restriction, NAD+ precursors and partial OSKM reprogramming can restore youthful features in some aged stem cells, but effects vary by tissue and stem cell type.

Methods

  • Design: narrative review of mammalian somatic stem cell ageing and rejuvenation, not a primary experimental study.
  • Scope: focuses primarily on brain, muscle and blood tissues, with examples from skin and intestine; covers stem cell-intrinsic defects, niche changes, molecular mechanisms, systemic interactions and rejuvenation interventions.
  • Analysis: synthesizes findings from single-cell transcriptomics, lineage tracing, clonal analysis, proteomics, transplantation and parabiosis studies; no systematic search strategy or meta-analysis is described.

Limitations

  • The paper states that most discussed studies were conducted in mice, sometimes rats, whose lifespan is relatively short (~3 years), and that stem cell maintenance mechanisms may differ from humans and other long-lived species.
  • The paper states that the extent to which organoid or cellular models recapitulate in vivo ageing features remains to be determined, and that an efficient and safe stem cell therapy to slow or reverse tissue ageing has not been identified.
  • Evident from the text: as a review, it provides no new primary data, and it notes unresolved debates such as the timing of human hippocampal neurogenesis decline.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41580-022-00510-w

Cites

260 of 260 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 266 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Ageing leads to a decline in tissue stem cell function.

    “Ageing leads to a decline in tissue stem cell function3–5.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Goodell, M. A. & Rando, T. A. Stem cells and healthy aging. Science 350, 1199–1204 (2015). source

      Not checked in the free run.

    • cites [4] Navarro Negredo, P., Yeo, R. W. & Brunet, A. Aging and rejuvenation of neural stem cells and their niches. Cell Stem Cell 27, 202–223 (2020). source

      Not checked in the free run.

    • cites [5] Oh, J., Lee, Y. D. & Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20, 870–880 (2014). source

      Not checked in the free run.

  • Premisenone given

    Cells with rapid turnover rates are largely replaced by the progeny of very active adult stem cells.

    “Cells with rapid turnover rates are largely replaced by the progeny of very active stem cells (often referred to as ‘adult stem cells’, ‘tissue stem cells’ or ‘somatic stem cells’).”
    Quote in the paperSubstantial claim
  • Premisenone given

    A main feature of ageing is a reduced ability of somatic stem cells to produce new differentiated cells that are essential for homeostasis and repair in brain, blood, muscle, fat, skin, lung and other tissues.

    “A main feature of ageing is a reduced ability of somatic stem cells to produce new differentiated cells that are essential for homeostasis and repair in brain, blood, muscle, fat, skin, lung and so on.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In the mouse brain, single-cell RNA-seq analyses indicate that the number of activated neural stem cells (NSCs) and neuroblasts decreases with ageing in both the subventricular zone (SVZ) NSC niche and the hippocampal NSC niche.

    “For example, in the mouse brain, single-cell RNA-seq analyses indicate that the number of activated neural stem cells (NSCs) and neuroblasts (progeny) decreases with ageing in both the subventricular zone (SVZ) NSC niche and the hippocampal NSC niche6–9 — the main locations of NSCs.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [6] Artegiani, B. et al. A single-cell RNA sequencing study reveals cellular and molecular dynamics of the hippocampal neurogenic niche. Cell Rep. 21, 3271–3284 (2017). source

      Not checked in the free run.

    • cites [7] Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019). source

      Not checked in the free run.

    • cites [8] Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176, 1407–1419.e14 (2019). source

      Not checked in the free run.

    • cites [9] Ibrayeva, A. et al. Early stem cell aging in the mature brain. Cell Stem Cell 28, 955–966.e7 (2021). source

      Not checked in the free run.

  • Premisenone given

    Cells with low or very low turnover rates are regenerated with smaller populations of stem cells.

    “By contrast, cells with a low or very low turnover rate (neurons and muscle fibres) are regenerated with smaller populations of stem cells (FIG. 1a).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 89
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisenone given

    The number and function of most somatic stem cells decline with ageing, with the exception of HSCs.

    “The number and function of most somatic stem cells decline with ageing, with the exception of HSCs.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Ageing is characterized by a decline in all organ function and a striking increase in multi-organ diseases.

    “Ageing is characterized by a decline in all organ function and a striking increase in multi-organ diseases1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Rando, T. A. & Wyss-Coray, T. Asynchronous, contagious and digital aging. Nat. Aging 1, 29–35 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Differentiated cell types in adult organs have different turnover rates; some last a lifetime while others are continuously lost and replenished quickly.

    “The cell types that build each organ are subject to different turnover rates. Some differentiated cell types can last a lifetime, such as neurons in the brain or cardiomyocytes in the heart. Other differentiated cell types are continuously lost and replenished quickly, such as red blood cells, monocytes and epithelial cells of the skin and intestine2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Sender, R. & Milo, R. The distribution of cellular turnover in the human body. Nat. Med. 27, 45–48 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The number of HSCs (defined by phenotype) increases but their function decreases with age.

    “The number of HSCs (defined by phenotype) increases but their function decreases with age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Stem cells can enter a state of senescence or excessive activation or can undergo aberrant differentiation.

    “Stem cells can enter a state of senescence or excessive activation or can undergo aberrant differentiation (FIG. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Subpopulations of MuSCs become more primed (poised towards a myogenic fate) with ageing, whereas others adopt a more fibrogenic state.

    “For example, subpopulations of MuSCs become more ‘primed’ (that is, poised towards a myogenic fate) with ageing32, whereas others adopt a more fibrogenic state16.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source

      Not checked in the free run.

    • cites [16] Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007). source

      Not checked in the free run.

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    Premisecitation

    In the brain, old progenitors exhibit reduced differentiation dynamics during ageing, and their fate potential is predominantly skewed towards astrocytes.

    “In the brain, old progenitors exhibit reduced differentiation dynamics during ageing45, and their fate potential is predominantly skewed towards astrocytes46.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Zhao, X. et al. 4D imaging analysis of the aging mouse neural stem cell niche reveals a dramatic loss of progenitor cell dynamism regulated by the RHO-ROCK pathway. Stem Cell Rep. 17, 245–258 (2022). source

      Not checked in the free run.

    • cites [46] White, C. W. III et al. Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation. Proc. Natl Acad. Sci. USA 117, 22214–22224 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Machine learning models of HSC division as a function of increasing age suggested that HSC division is intrinsically regulated in young adults and old adults, but is more extrinsically regulated in middle age.

    “Consistent with this possibility, machine learning models of HSC division as a function of increasing age suggested that HSC division is intrinsically regulated in young adults and old adults, but is more extrinsically regulated in middle age47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Arai, F. et al. Machine learning of hematopoietic stem cell divisions from paired daughter cell expression profiles reveals effects of aging on self-renewal. Cell Syst. 11, 640–652.e5 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Stem cell pools are heterogeneous, and different subpopulations arise with increasing age.

    “Thus, stem cells pools are heterogeneous, and different subpopulations arise with increasing age (FIG. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In muscle, MuSCs exist as a heterogeneous quiescent population in adult mice, with changes in heterogeneity with ageing.

    “In muscle, MuSCs also exist as a heterogeneous quiescent population in adult mice30–33, with changes in heterogeneity with ageing32,34,35.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [30] Kuang, S., Kuroda, K., Le Grand, F. & Rudnicki, M. A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007). source

      Not checked in the free run.

    • cites [31] Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012). source

      Not checked in the free run.

    • cites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source

      Not checked in the free run.

    • cites [33] Evano, B. et al. Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation. PLoS Genet. 16, e1009022 (2020). source

      Not checked in the free run.

    • cites [34] Brett, J. O. et al. Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of cyclin D1. Nat. Metab. 2, 307–317 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Clonal haematopoiesis is ubiquitous in aged individuals and is probably the result of variant stem cells having a survival and proliferation advantage.

    “This phenomenon is ubiquitous in aged individuals, and it is probably the result of variant stem cells having a survival and proliferation advantage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A subset of MuSCs identified by inducible Mx1-Cre lineage tracing is particularly resistant to stress, perhaps representing a population protected from ageing.

    “Another subset of MuSCs (identified by inducible Mx1–Cre lineage tracing) is particularly resistant to stress36, perhaps also representing a population that is protected from ageing37.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Scaramozza, A. et al. Lineage tracing reveals a subset of reserve muscle stem cells capable of clonal expansion under stress. Cell Stem Cell 24, 944–957.e5 (2019). source

      Not checked in the free run.

    • cites [37] Collins, C. A., Zammit, P. S., Ruiz, A. P., Morgan, J. E. & Partridge, T. A. A population of myogenic stem cells that survives skeletal muscle aging. Stem Cell 25, 885–894 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the brain, old age is accompanied by an increase in the number of quiescent NSCs and a decrease in their ability to activate.

    “In the brain, old age is accompanied by an increase in the number of quiescent NSCs and a decrease in their ability to activate6–8.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Artegiani, B. et al. A single-cell RNA sequencing study reveals cellular and molecular dynamics of the hippocampal neurogenic niche. Cell Rep. 21, 3271–3284 (2017). source

      Not checked in the free run.

    • cites [7] Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019). source

      Not checked in the free run.

    • cites [8] Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176, 1407–1419.e14 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In muscle, clonal expansion of MuSCs has been reported during tissue regeneration in response to acute injury, but has not yet been thoroughly examined during ageing.

    “In muscle, clonal expansion of MuSCs has been reported during tissue regeneration in response to acute injury55, but has not yet been thoroughly examined during ageing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Tierney, M. T., Stec, M. J., Rulands, S., Simons, B. D. & Sacco, A. Muscle stem cells exhibit distinct clonal dynamics in response to tissue repair and homeostatic aging. Cell Stem Cell 22, 119–127.e3 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Clonal haematopoiesis is associated with a tenfold increased risk of malignancy development, underlying the increase in incidence of blood cancer with ageing in humans.

    “Clonal haematopoiesis is associated with a tenfold increased risk of malignancy development, thus underlying the increase in the incidence of blood cancer with ageing in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Niche cells in many tissues experience drastic transcriptomic changes with ageing, which could indirectly impair stem cell function.

    “Niche cells in many tissues also experience drastic transcriptomic changes with ageing69, which could indirectly impair stem cell function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Tabula Muris, C. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Upregulation of cell adhesion markers in HSCs may be a direct indicator of their inflammatory state and may correlate with the bias towards myeloid cell production.

    “Upregulation of cell adhesion markers in HSCs may be a direct indicator of their inflammatory state and may correlate with the bias towards myeloid cell production68.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Svendsen, A. F. et al. A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood 138, 439–451 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clonal expansion has also been found in other human tissues, including skin, colon and oesophagus, and is thought to be a normal, possibly ubiquitous, process associated with ageing in all tissues, in particular those that experience significant cellular turnover.

    “Clonal expansion has also been found in other human tissues, including skin, colon and oesophagus52–54, and is thought to be a normal, possibly ubiquitous, process that is associated with ageing in all tissues, in particular those that experience significant cellular turnover.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [52] Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019). source

      Not checked in the free run.

    • cites [53] Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018). source

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    • cites [54] Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other types of immune cells, such as regulatory T cells, are reduced in number in aged skin, and this might contribute to the unbalance in tissue regulation for this regenerative niche.

    “Conversely, other types of immune cells, such as regulatory T cells, are reduced in number in aged skin11, and this might contribute to the unbalance in tissue regulation for this regenerative niche.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Ge, Y. et al. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, several stem cell types, including those of the colon and liver, acquire somatic mutations at a steady rate during ageing; this feature is likely universal.

    “In humans, several stem cell types, including those of the colon and liver, have been shown to acquire somatic mutations at a steady rate during ageing60; this feature is likely universal.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These ageing-dependent changes in the composition of the stem cell niche and infiltration of immune cells influence the extracellular milieu, but also impact the ageing of stem cells in a non-cell-autonomous manner.

    “These ageing-dependent changes in the composition of the stem cell niche and infiltration of immune cells influence the extracellular milieu, but also impact the ageing of stem cells in a non-cell-autonomous manner (see later).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    In the bone marrow, ageing HSCs display increased transcriptional heterogeneity, but a set of markers is consistently upregulated with ageing (for example, P-selectin).

    “In the bone marrow, ageing HSCs display increased transcriptional heterogeneity, but a set of markers is consistently upregulated with ageing (for example, the cell adhesion molecule P-selectin).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    While clonal expansion during normal ageing has not yet been observed in mice, it has been reported in mouse models for disease and in physiologically aged macaques.

    “While clonal expansion during normal ageing has not yet been observed in mice, it has been reported in mouse models for disease61 and in physiologically aged macaques62.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Heyde, A. et al. Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell 184, 1348–1361.e22 (2021). source

      Not checked in the free run.

    • cites [62] Yu, K. R. et al. The impact of aging on primate hematopoiesis as interrogated by clonal tracking. Blood 131, 1195–1205 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The infiltration of clonally expanded T cells and B cells is also observed in the brain and other tissues with ageing in mice and humans, and it is accentuated in age-related diseases.

    “The infiltration of clonally expanded T cells and B cells is also observed in the brain and other tissues with ageing in mice and humans69,71–73, and it is accentuated in age-related diseases74,75.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [69] Tabula Muris, C. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source

      Not checked in the free run.

    • cites [71] Gross, K. M. et al. Loss of slug compromises dna damage repair and accelerates stem cell aging in mammary epithelium. Cell Rep. 28, 394–407.e6 (2019). source

      Not checked in the free run.

    • cites [72] Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115.e12 (2021). source

      Not checked in the free run.

    • cites [73] Groh, J. et al. Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat. Aging 1, 357–367 (2021). source

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    • cites [74] Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020). source

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

    Interpretationnone given

    The specific changes in proliferative and differentiation capacity, the timing of decline and the type of molecular defects with ageing may differ depending on tissue and age time points.

    “However, the specific changes in proliferative and differentiation capacity, the timing of decline and the type of molecular defects with ageing may differ depending on tissue and age time points.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    These analyses have revealed profound changes in the composition of the niche and transcriptomic shifts in specific niche cells during ageing.

    “These types of analysis have revealed profound changes in the composition of the niche (that is, the proportion of different cell types other than the stem cells themselves) as well as transcriptomic shifts in specific niche cells during ageing (FIG. 2).”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Other signalling pathways and transcription factors implicated in inflammation signalling may also function downstream of systemic factors in stem cell niches during ageing.

    “Other signalling pathways and transcription factors implicated in inflammation signalling may also function downstream of systemic factors in stem cell niches during ageing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FOXO factors are also activated by oxidative stress and can induce interferon production in NSCs via the STING pathway.

    “FOXO factors are also activated by oxidative stress and can induce interferon production in NSCs via the STING pathway93.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Hwang, I. et al. Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification. Nat. Commun. 12, 640 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FOXO factors may integrate systemic or paracrine signals to orchestrate transcriptional changes that maintain stem cell quiescence during ageing and regulate inflammation.

    “Thus, FOXO factors may integrate systemic or paracrine signals to orchestrate transcriptional changes that maintain stem cell quiescence during ageing and regulate inflammation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cell death is also increased in ageing HSCs, and this is dependent on the DNA-damage signalling pathway ATM.

    “Cell death is also increased in ageing HSCs, and this is dependent on the DNA-damage signalling pathway ATM96.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Gutierrez-Martinez, P. et al. Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat. Cell Biol. 20, 413–421 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In muscle, DNA methylation changes with ageing in MuSCs, with increased heterogeneity (accompanied by transcriptional heterogeneity), suggesting an epigenetic drift with ageing.

    “In muscle, DNA methylation changes with ageing in MuSCs, with increased heterogeneity (accompanied by transcriptional heterogeneity), suggesting an epigenetic drift with ageing33,67.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Evano, B. et al. Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation. PLoS Genet. 16, e1009022 (2020). source

      Not checked in the free run.

    • cites [67] Hernando-Herraez, I. et al. Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat. Commun. 10, 4361 (2019). source

      Not checked in the free run.

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

    Premisenone given

    The transcription factors that induce stem cell rejuvenation remain largely unknown.

    “However, the transcription factors that induce stem cell rejuvenation remain largely unknown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the brain, expression of TET2 decreases during ageing in the hippocampal neurogenic niche, and Tet2 knockout mimics aspects of ageing, whereas its overexpression prevents the decline in neuronal differentiation during ageing.

    “In the brain, expression of TET2, the enzyme responsible for the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, decreases during ageing in the hippocampal neurogenic niche97, and Tet2 knockout mimics aspects of ageing, whereas its overexpression prevents the decline in neuronal differentiation during ageing97.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Gontier, G. et al. Tet2 rescues age-related regenerative decline and enhances cognitive function in the adult mouse brain. Cell Rep. 22, 1974–1981 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FOXO transcription factors integrate growth factors and stress signal transduction pathways, and may represent a hub for the action of various systemic factors in stem cells in ageing brain, muscle, blood and intestine.

    “For example, FOXO transcription factors integrate growth factors and stress signal transduction pathways, and may represent a ‘hub’ for the action of various systemic factors in stem cells in ageing brain, muscle, blood and intestine32,85–90.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source

      Not checked in the free run.

    • cites [85] Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009). source

      Not checked in the free run.

    • cites [86] Gopinath, S. D., Webb, A. E., Brunet, A. & Rando, T. A. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Rep. 2, 414–426 (2014). source

      Not checked in the free run.

    • cites [87] Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009). source

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    • cites [88] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). source

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    • cites [89] Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007). source

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    • cites [90] Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Constitutive deletion of three of the FOXO genes (FOXO1, FOXO3 and FOXO4) in the MuSC lineage during development results in the impairment of postnatal establishment of the MuSC population and a more rapid MuSC depletion with age.

    “Consistent with previous reports of the role of FOXO factors in HSC, MuSC and NSC quiescence85–90, constitutive deletion of three of the FOXO genes (FOXO1, FOXO3 and FOXO4) in the MuSC lineage during development results in the impairment of postnatal establishment of the MuSC population and a more rapid MuSC depletion with age32.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source

      Not checked in the free run.

    • cites [85] Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009). source

      Not checked in the free run.

    • cites [86] Gopinath, S. D., Webb, A. E., Brunet, A. & Rando, T. A. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Rep. 2, 414–426 (2014). source

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    • cites [87] Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009). source

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    • cites [88] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). source

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    • cites [89] Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007). source

      Not checked in the free run.

    • cites [90] Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008). source

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    Premisecitation

    STAT3 is modified by O-linked β-N-acetylglucosamine, and this post-translational modification is lost during ageing, contributing to the ageing-dependent bias towards glia.

    “STAT3 is modified by O-linked β-N-acetylglucosamine, and this post-translational modification is lost during ageing, contributing to the ageing-dependent bias towards glia46.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] White, C. W. III et al. Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation. Proc. Natl Acad. Sci. USA 117, 22214–22224 (2020). source

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  • May combine two claims.

    Premisecitation

    The ageing skin is characterized by niche stiffening and hair shaft miniaturization, which are accompanied by defects in hair follicle stem cells (HFSCs).

    “The ageing skin is characterized by niche stiffening and hair shaft miniaturization, which are accompanied by defects in hair follicle stem cells (HFSCs)83,84.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Xie, Y. et al. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis. Cell Stem Cell 29, 70–85.e6 (2022). source

      Not checked in the free run.

    • cites [84] Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021). source

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  • May combine two claims.

    Premisecitation

    Stem cell niches become stiffer during ageing, and they exhibit drastic changes in ECM composition.

    “Stem cell niches become stiffer during ageing, and they exhibit drastic changes in ECM composition.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    The general milieu of the niche may become more inflamed and stiffer, which may contribute to stem cell defects.

    “Hence, the general milieu of the niche may become more inflamed and stiffer, which may contribute to stem cell defects.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Age-dependent NSC decline can be reversed by expression of the master transcription factor for lysosomes TFEB and by nutrient deprivation.

    “Interestingly, age-dependent NSC decline can be reversed by expression of the master transcription factor for lysosomes TFEB and by nutrient deprivation64.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359, 1277–1283 (2018). source

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  • May combine two claims.

    Premisecitation

    Glucose metabolism is critical for MuSCs and influences histone acetylation.

    “Glucose metabolism is critical for MuSCs and influences histone acetylation124.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Yucel, N. et al. Glucose metabolism drives histone acetylation landscape transitions that dictate muscle stem cell function. Cell Rep. 27, 3939–3955.e6 (2019). source

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  • May combine two claims.

    Premisecitation

    Autophagy is also required for activation out of quiescence, and defects in autophagic activity with ageing lead to increased cell death during activation.

    “Autophagy is also required for activation out of quiescence109, and defects in autophagic activity with ageing lead to increased cell death during activation110.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [109] Tang, A. H. & Rando, T. A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 33, 2782–2797 (2014). source

      Not checked in the free run.

    • cites [110] White, J. P. et al. The AMPK/p27Kip1 axis regulates autophagy/apoptosis decisions in aged skeletal muscle stem cells. Stem Cell Rep. 11, 425–439 (2018). source

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  • May combine two claims.

    Premisecitation

    The protein chaperone network is entirely rewired when NSCs give rise to differentiated progeny, and this rewiring is impaired during ageing.

    “Indeed, the protein chaperone network is entirely rewired when NSCs give rise to differentiated progeny, and this rewiring is impaired during ageing112.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Vonk, W. I. M. et al. Differentiation drives widespread rewiring of the neural stem cell chaperone network. Mol. Cell 78, 329–345 e9 (2020). source

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  • May combine two claims.

    Premisecitation

    SIRT2 is necessary to prevent ageing in HSCs and can inhibit the inflammation (inflammasome) response that occurs in old HSCs.

    “SIRT2, another member of the sirtuin family, is necessary to prevent ageing in HSCs, and can inhibit the inflammation (inflammasome) response that occurs in old HSCs119.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Luo, H. et al. Mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome regulates the functional deterioration of hematopoietic stem cell aging. Cell Rep. 26, 945–954.e4 (2019). source

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  • May combine two claims.

    Premisecitation

    In old quiescent MuSCs, the repressive mark H3K27me3 increases, whereas the activating mark H3K4me3 decreases.

    “In old quiescent MuSCs, the repressive mark trimethylated histone H3 at lysine 27 (H3K27me3) increases, whereas the activating mark trimethylated histone H3 at lysine 4 (H3K4me3) decreases65.”
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    • cites [65] Liu, L. et al. Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. Cell Rep. 4, 189–204 (2013). source

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  • May combine two claims.

    Interpretationreasoning

    These results illustrate the critical nature of chromatin regulators for long-lasting changes during ageing, and their potential to integrate extrinsic stimuli.

    “Together, these results illustrate the critical nature of chromatin regulators for long-lasting changes during ageing, and their potential to integrate extrinsic stimuli.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Lysosomes and autophagy, which clear damaged proteins and organelles, are both critical to maintain stem cells and ameliorate their function during ageing.

    “Hence, lysosomes and autophagy, which clear damaged proteins and organelles, are both critical to maintain stem cells and ameliorate their function during ageing.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In MuSCs, autophagy is essential for the maintenance of MuSC quiescence, via mitophagy, and this declines with ageing.

    “In MuSCs, autophagy is essential for the maintenance of MuSC quiescence, via the process of mitophagy (degradation of damaged mitochondria), and this declines with ageing108.”
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    • cites [108] Garcia-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016). source

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  • May combine two claims.

    Premisecitation

    A comprehensive analysis of murine HSC ageing has found increased chromatin accessibility and an overall increase in transcription.

    “A comprehensive analysis of murine HSC ageing has found increased chromatin accessibility and an overall increase in transcription68.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Svendsen, A. F. et al. A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood 138, 439–451 (2021). source

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  • May combine two claims.

    Premisecitation

    Glycolysis and mitochondrial function decline during ageing.

    “Glycolysis and mitochondrial function also decline during ageing.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [121] Poisa-Beiro, L. et al. Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells. Sci. Rep. 10, 11597 (2020). source

      Not checked in the free run.

    • cites [122] Pala, F. et al. Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977 (2018). source

      Not checked in the free run.

    • cites [123] Hennrich, M. L. et al. Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nat. Commun. 9, 4004 (2018). source

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  • May combine two claims.

    Premisecitation

    Primary cultures of old quiescent NSCs exhibit increased chromatin accessibility at genes involved in quiescence, a potential mechanism underlying deep quiescence during ageing.

    “Primary cultures of old quiescent NSCs also exhibit increased chromatin accessibility at genes involved in quiescence, a potential mechanism underlying deep quiescence during ageing98.”
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    • cites [98] Maybury-Lewis, S. Y. et al. Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age. Aging Cell 20, e13499 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These age-dependent chromatin changes in HFSCs are affected by stiffening of the niche and could mediate the impact of external and biophysical properties on stem cells during ageing.

    “These age-dependent chromatin changes in HFSCs are affected by stiffening of the niche84, and could mediate the impact of external and biophysical properties on stem cells during ageing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HSC maintenance by autophagy is mediated at least in part by MAEA, although it is not yet clear whether this mechanism contributes to HSC ageing.

    “HSC maintenance by autophagy is mediated at least in part by a membrane ubiquitin ligase called ‘MAEA’ (macrophage–erythroblast attacher), although it is not yet clear whether this mechanism contributes to HSC ageing107.”
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    • cites [107] Wei, Q. et al. MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells. Nat. Commun. 12, 2522 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Protein homeostasis is influenced by the external milieu, and could connect cell-cell interaction and systemic factors to key cellular function for stem cells.

    “Protein homeostasis is influenced by the external milieu, and could connect cell–cell interaction and systemic factors to key cellular function for stem cells (FIG. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Expression of lamin B1 declines in old NSCs, and restoration of lamin B1 expression is sufficient to increase old NSC proliferation and neurogenesis.

    “Finally, expression of lamin B1, a key component of the nuclear architecture involved in epigenomic maintenance103, declines in old NSCs, and restoration of lamin B1 expression is sufficient to increase old NSC proliferation and neurogenesis104.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] Guerreiro, I. & Kind, J. Spatial chromatin organization and gene regulation at the nuclear lamina. Curr. Opin. Genet. Dev. 55, 19–25 (2019). source

      Not checked in the free run.

    • cites [104] Bin Imtiaz, M. K. et al. Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. Cell Stem Cell 28, 967–977.e8 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Quiescent MuSCs exhibit reduced energetic demands and perturbed oxidative phosphorylation during ageing.

    “Quiescent MuSCs exhibit reduced energetic demands and perturbed oxidative phosphorylation during ageing122.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Pala, F. et al. Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977 (2018). source

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  • May combine two claims.

    Premisecitation

    Chaperone-mediated autophagy is essential to preserve HSCs throughout the lifespan, not only by clearing proteins but also by altering lipid metabolism.

    “Finally, a particular form of autophagy — chaperone-mediated autophagy — is essential to preserve HSCs throughout the lifespan, not only by clearing proteins but also by altering lipid metabolism111.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Dong, S. et al. Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged MuSCs and HSCs have increased glucose use and higher levels of glycolysis.

    “Aged MuSCs and HSCs have increased glucose use and higher levels of glycolysis121–123.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [121] Poisa-Beiro, L. et al. Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells. Sci. Rep. 10, 11597 (2020). source

      Not checked in the free run.

    • cites [122] Pala, F. et al. Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977 (2018). source

      Not checked in the free run.

    • cites [123] Hennrich, M. L. et al. Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nat. Commun. 9, 4004 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT1 promotes autophagy in quiescent MuSCs, and loss of SIRT1 leads to a delay in MuSC activation out of quiescence.

    “SIRT1 was also found to promote autophagy in quiescent MuSCs, and in this case, a loss of SIRT1 leads to a delay in MuSC activation out of quiescence — similar to what is observed in aged muscles109.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Tang, A. H. & Rando, T. A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 33, 2782–2797 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Other protein homeostasis mechanisms (for example, protein chaperones) play a role in stem cell ageing and could respond to changes in the external milieu.

    “Other protein homeostasis mechanisms (for example, protein chaperones) play a role in stem cell ageing and could respond to changes in the external milieu.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sirtuin activity and NAD levels both decline with age.

    “Sirtuin activity and NAD levels both decline with age116,117.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [116] Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014). source

      Not checked in the free run.

    • cites [117] Schultz, M. B. & Sinclair, D. A. Why NAD+ declines during aging: it’s destroyed. Cell Metab. 23, 965–966 (2016). source

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  • May combine two claims.

    Premisecitation

    The H3K27me3 demethylase UTX helps maintain a youthful phenotype in HSCs, with UTX-deficient HSCs acquiring an early-ageing phenotype.

    “Consistently, the H3K27me3 demethylase UTX helps maintain a youthful phenotype in HSCs, with UTX-deficient HSCs acquiring an early-ageing phenotype100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Sera, Y. et al. UTX maintains functional integrity of murine hematopoietic system by globally regulating aging-associated genes. Blood 137, 908–922 (2020). source

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  • May combine two claims.

    Premisecitation

    During ageing, SDF1 signalling via CXCR4 receptors in NSCs is reduced, and this decline is in part responsible for impaired NSC proliferation during ageing.

    “During ageing, SDF1 signalling (via CXCR4 receptors in NSCs) is reduced, and this decline is in part responsible for impaired NSC proliferation during ageing135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Zhu, C., Mahesula, S., Temple, S. & Kokovay, E. Heterogeneous expression of SDF1 retains actively proliferating neural progenitors in the capillary compartment of the niche. Stem Cell Rep. 12, 6–13 (2019). source

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  • May combine two claims.

    Premisecitation

    In the bone marrow, TNF induces the expression of IL-27 receptor, and ablation of IL-27 receptor blunts the negative impact of ageing on HSCs.

    “In the bone marrow, TNF (likely produced by niche cells) induces the expression of IL-27 receptor, and ablation of IL-27 receptor blunts the negative impact of ageing on HSCs76.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] He, H. et al. Aging-induced IL27Ra signaling impairs hematopoietic stem cells. Blood 136, 183–198 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the skin, niche stiffening and persistent hair shaft miniaturization during ageing can contribute to HFSC ageing via a reduction in promoter bivalency in HFSCs and via a PIEZO1-TNF mechanism.

    “In the skin, niche stiffening and persistent hair shaft miniaturization during ageing can also contribute to HFSC ageing via a reduction in promoter bivalency in HFSCs84 and via a PIEZO1–TNF mechanism83.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021). source

      Not checked in the free run.

    • cites [83] Xie, Y. et al. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis. Cell Stem Cell 29, 70–85.e6 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFNα has an overall negative impact on the brain, and chronic inflammation and IFNα convert αNSCs into ΩNSCs, which are more quiescent.

    “Although IFNγ can also have positive effects, IFNα has an overall negative impact on the brain137. Chronic inflammation and IFNα convert αNSCs into ΩNSCs, which are more quiescent138.”
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    • cites [137] Baruch, K. et al. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014). source

      Not checked in the free run.

    • cites [138] Martin-Suarez, S., Valero, J., Muro-Garcia, T. & Encinas, J. M. Phenotypical and functional heterogeneity of neural stem cells in the aged hippocampus. Aging Cell 18, e12958 (2019). source

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  • May combine two claims.

    Premisereasoning

    Paracrine signalling is altered during ageing, and this change contributes to stem cell defects in a non-cell-autonomous manner.

    “Paracrine signalling is altered during ageing, and this change contributes to stem cell defects in a non-cell-autonomous manner (FIG. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ECM stiffness has a strong effect on OPC proliferation and differentiation during ageing; OPC niche stiffness drastically increases with age; a softer niche is sufficient to restore OPC proliferation; and niche stiffness is mediated by the mechanosensitive ion channel PIEZO1 in OPCs.

    “In the central nervous system, transplantation experiments in rats indicate that ECM stiffness has a strong effect on OPC proliferation and differentiation during ageing80. OPC niche stiffness drastically increased with age, as determined by atomic force microscopy in the prefrontal cortex80. A softer niche is sufficient to restore OPC proliferation. Interestingly, niche stiffness is mediated by”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Segel, M. et al. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 573, 130–134 (2019). source

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  • May combine two claims.

    Premisecitation

    Fumarate affects young HSC function and might restore defects in aged HSCs.

    “fumarate affects young HSC function126, and might restore defects in aged HSCs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Guitart, A. V. et al. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions. J. Exp. Med. 214, 719–735 (2017). source

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  • May combine two claims.

    Premisecitation

    In muscle, ECM stiffness also increases with age and is associated with decreased collagen tortuosity; these ECM changes induce MuSCs to adopt a more fibrogenic fate, thereby diminishing their myogenic potential.

    “In muscle, ECM stiffness also increases with age and is associated with decreased collagen tortuosity82. These ECM changes induce MuSCs to adopt a more fibrogenic fate, thereby diminishing their myogenic potential.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Stearns-Reider, K. M. et al. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16, 518–528 (2017). source

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  • May combine two claims.

    Premisecitation

    In the bone marrow, skeletal stem cells become inflammatory with ageing, which impedes HSC function in old mice.

    “In the bone marrow, skeletal stem cells become inflammatory with ageing, which impedes HSC function in old mice128.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Ambrosi, T. H. et al. Aged skeletal stem cells generate an inflammatory degenerative niche. Nature 597, 256–262 (2021). source

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  • May combine two claims.

    Premisecitation

    In the bone marrow, a specialized periarteriolar niche supports lymphoid progenitors and osteogenesis, is maintained by mechanosensation transduced via PIEZO1, is responsive to exercise, and is depleted with ageing, likely contributing to a reduced immune response.

    “In the bone marrow, a specialized periarteriolar niche supports lymphoid progenitors and osteogenesis. The niche is maintained by mechanosensation, is transduced via PIEZO1 and is responsive to exercise. This niche is depleted with ageing, likely contributing to a reduced immune response81.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Shen, B. et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 591, 438–444 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the skin, HFSCs exhibit significant transcriptomic changes in ECM proteins, and this is correlated with structural defects in the ageing stem cell niche.

    “In the skin, HFSCs exhibit significant transcriptomic changes in ECM proteins, and this is correlated with structural defects in the ageing stem cell niche11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Ge, Y. et al. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Deterioration and inflammation of niche cells and the lack of production of growth factors negatively impact stem cell function during ageing.

    “Thus, the deterioration and inflammation of niche cells and the lack of production of growth factors negatively impact stem cell function during ageing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Extrinsic signals from old niches appear to dominate over intrinsic function of young stem cells in transplantation experiments, whereas signals from young niches may have only limited rejuvenation effects on old stem cells, at least for HSCs.

    “Extrinsic signals from old niches appear to dominate over intrinsic function of young stem cells in transplantation experiments143,144. By contrast, signals from young niches may have only limited rejuvenation effects on old stem cells, at least for HSCs145.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [143] Carlson, B. M. & Faulkner, J. A. Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol. 256, C1262–C1266 (1989). source

      Not checked in the free run.

    • cites [144] Popplewell, L. L. & Forman, S. J. Is there an upper age limit for bone marrow transplantation? Bone Marrow Transpl. 29, 277–284 (2002). source

      Not checked in the free run.

    • cites [145] Kuribayashi, W. et al. Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche. J. Exp. Med. 218 (2021). source

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  • May combine two claims.

    Premisecitation

    Cell composition of the bone marrow shifts with ageing, with the proportion of adipocytes markedly increasing, creating an inflammatory environment through secretion of soluble factors.

    “Cell composition of the bone marrow shifts with ageing, with the proportion of adipocytes markedly increasing, creating an inflammatory environment through secretion of soluble factors129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Ambrosi, T. H. et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20, 771–784 e6 (2017). source

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  • May combine two claims.

    Premisecitation

    During ageing, the number of fibroadipogenic progenitors declines, and so does their ability to produce paracrine factors such as WISP1, leading to diminished MuSC support and contributing to the decline in MuSC function.

    “During ageing, the number the of fibroadipogenic progenitors declines, and so does their ability to produce paracrine factors such as WNT1-inducible signalling pathway protein 1 (WISP1), a non-structural protein of the ECM10. This leads to diminished MuSC support and contributes to the decline in MuSC function during ageing10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Lukjanenko, L. et al. Aging disrupts muscle stem cell function by impairing matricellular WISP1 secretion from fibro-adipogenic progenitors. Cell Stem Cell 24, 433–446.e7 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In muscle, quantitative proteomic studies reveal striking remodelling in ECM during ageing, and those changes can influence MuSC function.

    “In muscle, quantitative proteomic studies also reveal striking remodelling in ECM during ageing66,82, and those changes can influence MuSC function.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Schuler, S. C. et al. Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality. Cell Rep. 35, 109223 (2021). source

      Not checked in the free run.

    • cites [82] Stearns-Reider, K. M. et al. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16, 518–528 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the bone marrow, megakaryocytes show increased production of IL-6, which is modulated by β-adrenergic signalling and inducible nitric oxide synthase signalling; β3-adrenergic receptor agonist treatment reduces the myeloid shift of HSCs in prematurely aged mice caused by lamin A mutations.

    “In the bone marrow, megakaryocytes appear to show increased production of the inflammatory cytokine IL-6 (REF.78), which is modulated by both β-adrenergic signalling (from sympathetic nerves) and inducible nitric oxide synthase signalling78. Indeed, β3-adrenergic receptor agonist treatment reduces the myeloid shift of HSCs in prematurely aged mice, caused by germ line mutations in lamin A78.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Ho, Y. H. et al. Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging. Cell Stem Cell 25, e6 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the brain SVZ neurogenic region, T cells can secrete IFNγ, IFNγ signalling is increased, and NSCs respond to IFNγ by decreased proliferation, which is restored (at least in vitro) by blocking antibodies to IFNγ.

    “In the brain SVZ neurogenic region, T cells can secrete interferon-γ (IFNγ), and IFNγ signalling is increased in the entire neurogenic region. NSCs respond to IFNγ by decreased proliferation, which is restored (at least in vitro) by blocking antibodies to IFNγ7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the intestine, old Paneth cells can secrete increased amounts of NOTUM, which attenuates WNT signalling in ISCs and contributes to stem cell dysfunction and intestinal decline.

    “In the intestine, old Paneth cells, which are niche cells, can secrete increased amounts of NOTUM, which in turn attenuates WNT signalling in ISCs and contributes to stem cell dysfunction and intestinal decline132.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Pentinmikko, N. et al. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature 571, 398–402 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During ageing, expression of COL17A1 decreases owing to genomic stress (UV) in a heterogeneous manner in some epithelial stem cells but not others, resulting in competition and advantage of the subpopulation of COL17A1-positive stem cells during ageing and expansion of these cells.

    “during ageing, expression of collagen type XVII α1 chain (COL17A1) decreases owing to genomic stress (UV) in a heterogeneous manner in some epithelial stem cells (epidermal stem cells) but not others141. This results in competition and advantage of the subpopulation of COL17A1-positive stem cells during ageing and expansion of these cells141.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Liu, N. et al. Stem cell competition orchestrates skin homeostasis and ageing. Nature 568, 344–350 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a reconstituted slice system, increased fluid flow promotes proliferation of NSCs, and this is dependent on a sodium channel; fluid flow could be an important component, at least in some stem cell niches, to integrate environmental changes.

    “In a reconstituted slice system, increased fluid flow promotes proliferation of NSCs, and this is dependent on a sodium channel142. Thus, fluid flow could be an important component, at least in some stem cell niches, to integrate environmental changes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Petrik, D. et al. Epithelial sodium channel regulates adult neural stem cell proliferation in a flow-dependent manner. Cell Stem Cell 22, 865–878.e8 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockout of Tfam mimics ageing in NSCs, whereas enhancement of mitochondrial function by piracetam boosts neurogenesis in aged mice.

    “Knockout of Tfam (a central transcription factor for mitochondria) mimics ageing in NSCs, whereas enhancement of mitochondrial function by piracetam boosts neurogenesis in aged mice125.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Beckervordersandforth, R. et al. Role of mitochondrial metabolism in the control of early lineage progression and aging phenotypes in adult hippocampal neurogenesis. Neuron 93, 560–573.e6 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced levels of IGF1 in the bone marrow environment promote HSC ageing, and reduced production of IGF1 by stromal fibroblasts can impair skin stem cells during ageing.

    “Reduced levels of IGF1 in the bone marrow environment (probably because of reduced production by old niche cells) also promote HSC ageing133, although low IGF1 levels lead to increased longevity at the organismal level. Reduced production of IGF1 by stromal fibroblasts can also impair skin stem cells during ageing134.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] Young, K. et al. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell 28, 1473–1482.e7 (2021). source

      Not checked in the free run.

    • cites [134] Maity, P. et al. Persistent JunB activation in fibroblasts disrupts stem cell niche interactions enforcing skin aging. Cell Rep. 36, 109634 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Tissue crosstalk and communication at the system level are also important, and stem cells in one tissue are influenced by long-range interactions from other tissues and systems.

    “While many studies have focused on the role of local niche factors in regulating stem cell function, tissue crosstalk and communication at the system level are also important (FIG. 3). Here we discuss how stem cells in one tissue are influenced by long-range interactions from other tissues and systems altogether”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Alterations in the diet, particularly dietary restriction, have long been used to delay the ageing process.

    “Alterations in the diet, particularly dietary restriction, have long been used to delay the ageing process206,207.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [206] McCay, C. M., Cromwell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon ultimate body size. J. Nutr. 10, 63–79 (1935). source

      Not checked in the free run.

    • cites [207] McDonald, R. B. & Ramsey, J. J. Honoring Clive McCay and 75 years of calorie restriction research. J. Nutr. 140, 1205–1210 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary restriction and related regimens extend lifespan and healthspan.

    “While dietary restriction and related regimens extend lifespan and healthspan, a key question is whether they have a ‘rejuvenating’ effect and reverse ageing features in already old individuals.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [206] McCay, C. M., Cromwell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon ultimate body size. J. Nutr. 10, 63–79 (1935). source

      Not checked in the free run.

    • cites [207] McDonald, R. B. & Ramsey, J. J. Honoring Clive McCay and 75 years of calorie restriction research. J. Nutr. 140, 1205–1210 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dietary restriction and even complete fasting have a beneficial effect on stem cell pools.

    “Collectively, these studies indicate that dietary restriction and even complete fasting have a beneficial effect on stem cell pools.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Dietary restriction has a beneficial effect on stem cell function, but may not affect all stem cell niches (or all cells in the niche) in the same manner.

    “Thus, dietary restriction has a beneficial effect on stem cell function, but may not affect all stem cell niches (or all cells in the niche) in the same manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The HSC niche and lymphoid progenitors can respond positively to exercise.

    “However, old HSCs seem to be resistant to the effect of exercise201, although the HSC niche and lymphoid progenitors can respond positively to exercise81.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Shen, B. et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 591, 438–444 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cyclical expression of OSKM in all tissues of middle-aged mice improves migration of a subtype of newly born hippocampal cells and is associated with improved cognitive function.

    “For example, cyclical expression of OSKM in all tissues of middle-aged mice improves migration of a subtype of newly born hippocampal cells, and this is associated with improved cognitive function229.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Rodriguez-Matellan, A., Alcazar, N., Hernandez, F., Serrano, M. & Avila, J. In vivo reprogramming ameliorates aging features in dentate gyrus cells and improves memory in mice. Stem Cell Rep. 15, 1056–1066 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Full expression of the Yamanaka factors (OCT4, SOX2, KLF4 and MYC (OSKM)) in differentiated cells results in induction of pluripotency and a resetting of cellular ageing characteristics.

    “Full expression of the Yamanaka factors (OCT4, SOX2, KLF4 and MYC (OSKM)) in differentiated cells results in induction of pluripotency (induced pluripotent stem cells) and a resetting of cellular ageing characteristics223–225.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [223] Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). source

      Not checked in the free run.

    • cites [224] Izpisua Belmonte, J. C. Reprogramming development and aging: cell differentiation as a malleable process. Curr. Opin. Cell Biol. 24, 713–715 (2012). source

      Not checked in the free run.

    • cites [225] Mahmoudi, S. & Brunet, A. Aging and reprogramming: a two-way street. Curr. Opin. Cell Biol. 24, 744–756 (2012). source

      Not checked in the free run.

93 of 93

  • The paper relies on this without support.

    Stem cell function is critical for tissue homeostasis and repair upon injury.

    “Stem cell function is critical for tissue homeostasis and repair upon injury, and it is dependent on interactions with the niche.”

  • The paper relies on this without support.

    Stem cells are maintained and regulated by their micro-environment (the niche), which forms a regenerative unit or region.

    “Stem cells have a crucial role for tissue homeostasis, and they are maintained and regulated by their micro-environment (the ‘niche’), which forms a regenerative unit or region (FIG. 1b).”

  • The paper relies on this without support.

    Most adult stem cells are quiescent.

    “Whereas embryonic stem cells proliferate actively, a crucial characteristic of most adult stem cells is their quiescent state.”

  • The paper relies on this without support.

    The effects of dietary interventions are ultimately conveyed to cells, including stem cells, throughout the body via changes in the blood and then the local cellular milieu.

    “The effects of dietary interventions are ultimately conveyed to cells, including stem cells, throughout the body via changes in the blood and then the local cellular milieu.”

  • The paper relies on this without support.

    Mouse and rat lifespan is relatively short (~3 years).

    “Most of the studies discussed in this Review were conducted in mice (sometimes in rats), and it is important to note that mouse and rat lifespan is relatively short (~3 years) and that mechanisms of stem cell maintenance may differ from those in humans and other long-lived species.”

  • The paper relies on this without support.

    In the intestine, ageing is associated with impaired ISC function that can lead to malabsorption syndromes.

    “In the intestine, ageing is associated with impaired ISC function that can lead to malabsorption syndromes.”
6 of 6

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?

  • During ageing, tissue regenerative functions decline, in part due to stem cell-intrinsic accumulation of damage, functional decay of niche cells and increased inflammation (inflammageing) through uncharacterized mechanisms.

    “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 [8]

    The review’s ‘Defects in stem cells during ageing’ section links declining stem-cell function to poorer tissue repair, while ‘Accumulation of ageing markers’ discusses possible damage accumulation. Its sections on niche-cell signalling and immune cells describe age-related niche deterioration and inflammatory effects. The claim’s ‘through uncharacterized mechanisms’ qualifier is too broad: the review describes several mechanisms, including inflammatory cytokine signalling, although it also identifies questions that remain open. No page numbers are available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Brunet, A., Goodell, M. A., & Rando, T. A.
Affiliations
  • Stanford University (US)
  • Baylor College of Medicine (US)
  • University of California, Los Angeles (US)
Corresponding author
  • Brunet, Anne
  • Goodell, Margaret A.
  • Rando, Thomas A.
ORCID
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2022-07-20
Volume
24
Issue
1
Pages
45-62
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/s41580-022-00510-w
PMC
PMC9879573
OpenAlex
W4286001510
Semantic Scholar
f044f571a493f0ac2fe479eeae376cf4391e24e5
Cited by
407
References
260
Citations by year
2026: 105 · 2025: 126 · 2024: 97 · 2023: 72 · 2022: 7
FWCI
6.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (P01AG036695, R01AG071783, R01AG071711)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
stem cell aging, tissue stem cells, stem cell niche, tissue rejuvenation, stem cell quiescence, clonal expansion, immune cell infiltration, tissue homeostasis, tissue regeneration, age-related diseases, brain, muscle, blood, skin, intestine, non-cell-autonomous mechanisms, systemic factors
MeSH terms
Cell Differentiation, Rejuvenation, Stem Cells, Cellular Senescence, Stem Cell Niche

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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