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Cited by 796Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsPluripotent Stem Cells Research

Stem cell aging: mechanisms, regulators and therapeutic opportunities

Open access
Oh, Juhyun, Lee, Yang David, Wagers, Amy J·2014·Nature Medicine
DOI 10.1038/nm.3651PMC PMC4160113
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Abstract

Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity. Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline. Here we explore key molecular pathways that are commonly perturbed as tissues and stem cells age and degenerate. We further consider experimental evidence both suppoxrting and refuting the notion that modulation of these pathways per se can reverse aging phenotypes. Finally, we ask whether stem cell aging establishes an epigenetic 'memory' that is indelibly written or one that can be reset.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that aging of tissue-specific stem cells is driven by interacting cell-intrinsic damage pathways and changes in the niche and systemic environment, including ROS, DNA damage, proteostasis, mitochondrial dysfunction, senescence, and epigenetic remodeling. It concludes that some aging phenotypes can be reversed experimentally, but whether such interventions truly reset an epigenetic “memory” of age remains unresolved.

Key findings

  • Stem cell aging is linked to common processes: reactive oxygen species accumulation, DNA damage and altered DNA damage responses, impaired proteostasis/autophagy, mitochondrial dysfunction, proliferative exhaustion or senescence, niche and systemic changes, and epigenetic alterations.
  • Reversal has been reported in several models: N-acetyl-L-cysteine restores quiescence and reconstitution in ATM-null and FoxO-deficient hematopoietic stem cells; rapamycin restores self-renewal and hematopoietic potential of aged HSCs; short-term calorie restriction increases skeletal muscle stem cell frequency and function in young and old mice; heterochronic parabiosis, GDF11, or oxytocin improves aged muscle satellite cell and neural function; p16Ink4a silencing restores quiescence and regenerative potential in geriatric satellite cells; and late-life telomerase reactivation reverses degenerative phenotypes in telomerase-deficient mice.
  • Caveats are prominent: ROS can be adaptive and dose/context dependent; mtDNA mutations in mutator mice may not be a primary driver of chronological HSC aging; p16INK4a expression in HSCs is controversial; and telomerase overexpression can promote malignancy unless combined with a tumor-resistant background.
  • Epigenetic aging may be partly reversible: aged HSCs show site-specific DNA methylation changes and histone modification perturbations, and reprogramming aged hematopoietic progenitors to iPSCs followed by HSC generation in a chimeric embryo yielded complete rejuvenation of hematopoietic activity; a longevity memory in ASH-2 mutant *C. elegans* persisted in wild-type offspring for up to four generations.

Methods

  • Narrative review, not a primary experimental study; no new data, systematic search, or meta-analysis is described.
  • Synthesizes published findings from mouse, *Drosophila*, *C. elegans*, human cell, and progeroid syndrome studies to integrate mechanisms of stem cell aging and evaluate therapeutic strategies.

Limitations

  • The paper states that the causal role of oxidative damage in aging remains controversial, that antioxidant defense strength does not clearly correlate with extended function or longevity, and that ROS have essential signaling roles, making their effects context dependent.
  • The paper states that no studies yet directly test whether stimulating autophagy or proteasome activity benefits aged stem cells, that whether rejuvenating interventions reset the aged epigenome is unresolved, and that p16INK4a’s role in HSCs and mtDNA mutations as drivers of chronological stem cell aging are debated.
  • Evident from the text: as a review, conclusions depend on heterogeneous cited models and endpoints, and therapeutic translation remains uncertain because many proposed interventions lack direct evidence in aged stem cells or carry risks such as tumorigenesis.

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

Integrity signals

Registry

Crossref · 10.1038/nm.3651

Cites

192 of 192 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 268 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Conditional ablation of FoxO1, FoxO3, and FoxO4 in the mouse hematopoietic system markedly increases ROS accumulation in HSCs.

    “Conditional ablation in the mouse hematopoietic system of the transcription factors FoxO1, FoxO3 and FoxO4, downstream effectors of the insulin and insulin-like growth factor 1 (IGF-1) signaling pathways, induces a marked increase in ROS accumulation in HSCs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] 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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  • Premisecitation

    Aged human mesenchymal stem cells have elevated ROS.

    “studies of aged human mesenchymal stem cells have found elevated ROS9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Stolzing, A., Jones, E., McGonagle, D. & Scutt, A. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech. Ageing Dev. 129, 163–173 (2008). source

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  • Premisecitation

    The ability of stem cells to balance quiescence with proliferative activity is critical for their survival and for appropriate physiological and regenerative responses.

    “their ability to balance quiescence with proliferative activity appears to be critical for their survival and maintenance of appropriate physiological and regenerative responses1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Cheung, T.H. & Rando, T.A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013). source

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  • Premisecitation

    In mice, the frequency of hematopoietic stem cells with low ROS levels declines with age.

    “the frequency of blood-forming hematopoietic stem cells (HSCs) with low ROS levels declines with age in mice10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Jang, Y.Y. & Sharkis, S. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110, 3056–3063 (2007). source

      Not checked in the free run.

  • Premisecitation

    In many tissues, homeostatic maintenance and regenerative response to injury depend on tissue-specific stem cells.

    “In many tissues, homeostatic tissue maintenance and regenerative responsiveness to injury depend on tissue-specific stem cells—long-lived cells endowed with the capacity to both self-renew and differentiate to produce mature daughters.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Cheung, T.H. & Rando, T.A. Molecular regulation of stem cell quiescence. Nat. Rev. Mol. Cell Biol. 14, 329–340 (2013). source

      Not checked in the free run.

  • May combine two claims. 64
  • Classified as probably not a substantial claim. 8

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    Interpretationreasoning

    Stem cells in many tissues undergo profound age-related changes, including blunted injury responsiveness, dysregulated proliferation, and declining functional capacities.

    “Indeed, stem cells in many tissues have been found to undergo profound changes with age, exhibiting blunted responsiveness to tissue injury, dysregulation of proliferative activities and declining functional capacities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ROS induction in FoxO-deficient mice correlates with disrupted HSC quiescence, increased HSC apoptosis, and defective hematopoietic repopulating ability.

    “ROS induction in these FoxO-deficient mice correlates with disruption of HSC quiescence, increases in HSC apoptosis and defects in hematopoietic repopulating abilities15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS have essential roles in cell signaling and homeostasis, suggesting dose-dependent, context-dependent, and pleiotropic activity.

    “ROS also have essential roles in cell signaling and homeostasis7,8, suggesting a dose-dependent, context-dependent and pleiotropic activity of these reactive mediators”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Clément, M.V. & Stamenkovic, I. Superoxide anion is a natural inhibitor of FAS-mediated cell death. EMBO J. 15, 216–225 (1996). source

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      Not checked in the free run.

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    Premisecitation

    In mouse HSCs and neural stem cells, excessive cellular ROS concentrations cause abnormal proliferation, malignancy, and compromised self-renewal.

    “in HSCs and neural stem cells (NSCs) of mice, excessive cellular ROS concentrations lead to abnormal proliferation, malignancy and compromised stem cell self-renewal11–14”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004). source

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    • cites [12] Sahin, E. & Depinho, R.A. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464, 520–528 (2010). source

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    Premisecitation

    Reactive oxygen species are produced mainly by electron leak during mitochondrial oxidative phosphorylation and appear to contribute to perturbed stem cell function and fate control during aging.

    “Primary among these are pathways induced by reactive oxygen species (ROS), which are produced predominantly as a result of electron ‘leak’ during mitochondrial oxidative phosphorylation and appear to contribute to perturbed stem cell function and fate control in the context of aging2–5.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [2] Takubo, K. et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61 (2013). source

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

    Premisecitation

    The free radical theory of aging proposes that accumulated cellular damage and declining mitochondrial integrity in aged cells elevate ROS production, driving a vicious cycle that damages macromolecules and disrupts oxidative phosphorylation, leading to cellular decomposition.

    “This theory proposes that accumulated cellular damage and declining mitochondrial integrity in aged cells leads to elevated ROS production, which in turn drives a vicious cycle that further damages cellular macromolecules and disrupts mitochondrial oxidative phosphorylation, leading to eventual cellular decomposition6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    Quiescent HSCs show reduced expression of DNA repair genes and accumulate DNA damage that is repaired only when the cells enter the cell cycle.

    “Analysis of DDR pathways in HSCs indicates that, independent of age, quiescent HSCs show reduced expression of DNA repair genes and accumulate DNA damage that is repaired only when the cells enter the cell cycle, such as during self-renewal or proliferation of HSC-derived progenitors40.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Beerman, I., Seita, J., Inlay, M.A., Weissman, I.L. & Rossi, D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15, 37–50 (2014). source

      Not checked in the free run.

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    Premisecitation

    Similar effects occur in NSCs of FoxO-deficient mice and in HSCs and NSCs of mice lacking only FoxO3.

    “Similar results have been reported for NSCs in these FoxO-deficient mice14 and in HSCs and NSCs in mice lacking only FoxO3 (refs. 16–18).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [14] Paik, J.H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009). source

      Not checked in the free run.

    • cites [16] 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 [17] 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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    • cites [18] Renault, V.M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009). source

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    Premisecitation

    SOD2 is cytoprotective in mouse NSCs, and its overexpression increases NSC survival in vitro and in vivo.

    “A cytoprotective role of SOD2 was also observed in mouse NSCs, and its overexpression increased survival of NSCs both in vitro and in vivo23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Sakata, H. et al. Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice. Brain 135, 3298–3310 (2012). source

      Not checked in the free run.

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    Premisecitation

    SIRT3 is critical for maintaining mitochondria and metabolism and controls ROS production during HSC aging.

    “Another member of the sirtuin family, SIRT3, is critical to the maintenance of mitochondria and metabolism and controls ROS production during HSC aging29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Kim, H.-S.S. et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    It remains unclear whether NAC or other antioxidant treatments directly or indirectly affect age-dependent deficits in stem cells or stem cell function.

    “As yet, however, it remains unclear whether NAC or other antioxidant treatments have a direct or indirect effect on age-dependent deficits in stem cells or stem cell function”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The level of DNA damage in stem cells must be interpreted cautiously regarding its role in aging because such damage can be repaired, involved in normal differentiation, or asymmetrically passed to daughter cells.

    “However, the level of DNA damage in stem cells must be interpreted with caution as regards its role in aging because such damage can be repaired40 or involved in normal cellular process such as differentiation42 or asymmetrically passed on to daughter cells43.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] Beerman, I., Seita, J., Inlay, M.A., Weissman, I.L. & Rossi, D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15, 37–50 (2014). source

      Not checked in the free run.

    • cites [42] Larsen, B.D. et al. Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proc. Natl. Acad. Sci. USA 107, 4230–4235 (2010). source

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    Premisecitation

    SIRT1 has a role in maintaining mesenchymal stem cell growth and differentiation, which decline with age.

    “recent findings suggest a role for SIRT1 in maintaining mesenchymal stem cell growth and differentiation, which have been shown to decline with age27, 28.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Elevated damaged DNA in aged stem cells could result from accumulation over time, an increased damage rate, decreased repair, or a combination of these.

    “Elevated levels of damaged DNA in aged stem cells could result from an accumulation of damage over time, an increase in the rate of damage, a decrease in the rate of repair in response to DNA damage, or a combination of these possibilities.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Other studies challenge the view that proteolytic activity declines with age, showing that autophagic potential or proteasome activity remains intact in aged cells and attributing age-related proteostasis disruptions mainly to metabolic stress overwhelming protective capacity.

    “Yet other studies have challenged the view that proteolytic activity declines with age, showing instead that autophagic potential or proteasome activity remains intact in aged cells76,77 and attributing age-related disruptions in proteostasis mainly to increasing damage caused by metabolic stress that overwhelms the protective capacity of proteolytic systems76.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    When mTERTcs was overexpressed in a tumor-resistant background with increased p53 and p16/p19 gene dosage, function-promoting effects prolonged median lifespan and improved neuromuscular coordination.

    “Only when mTERTcs was overexpressed in a tumor-resistant background, produced by increasing gene dosage of p53 and p16/p19, could the balance be tipped in favor of function-promoting effects, resulting in prolonged median lifespan and improved neuromuscular coordination67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Proteostasis pathways are essential for development and for most cellular functions, including replication, metabolic catalysis, cellular architecture, signaling, and immune responses.

    “Proteostasis is essential for development and for most cellular functions, including replication of genetic material, catalysis of metabolic reactions, maintenance of cellular architecture, signaling and immune responses69,70.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Neural stem cells from mTERC-reactivated animals show enhanced multipotency, suggesting recovered neurogenic function.

    “neural stem cells from mTERC-reactivated animals showed enhanced multipotency, suggesting recovered neurogenic function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011). source

      Not checked in the free run.

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    Premisecitation

    Accumulation of DNA damage in stem cells may trigger defective progeny, stem cell senescence, or neoplastic transformation, leading to age-dependent loss of organ function and homeostasis.

    “Accumulation of DNA damage in stem cells may trigger the production of defective progeny, stem cell senescence or neoplastic transformation60,61, leading to age-dependent loss of organ function and homeostasis62”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    Mouse HSCs forced to proliferate showed fewer mutational events after DNA-damaging radiation, suggesting that a break from quiescence enabling homologous recombination can help maintain stem cell genomic integrity.

    “mouse HSCs that were forced to proliferate showed fewer mutational events after exposure to DNA-damaging radiation, suggesting that in certain instances a break from quiescence that enables engagement of the high-fidelity homologous recombination pathway can help to maintain stem cell genomic integrity56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    In Hutchinson-Gilford progeria syndrome, cells accumulate progerin, and its accumulation in the nuclear envelope leads to increased DNA damage in reprogrammed mesenchymal stem cells.

    “In Hutchinson-Gilford progeria syndrome, cells accumulate an abnormally processed nuclear intermediate filament called progerin. Progerin is a product of the lamin A gene, and its accumulation in the nuclear envelope leads to increased DNA damage in reprogrammed mesenchymal stem cells derived from patients with this syndrome190.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    Defects in proteostasis commonly lead to aberrant folding, toxic aggregation, and accumulation of damaged proteins, which can cause cellular damage and tissue dysfunction.

    “Defects in proteostasis commonly lead to aberrant folding, toxic aggregation and accumulation of damaged proteins, which can in turn cause cellular damage and tissue dysfunction68.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • May combine two claims.

    Premisenone given

    p16INK4a has been suggested to promote aging phenotypes in stem cells, whereas abolishing p16INK4a function can enhance the regenerative potential of stem cells from the brain and bone marrow.

    “An essential effector of senescence, p16INK4a, has been suggested to promote aging phenotypes in stem cells, whereas abolishing p16INK4a function can enhance the regenerative potential of stem cells from the brain and bone marrow (see below).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with dyskeratosis congenita have mutations in DKC1, and defects in telomere maintenance lead to telomere deprotection and HSC failure to sustain bone marrow reconstituting activity.

    “patients with dyskeratosis congenita have mutations in the DKC1 gene, an important component of the telomerase complex191. Defects in telomere maintainance lead to deprotection of telomeres and, in HSCs, cause failure to sustain bone marrow reconstituting activity192.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    FoxO transcriptionally activates several protein-folding chaperone genes, some of which may regulate aging.

    “FoxO transcriptionally activates several protein-folding chaperone genes82–84 some of which may regulate aging84–87.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
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    Premisecitation

    mTERC-reactivated animals show reduced 53BP1-marked DNA damage foci and decreased apoptosis.

    “Analysis of various cell types in these animals showed reduced foci of DNA damage, marked by staining with the DDR protein 53BP1, and decreased apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FOXO4 promotes proteasome activity in human embryonic stem cells by regulating PSDM11 expression, thereby encouraging proteostasis and maintenance of pluripotency markers.

    “FOXO4 promotes proteasome activity in hESCs by regulating PSDM11 expression, thereby encouraging proteostasis and maintenance of pluripotency markers, such as POU5F1, OCT4, NANOG, SOX2, UTF1, DPPA4, DPPA2, ZFP42 and TERT81.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Protein quality control is regulated by a complex network that monitors protein concentration, subcellular location, and folding, including molecular chaperones, folding enzymes, and degradation pathways.

    “Protein quality control is regulated by a complex protein network that monitors the concentration, subcellular location and folding of proteins and includes molecular chaperones and folding enzymes, as well as pathways that drive protein degradation when needed, through the proteasome, lysosome and autophagy pathways69–71.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [69] Balch, W.E., Morimoto, R.I., Dillin, A. & Kelly, J.W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008). source

      Not checked in the free run.

    • cites [70] Powers, E.T., Morimoto, R.I., Dillin, A., Kelly, J.W. & Balch, W.E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959–991 (2009). source

      Not checked in the free run.

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  • May combine two claims.

    Premisecitation

    Quiescent HSCs and hair follicle stem cells rely more heavily on non-homologous end joining for double-strand break repair, while actively proliferating intestinal stem cells rely on homologous recombination.

    “quiescent HSCs and hair follicle stem cells rely more heavily on non-homologous end joining for repair of double-strand breaks, while actively proliferating intestinal stem cells rely on the homologous recombination pathway56,187,188.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

    • cites [187] Hua, G. et al. Crypt base columnar stem cells in small intestines of mice are radioresistant. Gastroenterology 143, 1266–1276 (2012). source

      Not checked in the free run.

    • cites [188] Sotiropoulou, P.A. et al. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat. Cell Biol. 12, 572–582 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Upregulation of the telomeric pathway may reverse telomere attrition and rescue aged stem cells and postmitotic somatic cells, but cancer cells also use this pathway to overcome replicative senescence.

    “while upregulation of the telomeric pathway may in theory reverse telomere attrition and rescue the function of aged stem cells and postmitotic somatic cells, this pathway is also used by cancer cells to overcome replicative senescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Deletion of autophagy-related gene 7 increases ROS levels and depletes HSCs, implicating proteostasis in stem cell maintenance.

    “proteostasis has been implicated as an important determinant of stem cell maintenance through studies in HSCs showing that deletion of autophagy-related gene 7 (Atg7) increases ROS levels and depletes HSCs78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Mortensen, M. et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J. Exp. Med. 208, 455–467 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Because quiescent cells are restricted to error-prone non-homologous end joining for double-strand break repair, DNA repair in quiescent HSCs could introduce mutations and promote genomic instability.

    “because quiescent cells are restricted to using the error-prone non-homologous end joining pathway for repair of double-strand breaks, DNA repair, if it occurs in quiescent HSCs40, could introduce mutations and promote genomic instability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Beerman, I., Seita, J., Inlay, M.A., Weissman, I.L. & Rossi, D.J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15, 37–50 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of the PI3K-AKT pathway by growth factors inhibits FoxO transcription factors, which cross talk with AMPK to control the balance between oxidative phosphorylation and glycolysis.

    “activation of the Phosphoinositide 3-kinase (PI3K)–AKT pathway by growth factors leads to inhibition of FoxO transcription factors107, which cross talk with AMPK to control the balance between oxidative phosphorylation and glycolysis in response to intracellular and environmental cues108.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] Gross, D.N., van den Heuvel, A.P. & Birnbaum, M.J. The role of FoxO in the regulation of metabolism. Oncogene 27, 2320–2336 (2008). source

      Not checked in the free run.

    • cites [108] Peserico, A. et al. A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels. Cell. Mol. Life Sci. 70, 2015–2029 (2013). source

      Not checked in the free run.

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

    Interpretationnone given

    A direct link between chaperone function and stem cell aging has not yet been demonstrated.

    “However, a direct link between chaperone function and stem cell aging has not yet been demonstrated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    HSCs show an age-dependent decrease in nutrient uptake capacity, implying that the nutrient sensing pathway is involved in stem cell aging.

    “In HSCs, an age-dependent decrease in nutrient uptake capacity has been observed with age, implying that the nutrient sensing pathway is involved in stem cell aging76.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Warr, M.R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mtDNA mutator mice show decreased proliferation and increased apoptosis of epithelial crypt cells and impaired in vitro development of stem cell-derived organoids.

    “Another study reported decreased proliferation and increased apoptosis of epithelial crypt cells in mtDNA mutator mice and impaired in vitro development of stem cell–derived organoids99.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Fox, R.G., Magness, S., Kujoth, G.C., Prolla, T.A. & Maeda, N. Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G914–G924 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Calorie restriction's effects are probably not limited to enhanced mitochondrial function, because it also modulates mitochondrial hormesis, autophagy, ROS production/scavenging, and DNA damage.

    “CR effects are not likely to be limited to enhanced mitochondrial function, however, as CR also modulates mitochondrial hormesis, autophagy induction, production and scavenging of ROS, and DNA damage115–117.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [115] Schulz, T.J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007). source

      Not checked in the free run.

    • cites [116] Gredilla, R., Sanz, A., Lopez-Torres, M. & Barja, G. Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J. 15, 1589–1591 (2001). source

      Not checked in the free run.

    • cites [117] Sohal, R.S., Agarwal, S., Candas, M., Forster, M.J. & Lal, H. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech. Ageing Dev. 76, 215–224 (1994). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC-1 increases mitochondrial biogenesis and delays the age-dependent decline in intestinal stem cells and gut function in Drosophila, although its role in mammalian stem cells has not been tested.

    “Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) a key regulator of mitochondrial energy metabolism, increases mitochondrial biogenesis and delays the age-dependent decline in intestinal stem cells and gut function in Drosophila109, although its role in mammalian stem cells has yet to be tested.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Rera, M. et al. Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab. 14, 623–634 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long-term calorie restriction can postpone age-related pathologies and prolong lifespan across many species, from yeast to primates.

    “CR has been widely employed as a dietary intervention to prevent or reduce the severity of aging phenotypes, and long-term CR can delay the onset of age-related pathologies and extend lifespan in many species, from yeast to primates111.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Piper, M.D. & Bartke, A. Diet and aging. Cell Metab. 8, 99–104 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In adult mouse HSCs, rapidly accumulating mtDNA mutations induced by proofreading-defective mtDNA polymerase have little functional effect on the HSC pool and instead cause differentiation blocks or disappearance of downstream progenitors.

    “in adult mouse HSCs, rapidly accumulating mtDNA mutations induced by the presence of proofreading-defective mtDNA polymerase have little functional effect on the HSC pool and instead cause differentiation blocks and/or disappearance of downstream progenitors103.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Norddahl, G.L. et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell 8, 499–510 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice genetically manipulated to preserve chaperone-mediated autophagy show improved cellular homeostasis, enhanced stress resistance, and preservation of organ functions with age.

    “data from mice genetically manipulated to preserve chaperone-mediated autophagy (CMA), a form of autophagy involving chaperone-dependent selection of substrates, show improved cellular homeostasis, enhanced resistance to stressors and preservation of organ functions with age89.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Zhang, C. & Cuervo, A.M. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14, 959–965 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Short-term calorie restriction raises the number and function of skeletal muscle stem cells in young and old mice, possibly via increased mitochondrial content and oxidative metabolism.

    “Short-term calorie restriction (CR) increases the frequency and function of skeletal muscle stem cells in both young and old mice, potentially by increasing mitochondrial content and promoting oxidative metabolism110.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Cerletti, M., Jang, Y.C., Finley, L.W., Haigis, M.C. & Wagers, A.J. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell 10, 515–519 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-dependent reductions in mitochondrial function leading to respiratory chain dysfunction have been observed in several cell systems and are thought to result largely from accumulation of mutations in mitochondrial DNA.

    “Age-dependent reductions in mitochondrial function leading to respiratory chain dysfunction have been observed in several cell systems and have been thought to result largely from accumulation of mutations in mitochondrial DNA (mtDNA)94.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Miquel, J., Economos, A.C., Fleming, J. & Johnson, J.E. Mitochondrial role in cell aging. Exp. Gerontol. 15, 575–591 (1980). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hematopoietic progenitor cells of mtDNA mutator mice are affected during fetal development, and their neural stem cells show declining quiescence and decreased self-renewal capacity in response to mtDNA mutation accumulation.

    “hematopoietic progenitor cells of the mtDNA mutator mice are affected during fetal development, and their neural stem cells exhibit declining quiescence and decreased self-renewal capacity in response to mtDNA mutation accumulation98.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Ahlqvist, K.J. et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100–109 (2012). source

      Not checked in the free run.

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

    Premisecitation

    An alternative view suggests that replication errors mediated by mitochondrial DNA polymerase γ drive mtDNA mutation.

    “An alternative view on mtDNA mutagenesis suggests that replication errors mediated by mitochondrial DNA polymerase γ may instead drive mtDNA mutation95.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Zheng, W., Khrapko, K., Coller, H.A., Thilly, W.G. & Copeland, W.C. Origins of human mitochondrial point mutations as DNA polymerase gamma-mediated errors. Mutat. Res. 599, 11–20 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Abnormal phenotypes in somatic stem cells from mtDNA mutator mice can be rescued by NAC supplementation, implying that mtDNA mutations alter the oxidative state of stem cells and impair their functional capacity.

    “The abnormal phenotypes observed in somatic stem cells from mtDNA mutator mice can be rescued by supplementation with NAC, implying that mtDNA mutations alter the oxidative state of stem cells and that this impairs their functional capacity98.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Ahlqvist, K.J. et al. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100–109 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Aged animals experience functional depletion of the HSC pool, with aged HSCs showing reduced hematopoietic reconstituting activity and skewed differentiation toward myeloid over lymphoid lineages.

    “Yet aged animals still experience a functional depletion of the HSC pool, as aged HSCs show reduced hematopoietic reconstituting activity and skewed differentiation potential such that they overproduce myeloid lineage cells and underproduce lymphoid lineage cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Reports show lower stem cell numbers or altered cell-cycle activity with age in skeletal muscle, neural and germline stem cells.

    “Age-dependent reduction in stem cell number or perturbed cell-cycle activity has been reported in skeletal muscle stem cells, neural stem cells and germline stem cells110, 120–122.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [110] Cerletti, M., Jang, Y.C., Finley, L.W., Haigis, M.C. & Wagers, A.J. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell 10, 515–519 (2012). source

      Not checked in the free run.

    • cites [120] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

    • cites [121] Molofsky, A.V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006). source

      Not checked in the free run.

    • cites [122] Boyle, M., Wong, C., Rocha, M. & Jones, D.L. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1, 470–478 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged HSCs show increased cell number, possibly due to reduced capacity for asymmetric division.

    “Regulation of cell number and cycling activity is different for aging HSCs, which actually show increases in cell number, possibly due to a reduced capacity for asymmetric division123, with no difference in cycling activity124.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Florian, M.C. et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 10, 520–530 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Old p16INK4a−/− HSCs exhibit increased cell cycle activity and enhanced engraftment.

    “Old p16INK4a−/− HSCs also exhibit increased cell cycle activity and enhanced engraftment128, although these enhancements come with a price, as p16INK4a−/− animals show an increased incidence of malignancy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421–426 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Mitochondrial decline with age can be reversed and plays a part in aged tissue dysfunction.

    “These data indicate that age-related mitochondrial dysfunction is reversible and contributes to dysfunction in aged tissues.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Gomes, A.P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knocking down p16INK4a in old satellite cells brings back quiescence and regenerative capacity.

    “Silencing p16INK4a in geriatric satellite cells restores their quiescence and regenerative potential, suggesting that this pre-senescent state is potentially escapable120.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stem cell therapy still faces major hurdles: making enough cells, helping them survive and engraft, and avoiding immune rejection.

    “However, there remain important obstacles that must be overcome to realize the full potential of stem cell–based therapy for these and other disorders, including the generation of sufficient numbers of cells for transplantation, the promotion of stem cell survival and engraftment in host tissues, and potential immunological barriers to long-term engraftment of allogeneic or even gene-corrected aut”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Tabebordbar, M., Wang, E. & Wagers, A.J. Skeletal muscle degenerative diseases and strategies for therapeutic muscle repair. Annu. Rev. Pathol. 8, 441–475 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Therapies that pull aged stem cells out of senescence or quiescence might improve tissue regeneration, but they must preserve the balance between self-renewal and differentiation.

    “Rescuing stem cells from senescence or activating them from a quiescent state could potentially enhance regenerative potential in aged tissues; however, such strategies must maintain the balance of stem cell self-renewal and differentiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Stem cells live in specialized niches that support their upkeep and control what they do.

    “Stem cells reside in specialized microenvironments, called niches, that promote their maintenance and regulate their functions150–152.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [150] Kuhn, H.G., Dickinson-Anson, H. & Gage, F.H. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033 (1996). source

      Not checked in the free run.

    • cites [151] Maslov, A.Y., Barone, T.A., Plunkett, R.J. & Pruitt, S.C. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24, 1726–1733 (2004). source

      Not checked in the free run.

    • cites [152] Morrison, S.J. & Spradling, A.C. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598–611 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Quiescence and stem cell maintenance need low ROS, while raising ROS triggers proliferation and differentiation.

    “Low levels of ROS are required for quiescence and stem cell maintenance, whereas ROS induction leads to proliferation and differentiation programs26.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Owusu-Ansah, E. & Banerjee, U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461, 537–541 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAPs support muscle regeneration and are a main source of soluble regulators of the extracellular matrix.

    “Likewise, fibro/adipogenic progenitors (FAPs), stromal constituents of skeletal muscle, facilitate muscle regeneration and serve as a principal source of soluble extracellular matrix regulators158,159.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [158] Murphy, M.M., Lawson, J.A., Mathew, S.J., Hutcheson, D.A. & Kardon, G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138, 3625–3637 (2011). source

      Not checked in the free run.

    • cites [159] Joe, A.W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During muscle regeneration, immune cells are key regulators of satellite cells: they coordinate inflammation and keep myogenic cells proliferating without differentiating too early.

    “For example, immune cells serve as critical regulators of satellite cell function during muscle regeneration, orchestrating inflammatory responses and ensuring appropriate proliferation of myogenic cells to prevent their premature differentiation157.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Schnoor, M. et al. Production of type VI collagen by human macrophages: a new dimension in macrophage functional heterogeneity. J. Immunol. 180, 5707–5719 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In old mice, extra GDF11 reverses cardiac hypertrophy, improves neural stem cell and neuronal function, and increases physical activity.

    “GDF11 supplementation in old mice further reverses age-related hypertrophy in cardiac muscle168, enhances neural stem cell and neuronal function166 and improves physical activity38.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [168] Loffredo, F.S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013). source

      Not checked in the free run.

    • cites [166] Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014). source

      Not checked in the free run.

    • cites [38] Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Old muscle fibers do not induce enough Notch ligand delta and make too much FGF2.

    “Aged muscle fibers fail to adequately induce the Notch ligand delta, and they overproduce fibroblast growth factor 2 (ref. 132,160).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [132] Chakkalakal, J.V., Jones, K.M., Basson, M.A. & Brack, A.S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012). source

      Not checked in the free run.

    • cites [160] Conboy, I.M., Conboy, M.J., Smythe, G.M. & Rando, T.A. Notch-mediated restoration of regenerative potential to aged muscle. Science 302, 1575–1577 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Many intrinsic and extrinsic pathways influence stem cell aging, and they often interact to shape stem cell function.

    “Stem cell aging is affected by many different cell-intrinsic and cell-extrinsic pathways, which often show cross-talk in the determination of stem cell function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Giving old mice recombinant GDF11 or oxytocin fixes aged satellite cell dysfunction and brings back strong regeneration.

    “Treatment of aged mice with either recombinant GDF11 or oxytocin reverses dysfunction of aged satellite cells and restores robust regenerative function in aged mice38,169.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014). source

      Not checked in the free run.

    • cites [169] Elabd, C. et al. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat. Commun. 5, 4082 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The ASH-2 trithorax complex adds H3K4me3 marks, and deleting it lengthens C. elegans lifespan.

    “For example, the ASH-2 trithorax complex mediates trimethylation of histone H3 on Lys4 (H3K4me3), and its deletion increases Caenorhabditis elegans lifespan, consistent with excessive H3K4me3 being associated with an aging epigenome172,173.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [172] Greer, E.L. et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387 (2010). source

      Not checked in the free run.

    • cites [173] Han, S. & Brunet, A. Histone methylation makes its mark on longevity. Trends Cell Biol. 22, 42–49 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Epigenetic control appears central to stem cell function, and aging-related epigenome changes can affect cells in old organisms and their stem cells.

    “Many studies point to epigenetic regulation as important in determining stem cell function and further indicate that alterations in the epigenome that occur with aging can impinge on cellular processes in aged organisms and their stem cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DNA acetylation and methylation patterns shift with age, and altering the enzymes that make these marks can change lifespan.

    “The acetylation and methylation status of DNA changes with age, while deletion or overexpression of enzymes responsible for these modifications can alter organismal longevity171.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Fraga, M.F. & Esteller, M. Epigenetics and aging: the targets and the marks. Trends Genet. 23, 413–418 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clearing senescent cells only in late life did not improve age-related pathologies, though it slowed their progression.

    “Clearance of senescent cells only late in life did not improve age-related pathologies but did attenuate their progression170.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The aged epigenome behaves like a trait that can be inherited, yet it is also modifiable.

    “This intriguing observation demonstrates that the aging epigenome functions like a heritable trait, but also can be modified.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174] Greer, E.L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sirtuin-regulated mitochondrial activity acts directly on stem cells and also indirectly alters ROS and nutrient sensing, further changing stem cell phenotypes.

    “Likewise, mitochondrial function, largely regulated by sirtuins, not only affects stem cell functions directly but also causes secondary effects on ROS and nutrient-sensing activities, which further modulate stem cell phenotypes29,30,108,113,184.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [29] Kim, H.-S.S. et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52 (2010). source

      Not checked in the free run.

    • cites [30] Brown, K. et al. SIRT3 reverses aging-associated degeneration. Cell Reports 3, 319–327 (2013). source

      Not checked in the free run.

    • cites [108] Peserico, A. et al. A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels. Cell. Mol. Life Sci. 70, 2015–2029 (2013). source

      Not checked in the free run.

    • cites [113] Narala, S.R. et al. SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity. Mol. Biol. Cell 19, 1210–1219 (2008). source

      Not checked in the free run.

    • cites [184] Price, N.L. et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675–690 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Both cell-intrinsic damage (DNA and protein harm from toxic metabolites) and extrinsic stresses from extracellular signals drive stem cell functional decline and pool depletion.

    “Stem cell–autonomous phenotypes, such as DNA and protein damage caused by accumulated toxic metabolites, as well as non-autonomous stresses resulting from extracellular signals, contribute to a decline in stem cell function and depletion of the stem cell pool.”
    Quote in the paperSubstantial claim
69 of 69

  • The paper relies on this without support.

    Age-related decline in tissue homeostasis and regeneration is caused by degenerative changes in tissue-specific stem cells, stem cell niches, and systemic cues.

    “Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity.”

  • The paper relies on this without support.

    Findings about stem cell aging from animal models such as mice, Drosophila, and yeast are informative for human stem cell aging and for developing human therapies.

    “Understanding the molecular pathways involved in this age-dependent deterioration of stem cell function will be critical for developing new therapies for diseases of aging that target the specific causes of age-related functional decline.”

  • The paper relies on this without support.

    ROS levels increase with aging.

    “When combined with the prevailing notion that ROS increases with aging, this result provides a possible explanation for how stem cells lose quiescence and are depleted in aged tissues.”
3 of 3

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Each contradiction between two passages listed here was confirmed by an independent check.

  • Proteasome regulator has two different gene symbols

    Minor

    The text identifies the regulator as PSDM11, but the cited reference identifies it as PSMD11. The symbols differ in letter order for what is presented as the same regulator.

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Authors
Oh, J., Lee, Y. D., & Wagers, A. J.
Affiliations
Joslin Diabetes Center (US)
Corresponding author
Wagers, Amy J
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2014-08
Volume
20
Issue
8
Pages
870-880
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3651
PMC
PMC4160113
OpenAlex
W2042518400
Semantic Scholar
4287d6e55135bb566bef8017ec2e044207f66a90
Cited by
796
References
192
Citations by year
2026: 54 · 2025: 69 · 2024: 73 · 2023: 64 · 2022: 83 · 2021: 81 · 2020: 63 · 2019: 72 · 2018: 60 · 2017: 72 · 2016: 54 · 2015: 43 · 2014: 6 · 2013: 1
FWCI
6.83
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute on Aging (R01AG033053)
  • National Heart, Lung, and Blood Institute (U01HL100402, T32HL007572)
  • National Cancer Institute (T32CA-0216, T32CA009216)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007260)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
stem cell aging, tissue aging, stem cell niche, regenerative capacity, age-related decline, epigenetic memory, age-related diseases, stem cell therapy
MeSH terms
DNA Damage, DNA Repair, Humans, Mitochondria, Stem Cells, Cellular Senescence, Reactive Oxygen Species, Stem Cell Transplantation, Stem Cell Niche

About these checks

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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