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Cited by 759Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsNuclear Structure and Function

Telomere dysfunction in ageing and age-related diseases

Open access
Rossiello, Francesca, Jurk, Diana, Passos, João F., d’Adda di Fagagna, Fabrizio·2022·Nature Cell Biology
DOI 10.1038/s41556-022-00842-xPMC PMC8985209
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Abstract

Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies. Rossiello et al. review the contributions of telomere shortening and/or dysfunction to ageing and a broad spectrum of age-associated human diseases.

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Crossref · 10.1038/s41556-022-00842-x

Cites

208 of 208 references verified0 citation errors · 0 not checkable

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Nothing to recompute.

Claims the paper makes

199 of 257 cited sources checked · 113 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    In mouse and fish models, telomere shortening caused by deletion of telomerase components progressively causes tDDR activation and cellular senescence, recapitulating features of ageing and age-related diseases.

    “In these models, telomere shortening progressively causes tDDR activation and cellular senescence, which recapitulates features of ageing and age-related diseases30,31.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [30] Henriques, C. M., Carneiro, M. C., Tenente, I. M., Jacinto, A. & Ferreira, M. G. Telomerase is required for zebrafish lifespan. PLoS Genet. 9, e1003214 (2013). source
    • cites [31] Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997). source

      The paper’s Abstract reports progressive telomere shortening in telomerase-deficient mice, but its discussion of primary mouse-cell cultures says they showed no difference in overcoming senescence/crisis across the generations tested. It concludes that telomere length is not a primary determinant of senescence/crisis in mouse cells, contrary to the claim that shortening progressively causes senescence in these models. The cited paper does not study fish or establish tDDR activation. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    TAFs and senescence have been reported in ageing post-mitotic cells including cardiomyocytes, adipocytes, neurons, osteocytes and osteoblasts.

    “Nevertheless, TAFs and senescence have been reported in ageing post-mitotic cells, including cardiomyocytes, adipocytes, neurons, osteocytes and osteoblasts17.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021). source

      The section ‘Can postmitotic cells become “senescent”?’ reports senescence-associated findings in neurons, adipocytes, osteocytes and cardiomyocytes, including telomeric dysfunction in osteocytes and persistent telomeric DNA damage in cardiomyocytes (page unavailable). It does not report TAFs in all the listed cell types: DNA-damage accumulation was not reported for adipocytes, and the cited passages do not address osteoblasts. The adipocyte finding was also in mice subjected to excessive caloric intake, rather than specifically ageing mice. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    Telomere-binding proteins inhibit DNA repair in cis to maintain linear chromosome structure and prevent fusions.

    “These observations can be explained by an evolutionary perspective by which telomere-binding proteins inhibit DNA repair in cis18,19 to maintain the linear structure of chromosomes and to prevent fusions.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [18] Bae, N. S. & Baumann, P. A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Mol. Cell 26, 323–334 (2007). source
    • cites [19] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source
  • Premisecitation

    Telomeric DNA is hyper-sensitive to oxidative DNA damage, a phenomenon named TelOxidation.

    “In addition to being hard to repair, telomeric DNA is hyper-sensitive to oxidative DNA damage, a phenomenon recently named TelOxidation22.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Jacome Burbano, M. S., Cherfils-Vicini, J. & Gilson, E. Neutrophils: mediating TelOxidation and senescence. EMBO J. 40, e108164 (2021). source
  • Premisereasoning

    DNA damage within telomeric repeats resists repair, causing persistent tDDR signalling and TAF formation even at long telomeres.

    “As a consequence, DNA damage that occurs within telomeric repeats (tDD) resists repair, which causes persistent tDDR signalling and TAF formation also at long telomeres19–21.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [19] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source
    • cites [20] Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708–708 (2012). source

      The Discussion reports a persistent DNA damage response at telomeres irrespective of telomere length and proposes that repair inhibition could allow it to persist. But it explicitly says the authors could not determine whether the damage occurred within telomeric repeats or at chromosome ends. The claim presents that proposed location and causal mechanism as established. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [21] Fumagalli, M., Rossiello, F., Mondello, C. & d’Adda di Fagagna, F. Stable cellular senescence is associated with persistent DDR activation. PLoS ONE 9, e110969 (2014). source

      The Results section ('DDR signaling persists for years after cellular senescence establishment'; page unavailable) reports persistent DDR foci in telomere-initiated senescent cells. The paper also cites irreparable DNA damage as a driver of persistent DDR, but its own reported foci are not identified as TAF at long telomeres, and it does not establish repair resistance specifically within long telomeric repeats. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 61
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    Senescent cell clearance alleviates plaque formation and disease progression.

    “alleviated plaque formation and disease progression46,118”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [46] Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016). source

      In the section on hypercholesterolemia-induced vascular pathology, the paper reports that senolytic treatment did not affect intimal plaque size or overall plaque lipid content. It found reduced plaque calcification and improved vascular function, but those findings do not establish that treatment alleviated plaque formation or disease progression. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [118] Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). source
    • Rests on an assumption: Clearance or senolytic elimination of senescent cells acts specifically by removing senescent cells and not through other mechanisms.

  • May combine two claims.

    Premisecitation

    Short telomeres retain enough telomere-binding proteins to inhibit DNA repair and avoid fusions, producing a persistent DNA damage signal and permanent proliferative arrest.

    “Such short telomeres, however, retain a sufficient number of telomere-binding proteins to inhibit DNA repair and avoid fusions5, and consequently fuel a persistent DNA damage signal that enforces a permanent DNA damage-induced proliferative arrest.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [5] Cesare, A. J. & Karlseder, J. A three-state model of telomere control over human proliferative boundaries. Curr. Opin. Cell Biol. 24, 731–738 (2012). source

  • May combine two claims.

    Premisecitation

    Senescent cells secrete SASP, which alters the extracellular matrix, impairs stem cell functions, promotes transdifferentiation, can spread senescence to surrounding cells, and causes systemic chronic inflammation.

    “Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell transdifferentiation and can spread the senescence phenotype to surrounding cells, thereby causing systemic chronic inflammation12.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source

      The Figure 2 passage links the SASP to extracellular-matrix degradation and says it appears to spread between cells. The SASP section says its cytokines can cause epithelial-to-mesenchymal transitions, but describes systemic inflammation as potential and context-dependent. Figure 2 attributes removal from the progenitor/stem-cell pool to senescence, not specifically to SASP-mediated impairment of stem-cell function. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Cellular senescence includes changes in chromatin, gene expression, organelles and cell morphology.

    “In addition to irreversible cell cycle arrest, cellular senescence is characterized by changes in chromatin, gene expression, organelles and cell morphology11.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). source

  • May combine two claims.

    Premisecitation

    SASP is promoted by DDR and can promote DDR and TAF formation in autocrine and paracrine fashion.

    “SASP is both promoted by DDR13 and can promote DDR and TAF formation in an autocrine and paracrine fashion14–16.”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [13] Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). source
    • cites [14] Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008). source

      The Discussion reports that CXCR2 expression increases DNA damage and that CXCR2 depletion diminishes DDR activation, supporting a link between senescence-associated chemokine signaling and DDR. But it does not report TAF formation, and it says whether secreted CXCR2 ligands act on normal cells in a paracrine fashion requires further investigation. The preceding claim that DDR promotes SASP carries a different citation and is not assessed here. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [15] Victorelli, S. et al. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J. 38, e101982 (2019). source

      The Results and Discussion report that factors secreted by senescent melanocytes induce a DDR at telomeres and TAF in neighbouring cells, supporting the paracrine part. The Results also suggest autocrine CXCR3 signalling contributes to melanocyte senescence, but do not show that it induces DDR or TAF autocrinely. The claim that DDR promotes SASP is attached to citation 13, not this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [16] Razdan, N., Vasilopoulos, T. & Herbig, U. Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts. Aging Cell 17, e12838 (2018). source

      The Results section, “The SASP promotes telomere dysfunction in a paracrine manner” (page not available), reports that SASP factors induced DDR foci and telomere-associated damage foci in neighboring fibroblasts. The paper supports the paracrine part of the claim, but the passages do not establish that SASP promotes those foci through autocrine signaling. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    When telomeres reach a critical length, they cannot bind enough capping proteins and are sensed as exposed DNA ends, activating DDR pathways that arrest proliferation through p21 and p16.

    “As telomeres reach a critical length, they become unable to bind enough telomere-capping proteins and are sensed as exposed DNA ends2, which activates the DDR pathways that, through the induction of the cell cycle inhibitors p21 and p16, arrest proliferation3,4.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [2] de Lange, T. How telomeres solve the end-protection problem. Science 326, 948–952 (2009). source

      In “How Shelterin Solves the End-Protection Problem in Mammals” (page unavailable), the paper says telomeric repeats provide shelterin-binding sites and that shelterin prevents a DNA damage response at chromosome ends. It also reports that loss of TRF2 activates ATM at those ends. It does not establish the claimed critical-length threshold at which shortening leaves too few capping proteins; the p21/p16 portion is cited to other sources in the printed sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [3] d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source
    • cites [4] Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14, 501–513 (2004). source

  • May combine two claims.

    Premisereasoning

    This process initiates and maintains cellular senescence, which is a key contributor to organismal ageing and multiple age-related diseases.

    “This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases6,7.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [6] He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). source
    • cites [7] Schumacher, B., Pothof, J., Vijg, J. & Hoeijmakers, J. H. J. The central role of DNA damage in the ageing process. Nature 592, 695–703 (2021). source

  • May combine two claims.

    Premisecitation

    In independent cohorts, shorter telomere length is a robust independent predictor of disease progression, response to therapy and death in IPF, and is associated with shorter time to allograft dysfunction after lung transplant.

    “In independent cohorts, a shorter telomere length was demonstrated to be a robust independent predictor of disease progression, response to therapy and death55, and to be associated with a shorter time to allograft dysfunction following lung transplant56.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [55] Stuart, B. D. et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir. Med. 2, 557–565 (2014). source

      The Results (Association between telomere length and survival time in ILD; Replication Cohorts) show that shorter telomere length independently predicted shorter transplant-free survival in three IPF cohorts. The Discussion says future studies are needed to determine whether telomere-based subgroups predict responsiveness to therapy. This source therefore supports the survival finding, but not the attributed prediction of treatment response or a separately measured disease-progression outcome. The lung-transplant allograft claim is attached to a different citation. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [56] Newton, C. A. et al. Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival. J. Heart Lung Transplant. 36, 845–853 (2017). source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Several lung diseases have been associated with ageing and causally linked to telomere dysfunction and senescent cell accumulation.

    “Several lung diseases have been associated with ageing50 and causally linked to telomere dysfunction and senescent cell accumulation.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] Schneider, J. L. et al. The aging lung: physiology, disease, and immunity. Cell 184, 1990–2019 (2021). source

  • May combine two claims.

    Premisecitation

    Individual patients with telomeropathies often show more than one clinical manifestation, supporting the notion of a spectrum disorder caused by telomere dysfunction.

    “Although we describe diseases individually, grouped by the organs affected, individual patients with telomeropathies often show more than one clinical manifestation, which supports the notion of a “spectrum disorder”49 caused by telomere dysfunction.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Holohan, B., Wright, W. E. & Shay, J. W. Cell biology of disease: telomeropathies: an emerging spectrum disorder. J. Cell Biol. 205, 289–299 (2014). source

  • May combine two claims.

    Premisecitation

    TAFs accumulate after chronic inflammation, obesity, mitochondrial dysfunction and impaired autophagy, which are all known to accelerate ageing.

    “Conversely, TAFs accumulate after chronic inflammation47, obesity37,41, mitochondrial dysfunction36 and impaired autophagy48, which are all known to accelerate ageing.”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [47] Jurk, D. et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat. Commun. 2, 4172 (2014). source
    • cites [37] Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1233 (2019). source
    • cites [41] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source
    • cites [36] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). source
    • cites [48] Cassidy, L. D. et al. Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk. Nat. Commun. 11, 307 (2020). source

  • May combine two claims.

    Premisecitation

    Mice with short telomeres induced by knockout of telomerase components show TAFs, inflammation and fibrosis in lungs, aggravated by cigarette smoke or low-dose bleomycin.

    “Mice with short telomeres induced by knockout of telomerase components show TAFs, inflammation and fibrosis in lungs59, which is aggravated by cigarette smoke60 or a low dose of bleomycin, a DNA-damaging agent61.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [59] Chen, R. et al. Telomerase deficiency causes alveolar stem cell senescence-associated low-grade inflammation in lungs. J. Biol. Chem. 290, 30813–30829 (2015). source

      The Results (Fig. 3) report telomere dysfunction-induced foci in alveolar cells, and the Abstract reports inflammation and fibrotic lesions in telomerase-knockout mice. But the paper also says TERC-deficient mice with short telomeres do not show obvious pulmonary fibrosis, so describing the finding simply as lung fibrosis overstates it. Cigarette smoke and bleomycin are attached to separate citations in the citing sentence, not this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [60] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 184, 904–912 (2011). source

      Citation 60 is attached to the cigarette-smoke portion of the sentence. The Abstract and Results report that smoke exposure caused additive DNA damage and emphysema in mice with short telomeres. They do not show smoke-aggravated lung fibrosis or increased inflammation specifically in those mice; the Results report no statistically significant difference in alveolar macrophages between the smoke-exposed groups. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [61] Povedano, J. M., Martinez, P., Flores, J. M., Mulero, F. & Blasco, M. A. Mice with pulmonary fibrosis driven by telomere dysfunction. Cell Rep. 12, 286–299 (2015). source

      The low-dose-bleomycin results (p. 9) report inflammation and fibrosis in treated mice with short telomeres, but no lung fibrosis in untreated counterparts. Thus, the paper supports bleomycin triggering fibrosis in these mice, not aggravating fibrosis already present. The cigarette-smoke clause carries a different citation and is not assessed here. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Patients with IPF accumulate TAFs and senescence markers in lungs that increase with disease severity and activate SASP.

    “Patients with IPF accumulate TAFs and senescence markers in lungs that increase with disease severity and activate SASP52.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017). source

      The Results section, “Senescence biomarkers accumulate in IPF lung” (page unavailable), reports more TAF-positive cells in IPF lungs than controls, p16 expression increasing with disease severity, and elevated expression of SASP components. It does not show that TAF increase with severity or that the markers themselves activate the SASP; the Discussion describes elevated SASP transcription as associated with the senescence markers. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    tDDR activation and TAF accumulation are often causally connected to other ageing-associated processes including mitochondrial dysfunction, altered nutrient sensing, impaired autophagy, loss of proteostasis and epigenetic dysregulation, suggesting a telomere-centric rationale for many ageing hallmarks.

    “tDDR activation and TAF accumulation are often causally connected to other ageing-associated processes. These include mitochondrial dysfunction, altered nutrient sensing, impaired autophagy, loss of proteostasis and epigenetic dysregulation, which suggests that there is a unifying ‘telomere-centric’ mechanistic rationale for many ageing hallmarks, as also proposed in ref.29.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Chakravarti, D., LaBella, K. A. & DePinho, R. A. Telomeres: history, health, and hallmarks of aging. Cell 184, 306–322 (2021). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Telomere shortening rates and the increase in short telomeres have been proposed to predict lifespan.

    “Instead, telomere shortening rates and the increase in short telomeres has been proposed to predict lifespan32.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Whittemore, K., Vera, E., Martínez-Nevado, E., Sanpera, C. & Blasco, M. A. Telomere shortening rate predicts species life span. Proc. Natl Acad. Sci. USA 116, 15122–15127 (2019). source

      The Conclusions state that telomere shortening rate can predict species life span in the paper’s dataset. The copy does not report an analysis of whether the increase in short telomeres predicts life span; that proposition appears in the title of a different study listed in the References. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Short telomeres are an established risk factor for IPF, and 37% of familial and 25% of sporadic cases have telomere lengths below the tenth percentile for age in circulating leukocytes and alveolar epithelial cells.

    “Short telomeres are an established risk factor for IPF, and 37% of familial cases and 25% of sporadic cases show telomere lengths below the tenth percentile for their age, as assessed in circulating leukocytes and alveolar epithelial cells54.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [54] Cronkhite, J. T. et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 729–737 (2008). source

      The Discussion reports that 37% of familial probands and 25% of sporadic cases had leukocyte telomere lengths below the age-adjusted tenth percentile. But these figures concern pulmonary fibrosis cases, not exclusively IPF, and the measurements were made in circulating leukocytes, not alveolar epithelial cells. The paper describes an association and says short telomeres may mark increased predisposition; it does not establish them as a risk factor. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Oxidative stress induces tDD without telomere shortening and accelerates telomere shortening by inhibiting telomerase and disrupting recognition by telomere-binding proteins, contributing to uncapping.

    “Oxidative stress reportedly both induces tDD without telomere shortening and accelerates telomere shortening23–26 by inhibiting telomerase27 and disrupting the recognition by telomere-binding proteins, which contributes to telomere uncapping22,28.”
    Quote in the paperSubstantial claim6 of 7 sources checked
    • cites [23] Fouquerel, E. et al. Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis. Mol. Cell 75, 117–130.e6 (2019). source

      The Results section (page unavailable) says oxidative lesions can disrupt TRF1 and TRF2 binding in vitro and that TRF2 loss causes telomere deprotection, supporting the binding-and-uncapping portion associated with this citation. But this paper did not establish that its induced damage uncapped telomeres: it found no TRF2 loss or substantial increase in telomere-dysfunction markers. The separate shortening and telomerase clauses have other citations in the printed sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] von Zglinicki, T. Oxidative stress shortens telomeres. Trends Biochem. Sci. 27, 339–344 (2002). source
    • cites [25] Lagnado, A. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 40, e106048 (2021). source

      The Discussion (page unavailable) says oxidative stress may disrupt the binding of protective shelterin proteins, supporting the telomere-binding part of the claim, but it does not establish that this causes uncapping. Results section 4 reports telomere damage without a statistically significant difference in telomere length in an acute liver-injury model. The separate claim about inhibiting telomerase is attached to citation 27, not this source. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [26] Barnes, R. P. et al. Telomeric 8-oxoguanine drives rapid premature senescence in the absence of telomere shortening. Preprint at bioRxiv https://doi.org/10.1101/2021.05.05.442662 (2021). source

      The Discussion (page unavailable) reports that telomeric oxidative damage causes dysfunction without shortening, and the Introduction associates chronic oxidative stress with accelerated shortening. But the paper does not establish telomerase inhibition; in ‘Acute Telomeric 8oxoG Formation Causes Telomere Fragility But Not Shortening’ (page unavailable), it reports no significant loss of TRF1 or TRF2 from telomeres and attributes the observed dysfunction to replication stress rather than uncapping through shelterin disruption. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [27] Fouquerel, E. et al. Oxidative guanine base damage regulates human telomerase activity. Nat. Struct. Mol. Biol. 23, 1092–1100 (2016). source
    • cites [22] Jacome Burbano, M. S., Cherfils-Vicini, J. & Gilson, E. Neutrophils: mediating TelOxidation and senescence. EMBO J. 40, e108164 (2021). source

      In the passage beginning “A notable finding,” the paper says oxidative stress shortens telomeres and that oxidation disrupts binding of telomere protective factors and prevents extension by telomerase. It does not say telomere DNA damage occurs without shortening or that oxidative stress inhibits telomerase itself. The relevant passage has no section or page label in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [28] Opresko, P. L., Fan, J., Danzy, S., Wilson, D. M. 3rd & Bohr, V. A. Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2. Nucleic Acids Res. 33, 1230–1239 (2005). source

  • May combine two claims.

    Premisecitation

    The most prevalent hypothesis is that telomere dysfunction-activated tDDR, rather than telomere dysfunction per se, causes cellular senescence, which via SASP facilitates age-related loss of tissue functions.

    “The most prevalent hypothesis is that it is not telomere dysfunction per se that leads to ageing and age-associated diseases but telomere dysfunction-activated tDDR that causes cellular senescence, which, also by SASP, facilitates the age-related loss of tissue functions11.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). source

      The Macromolecular Damage section says telomere dysfunction-induced foci activate the DNA damage response and eventually cause cell-cycle arrest. The Secretion section says the SASP can explain some deleterious, pro-aging effects of senescent cells. The paper does not identify this as the “most prevalent hypothesis,” establish that telomere dysfunction itself does not contribute to aging or disease, or specifically trace this pathway to age-related loss of tissue function. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Lung tissues from patients with non-cystic fibrosis bronchiectasis show shorter telomeres and increased TAFs and senescence markers.

    “Lung tissues from these patients show shorter telomeres and increased levels of TAFs and senescence markers69.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [69] Birch, J. et al. Telomere dysfunction and senescence-associated pathways in bronchiectasis. Am. J. Respir. Crit. Care Med. 193, 929–932 (2016). source

  • May combine two claims.

    Premisecitation

    COVID-19 disease severity correlates with patient age and leukocyte telomere length, and tDDR activation induced by telomere shortening increases ACE2 expression on human lung cells.

    “Disease severity has been correlated with patient age and leukocyte telomere length71, which is consistent with a recent finding that tDDR activation induced by telomere shortening increases the expression of ACE2, the SARS-CoV-2 receptor on human lung cells72.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [71] Aviv, A. Telomeres and COVID-19. FASEB J. 34, 7247–7252 (2020). source

      The “Major features of COVID-19” section reports worse outcomes among older people and proposes that their comparatively short telomeres may help explain those outcomes. The Abstract describes short telomere length as a potential risk marker, not an established patient-level correlation with disease severity. The ACE2 finding is attached to citation 72, so it is not assessed against this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [72] Sepe, S. et al. DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging. EMBO Rep. https://doi.org/10.15252/embr.202153658 (2021). source

  • May combine two claims.

    Premisecitation

    TAF and p21 levels in hepatocytes positively correlate with NAFLD severity, and clearance of senescent cells in aged and obese mice reduces TAF-positive hepatocytes and alleviates liver steatosis.

    “TAF and p21 levels in hepatocytes positively correlate with NAFLD severity41, and the clearance of senescent cells in aged and obese mice reduced the fraction of TAF-positive hepatocytes and alleviated liver steatosis41.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [41] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source

  • May combine two claims.

    Premisecitation

    Around 9% of patients with acquired aplastic anaemia carry mutations in TERC, TERT and DKC1, which are also mutated in inherited aplastic anaemia such as dyskeratosis congenita.

    “Around 9% of patients with acquired aplastic anaemia carry mutations in the telomerase components TERC, TERT and DKC1, which are also mutated in inherited aplastic anaemia, as in dyskeratosis congenita74,75.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [74] Yamaguchi, H. et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 102, 916–918 (2003). source

      The Introduction (page unavailable) says TERC and DKC1 mutations occur in dyskeratosis congenita, and Table 2 lists TERC mutations in two patients diagnosed with aplastic anemia. But the paper does not establish a 9% prevalence for acquired aplastic anemia or report TERT mutations. The TERC abnormalities section instead reports three TERC mutations among 210 patients with several marrow-failure diagnoses, approximately 1.5%. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [75] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). source

      The Mutations section (page not provided) reports TERC mutations in 5 of 205 patients and TERT mutations in 7 of the remaining 200—12 of 205 overall, or about 6%, rather than 9%. It explicitly reports no DKC1 mutations in the patients studied. The background section (page not provided) does link DKC1 and TERC mutations to dyskeratosis congenita. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Cigarette smoke induces TAFs, cellular senescence and SASP in cultured primary human airway epithelial cells and fibroblasts and reduces TPP1 levels in mouse and human lungs, causing tDDR activation.

    “Cigarette smoke (a major risk factor for COPD) induced TAFs, cellular senescence and SASP in cultured primary human airway epithelial cells and fibroblasts34 and reduced telomere protection protein 1 (TPP1) levels in mouse and human lungs, which caused tDDR activation66.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [34] Birch, J. et al. DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 309, L1124–L1137 (2015). source

      The Results (Fig. 6) report that cigarette smoke extract increased telomere-associated foci (TAF) in cultured primary airway epithelial cells, and induced senescence and SASP markers in MRC5 fibroblasts. They report no significant increase in a senescence marker in the epithelial cells, so the claim overextends those findings to both cell types. The TPP1 clause cites a different source (66) and is not assessed here. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [66] Ahmad, T. et al. Shelterin telomere protection protein 1 reduction causes telomere attrition and cellular senescence via sirtuin 1 deacetylase in chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 56, 38–49 (2017). source

  • May combine two claims.

    Premisecitation

    Partial depletion of TRF1 in hematopoietic stem and progenitor cells causes TAF formation, cell depletion and compensatory proliferation, resulting in rapid telomere attrition and cellular senescence.

    “First, partial depletion of TRF1 in hematopoietic stem and progenitor cells caused TAF formation, cell depletion and a compensatory proliferation, which resulted in rapid telomere attrition and cellular senescence84.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [84] Beier, F., Foronda, M., Martinez, P. & Blasco, M. A. Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of dyskeratosis congenita. Blood 120, 2990–3000 (2012). source

  • May combine two claims.

    Premisecitation

    Patients with cirrhosis have a higher incidence of telomerase mutations and bear shorter telomeres than unaffected individuals.

    “Patients with cirrhosis have a higher incidence of telomerase mutations and bear shorter telomeres than unaffected individuals96.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [96] Hartmann, D. et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 53, 1608–1617 (2011). source

      The Abstract reports a higher frequency of telomerase mutations in 521 patients with cirrhosis than in 600 noncirrhosis controls. The Functional Analysis section reports shorter telomeres only in cirrhosis patients carrying telomerase mutations compared with controls without those mutations; it does not establish the telomere comparison for cirrhosis patients generally. Page numbers were not provided in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    About one-third of patients with aplastic anaemia show short telomeres in peripheral blood, suggesting a causative link between aplastic anaemia pathology and telomere dysfunction.

    “About one-third of patients with aplastic anaemia show short telomeres in peripheral blood, which suggests that there is a causative link between aplastic anaemia pathology and telomere dysfunction75,76,79.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [75] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). source

      The paper’s introductory passage (indexed under Abstract; page unavailable) says that approximately one third of patients with *acquired* aplastic anemia have short telomeres in leukocytes, especially those who do not respond to immunosuppressive therapy. Its conclusion says TERT mutations impair telomerase activity and may be risk factors for marrow failure, supporting the suggested link. The citing sentence omits the restriction to acquired aplastic anemia and thus states the one-third figure for a broader population. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [76] Savage, S. A. et al. Genetic variation in telomeric repeat binding factors 1 and 2 in aplastic anemia. Exp. Hematol. 34, 664–671 (2006). source
    • cites [79] Brümmendorf, T. H., Maciejewski, J. P., Mak, J., Young, N. S. & Lansdorp, P. M. Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood 97, 895–900 (2001). source

  • May combine two claims.

    Premisecitation

    Danazol treatment in aplastic anaemia patients with critically short telomeres improves their condition by increasing telomerase expression and lengthening telomeres, supporting a causative role of telomere length.

    “The use of the androgen receptor agonist danazol in patients with aplastic anaemia with critically short telomeres improved their condition by increasing telomerase expression and lengthening telomeres. This provides support for a causative role of telomere length in this disease83.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [83] Townsley, D. M. et al. Danazol treatment for telomere diseases. N. Engl. J. Med. 374, 1922–1931 (2016). source

      The Abstract Results and Discussion (page not provided) report telomere elongation and hematologic improvement during danazol treatment. But the study enrolled patients with a range of telomere diseases, not only aplastic anaemia, and the Discussion says telomerase activity could not be reliably measured. It does not establish that increased telomerase expression caused the improvement or that telomere length was the causal factor. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Patients with aplastic anaemia and shorter telomeres at diagnosis show more severe disease, poorer response to treatment, increased risk of relapse and MDS, and lower survival.

    “Patients with shorter telomeres at diagnosis show a more severe disease, a poorer response to treatments, an increased risk of relapse and development of myelodysplastic syndrome (MDS; see below) and a lower survival rate75,80,81.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [75] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). source

      The introductory passage reports short telomeres in patients with acquired aplastic anemia, especially those who do not respond to immunosuppressive therapy; the discussion also notes poor response among patients with TERT mutations. The paper does not establish that telomere length at diagnosis predicts disease severity, relapse, development of MDS, or survival. Its treatment-response evidence is narrower than the full claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [80] Scheinberg, P. et al. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 304, 1358–1364 (2010). source

      The Results (Response and relapse according to telomere length; Clonal evolution and survival according to telomere length) associate shorter pretreatment telomeres with relapse, clonal evolution and lower survival. They do not establish more severe disease at diagnosis, and explicitly report no correlation between telomere length and response to initial immunosuppressive treatment. The paper reports clonal evolution, including changes associated with myelodysplasia, rather than a separate MDS risk estimate. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
    • cites [81] Sakaguchi, H. et al. Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia. Haematologica 99, 1312–1316 (2014). source

      The Results (page unavailable) show that children with shorter telomeres at diagnosis responded less often to immunosuppressive therapy. They report no statistical tendency linking telomere length to relapse, clonal evolution or overall survival, and do not establish that shorter telomeres indicate more severe disease. The Introduction attributes the relapse, MDS and survival associations to an earlier study, rather than to this paper's findings. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    MDS can be secondary to chemotherapy or radiation or be associated with inherited abnormalities in DNA repair and telomere maintenance genes.

    “MDS can also be secondary to chemotherapy or radiation or be associated with inherited abnormalities in DNA repair and telomere maintenance genes89.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [89] Savage, S. Beginning at the ends: telomeres and human disease [version 1; peer review: 4 approved]. F1000Res. https://doi.org/10.12688/f1000research.14068.1 (2018). source

      In “Dyskeratosis congenita – a direct connection between germline telomere biology and human disease” (Table 2; page unavailable), the paper links the telomere-biology gene TERT with MDS. “Telomeres and cancer” also reports increased MDS risk in patients with telomere biology disorders. The passages do not address MDS secondary to chemotherapy or radiation, or its association with inherited DNA-repair abnormalities. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    COPD exhibits accelerated lung ageing characterized by inflammation of parenchyma and airways, chronic remodelling of peripheral bronchi and inter-alveolar septa disruption towards emphysema.

    “COPD exhibits accelerated lung ageing characterized by inflammation of parenchyma and airways, chronic remodelling of the peripheral bronchi and inter-alveolar septa disruption towards emphysema.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [65] James, S. L. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1789–1858 (2018). source

      The Results section reports COPD prevalence, incidence, and years lived with disability, while the Discussion’s “Emerging trends” section addresses respiratory-disease burden in older people. Searches for accelerated lung ageing, airway remodelling, and emphysema found no passage in our copy addressing the claimed pathological changes. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Telomerase expression using AAVs in alveolar epithelial type II cells reduces TAFs, decreases inflammation and improves lung function in telomerase-mutant and wild-type aged mice.

    “Consistently, expression of telomerase using adeno-associated vectors (AAVs) in alveolar epithelial type II cells led to TAF reduction, decreased inflammation and improved lung function in telomerase-mutant and wild-type aged mice63,64.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [63] Povedano, J. M. et al. Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres. eLife 7, e31299 (2018). source

      The Results report that AAV9-Tert preferentially targeted alveolar type II cells, reduced lung inflammation, and improved lung function. They also report less DNA damage in those cells, but do not identify that measurement as a reduction in telomere-associated foci (TAFs). The Materials and methods describe young telomerase-deficient mice, not aged wild-type mice, for the treatment experiment. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Pineiro-Hermida, S. et al. Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging. J. Cell Biol. https://doi.org/10.1083/jcb.202002120 (2020). source

      The Results report that AAV9-Tert reduced inflammatory markers in both aged wild-type and telomerase-deficient mice, and improved pulmonary surfactant activity in both groups. They report fewer γ-H2AX-positive lung cells, but do not establish a reduction in telomere-associated foci (TAFs); surfactant activity is not a direct measure of lung function. The Discussion says ATII-cell transduction was shown previously, rather than established in this treatment experiment. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    MDS is a heterogeneous group of clonal haematopoietic disorders characterized by ineffective haematopoiesis and DNA damage accumulation in haematopoietic stem and progenitor cells.

    “MDS is a heterogeneous group of clonal haematopoietic disorders characterized by ineffective haematopoiesis and DNA damage accumulation in haematopoietic stem and progenitor cells87.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [87] Zhou, T. et al. Myelodysplastic syndrome: an inability to appropriately respond to damaged DNA? Exp. Hematol. 41, 665–674 (2013). source

      The Introduction describes MDS as a group of HSC-based disorders characterized by ineffective differentiation, and the genomic-instability section discusses accumulating genetic alterations. But the paper does not establish DNA damage accumulation in MDS haematopoietic stem and progenitor cells as a defining characteristic; its direct evidence of increased DNA damage concerns bone marrow cells in MDS mouse models (DNA repair > Double strand break repair; page unavailable). (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Removing senescent cells in aged mice improves heart function and lowers the proportion of TAF-positive cardiomyocytes, with no significant change in mean telomere length.

    “The clearance of senescent cells in aged mice improves heart functions and reduces the fraction of TAF-positive cardiomyocytes without a significant effect on mean telomere length36.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [36] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). source

      The Results section, “Senescent-cell clearance reduces cardiac hypertrophy and fibrosis” (page unavailable), reports reduced TAF in cardiomyocytes after senescent-cell clearance, with no detected difference in telomere FISH signals. It does not support improved heart function: ejection fraction was unchanged after genetic clearance, and navitoclax had no significant impact on cardiac function. The reported improvements were in hypertrophy and fibrosis. (LLM, conf=0.93)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Clearance or senolytic elimination of senescent cells acts specifically by removing senescent cells and not through other mechanisms.

  • May combine two claims.

    Premisecitation

    CKD shows features of accelerated ageing including decreased kidney weight, atrophy, sclerosis, fibrosis, and a CKD-associated secretory phenotype similar to SASP.

    “CKD shows several features of accelerated ageing, including decreased kidney weight, atrophy, sclerosis, fibrosis and a CKD-associated secretory phenotype, which is similar to SASP135.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [135] Wang, W. J., Cai, G. Y. & Chen, X. M. Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease. Oncotarget 8, 64520–64533 (2017). source

  • May combine two claims.

    Premisecitation

    Late-generation telomerase-deficient mice show severe left ventricular dysfunction, increased cardiomyocyte hypertrophy, and fewer cardiomyocytes.

    “Late-generation telomerase-deficient mice show severe left ventricular loss of function, increased cardiomyocyte hypertrophy and decreased number of cardiomyocytes111.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [111] Leri, A. et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 22, 131–139 (2003). source
    • Rests on an assumption: Findings from mouse models of telomere dysfunction can be generalized to human age-related disease mechanisms.

  • May combine two claims.

    Premisecitation

    Cultured chondrocytes near hip osteoarthritis lesions have shorter mean telomere length and more senescence markers than chondrocytes from distal sites in the same joint.

    “cultured chondrocytes isolated from areas close to the osteoarthritis lesions from the hips of patients have shorter mean telomere length and increased levels of senescence markers than those from distal sites in the same joint126”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [126] Price, J. S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65 (2002). source
    • Rests on an assumption: Senescence markers such as p16, p21, and DDR activation indicate cellular senescence.

  • May combine two claims.

    Premisecitation

    In cardiomyocytes, telomere-associated foci are linked to p16 and p21 induction and a cardiac-specific SASP that promotes cardiac hypertrophy and fibrosis.

    “This is associated with the induction of p16 and p21 and a cardiac-specific form of SASP that contributes to cardiac hypertrophy and fibrosis36.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [36] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). source
    • Rests on an assumption: Senescence markers such as p16, p21, and DDR activation indicate cellular senescence.
    • Rests on an assumption: Telomere-associated foci indicate telomere dysfunction.

  • May combine two claims.

    Premisecitation

    DNA damage and DDR markers are observed in Alzheimer's disease models and in neurons from postmortem patient brains.

    “DNA damage and DDR markers have been observed in models of Alzheimer’s disease154,155 and in neurons in postmortem brains from patients with the disease156.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [154] Fielder, E., von Zglinicki, T. & Jurk, D. The DNA damage response in neurons: die by apoptosis or survive in a senescence-like state? J. Alzheimers Dis. 60, S107–S131 (2017). source
    • cites [155] Thadathil, N. et al. DNA double-strand break accumulation in Alzheimer’s disease: evidence from experimental models and postmortem human brains. Mol. Neurobiol. 58, 118–131 (2021). source

      The indexed passages are labeled as a Parkinson’s disease paper, despite the supplied Alzheimer’s disease title. Its Results section reports DNA-damage markers in postmortem PD neurons, while its Discussion only briefly mentions a previous study of 53BP1 in AD brain tissue. Searches for AD models and postmortem AD neurons did not retrieve a passage establishing the attributed claim in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [156] Shanbhag, N. M. et al. Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease. Acta Neuropathol. Commun. 7, 77 (2019). source

  • May combine two claims.

    Premisecitation

    In aged mice, clearing senescent cells reduces glomerulosclerosis and preserves blood urea nitrogen levels.

    “In aged mice, clearance of senescent cells reduced glomerulosclerosis and retained blood urea nitrogen levels”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [147] Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source
    • Rests on an assumption: Clearance or senolytic elimination of senescent cells acts specifically by removing senescent cells and not through other mechanisms.

  • May combine two claims.

    Premisecitation

    Kidneys of CKD patients have more tubules positive for γH2AX, inversely correlated with estimated glomerular filtration rate, and more phosphorylated ATR-positive cells.

    “Kidneys in patients with CKD exhibited an increased number of tubules positive for the DDR marker γH2AX, which was inversely correlated with the estimated glomerular filtration rate, and a greater number of phosphorylated ATR-positive cells137.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [137] Kishi, S. et al. Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses. J. Clin. Invest. 129, 4797–4816 (2019). source

  • May combine two claims.

    Premisecitation

    Senescent cells accumulate with age in the murine brain, and this accumulation is exacerbated in late-generation telomerase-deficient mice.

    “Senescent cells accumulate with age in the murine brain and is exacerbated in late-generation telomerase-deficient mice150”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [150] Jurk, D. et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996–1004 (2012). source

      The Results report that frequencies of neurons positive for senescence-associated markers increased with age, and the Abstract says the phenotype was aggravated in brains of late-generation TERC−/− mice. The paper describes this as evidence suggesting a senescence-like phenotype in neurons, rather than establishing that senescent cells generally accumulate in the brain. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Senescence markers such as p16, p21, and DDR activation indicate cellular senescence.

  • May combine two claims.

    Premisecitation

    Telomerase activators decrease pathological α-synuclein protein and improve motor symptoms in a mouse model of Parkinson's disease.

    “telomerase activators led to decreased levels of pathological α-synuclein protein and improved motor symptoms in a mouse model of Parkinson’s disease171”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [171] Wan, T., Weir, E. J., Johnson, M., Korolchuk, V. I. & Saretzki, G. C. Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson’s disease associated with enhanced autophagy. Prog. Neurobiol. 199, 101953 (2021). source
    • Rests on an assumption: Findings from mouse models of telomere dysfunction can be generalized to human age-related disease mechanisms.

  • May combine two claims.

    Premisecitation

    Danazol, a synthetic testosterone, has been used clinically for many years in aplastic anaemia with some efficacy.

    “androgen therapy, based on the clinical use of danazol, a synthetic testosterone, has been part of clinical practice for many years in the treatment of aplastic anaemia with some efficacy83”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [83] Townsley, D. M. et al. Danazol treatment for telomere diseases. N. Engl. J. Med. 374, 1922–1931 (2016). source

      The Discussion says androgens have been used for marrow failure syndromes since the 1960s, and the References include studies of androgen treatment for aplastic anemia. The Methods identify danazol as a synthetic sex hormone with androgenic properties, and the Results report hematologic responses in patients with telomere diseases. The paper does not establish that danazol itself has been used for many years to treat aplastic anemia or that its efficacy was demonstrated in that population. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TA-65 has been reported to boost telomerase activity and lengthen telomeres in mice.

    “A natural plant compound named TA-65 has been reported to boost telomerase activity and lengthen telomeres in mice189.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [189] de Jesus, B. B. et al. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 10, 604–621 (2011). source

      The Results section on mouse embryonic fibroblasts reports increased telomerase activity after TA-65 treatment. The Results section on dietary supplementation in mice reports fewer very short telomeres, but not a significant increase in average telomere length; it reports increased telomerase expression in liver rather than a direct measurement of activity in treated mice. The claim therefore omits important limits on both findings. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Findings from mouse models of telomere dysfunction can be generalized to human age-related disease mechanisms.

  • May combine two claims.

    Premisecitation

    Telomere shortening and telomere damage are recognized causes of cellular senescence and ageing.

    “Telomere shortening and damage are recognized causes of cellular senescence and ageing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Endogenous or exogenous DNA damage is constantly generated, and the fraction at telomeres, being less efficiently repaired, accumulates and induces a senescence-like phenotype.

    “Endogenous or exogenous DNA damage is constantly generated, and the fraction that occurs at telomeres, which is less efficiently repaired, thus accumulates and induces a senescence-like phenotype (Fig. 1a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DNA replication progressively shortens telomeres because standard DNA polymerases cannot fully replicate linear DNA templates without telomerase and because of nucleolytic processing.

    “As standard DNA polymerases cannot fully replicate linear DNA templates in the absence of telomerase, a DNA-template-independent DNA polymerase, and because of nucleolytic processing, DNA replication results in the generation of chromosomes with progressively shortened telomeres1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). source

  • May combine two claims.

    Premisenone given

    Across species, short telomeres do not necessarily predict short lifespan; humans have shorter telomeres but longer lifespans than rodents.

    “Across species, however, short telomeres do not necessarily predict short lifespan—that is, humans have shorter telomeres but longer lifespans than rodents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Primary biliary cirrhosis is associated with short telomeres, DDR activation and senescence marker accumulation in biliary epithelial cells.

    “Primary biliary cirrhosis, an autoimmune disease with chronic, progressive cholestasis and liver failure, is associated with short telomeres, DDR activation and senescence marker accumulation in biliary epithelial cells98.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Sasaki, M., Ikeda, H., Yamaguchi, J., Nakada, S. & Nakanuma, Y. Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence. Hepatology 48, 186–195 (2008). source

  • May combine two claims.

    Premisecitation

    Both telomere shortening and telomere damage have been reported as hallmarks and potential drivers of heart diseases and as indicators of therapeutic outcomes.

    “Both telomere shortening and telomere damage have been reported as hallmarks and potential drivers of heart diseases and as indicators of therapeutic outcomes105.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Boniewska-Bernacka, E., Pańczyszyn, A. & Klinger, M. Telomeres and telomerase in risk assessment of cardiovascular diseases. Exp. Cell. Res. 397, 112361 (2020). source

  • May combine two claims.

    Premisecitation

    Telomere shortening has been implicated in hepatocyte senescence and disease progression in patients with liver cirrhosis.

    “Telomere shortening has been implicated in hepatocyte senescence94 and in disease progression in patients with liver cirrhosis95.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Wiemann, S. U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16, 935–942 (2002). source
    • cites [95] Kitada, T., Seki, S., Kawakita, N., Kuroki, T. & Monna, T. Telomere shortening in chronic liver diseases. Biochem. Biophys. Res. Commun. 211, 33–39 (1995). source

  • May combine two claims.

    Premisecitation

    Short telomeres in adipose tissues are associated with metabolic disease progression, and causality is demonstrated by telomerase inactivation in mouse adipocyte precursors leading to hypertrophy and inflammation.

    “Short telomeres in adipose tissues are associated with metabolic disease progression, and causality was demonstrated by telomerase inactivation in mouse adipocyte precursors that led to hypertrophy and inflammation93.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Gao, Z. et al. Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease. Nat. Metab. 2, 1482–1497 (2020). source

  • May combine two claims.

    Premisecitation

    In a female cohort, long telomeres are associated with high bone mineral density and lower osteoporosis risk.

    “long telomeres in a female cohort were associated with high bone mineral density and reduced risk of osteoporosis131”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Valdes, A. M. et al. Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos. Int. 18, 1203–1210 (2007). source
    • Rests on an assumption: Leukocyte telomere length reflects telomere length or dysfunction in the relevant tissue or organ.

  • May combine two claims.

    Premisecitation

    Cats with CKD show shortened telomeres and more senescent cells in the kidney.

    “Cats with CKD also show shortened telomeres and increased numbers of senescent cells in the kidney148.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Quimby, J. M. & Lunn, K. F. Mirtazapine as an appetite stimulant and anti-emetic in cats with chronic kidney disease: a masked placebo-controlled crossover clinical trial. Vet. J. 197, 651–655 (2013). source
    • Rests on an assumption: Senescence markers such as p16, p21, and DDR activation indicate cellular senescence.

  • May combine two claims.

    Premisecitation

    Cellular senescence markers are present in neurons and astrocytes from Alzheimer's patients and in cultured human astrocytes exposed to β-amyloid.

    “Cellular senescence markers have been reported in neurons and astrocytes from patients with Alzheimer’s disease and in cultured human astrocytes exposed to β-amyloid153.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Saez-Atienzar, S. & Masliah, E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat. Rev. Neurosci. 21, 433–444 (2020). source
    • Rests on an assumption: Senescence markers such as p16, p21, and DDR activation indicate cellular senescence.

  • May combine two claims.

    Premisecitation

    β-amyloid can induce telomere shortening and inhibit telomerase activity.

    “β-amyloid can induce telomere shortening and inhibit telomerase activity167.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Wang, J. et al. New insights in amyloid beta interactions with human telomerase. J. Am. Chem. Soc. 137, 1213–1219 (2015). source

  • May combine two claims.

    Premisecitation

    A woman with dyskeratosis congenita responded poorly to hormonal treatment before IVF and her oocytes contained critically short telomeres.

    “a woman with dyskeratosis congenita, a telomeropathy associated with a reduced ovarian reserve, responded poorly to hormonal treatment before in vitro fertilization and her oocytes contained critically short telomeres181”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Robinson, L. G. Jr et al. Impaired reproductive function and fertility preservation in a woman with a dyskeratosis congenita. J. Assist. Reprod. Genet. 37, 1221–1225 (2020). source

  • May combine two claims.

    Interpretationreasoning

    TERT expression and tASO approaches act upstream in the pathological cascade and are expected, with some demonstrated, to make a promising impact on consequences of telomere dysfunction such as impaired proliferation, inflammation, and fibrosis.

    “both TERT expression and tASO approaches, by acting upstream in the pathological cascade, are expected, and some have demonstrated, to make a promising impact on the many consequences of telomere dysfunction, such as impaired proliferation, inflammation and fibrosis.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Use of immunogenic viral vectors such as AAV may reduce the possibility of repeated treatments.

    “the use of immunogenic viral vectors such as AAV may reduce the possibility of repeated treatments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with premature ovarian insufficiency have shorter telomeres and reduced telomerase activity in leukocytes and granulosa cells than healthy individuals.

    “patients with premature ovarian insufficiency have shorter telomeres and reduced telomerase activity in leukocytes and granulosa cells than healthy individuals179”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Xu, X. et al. Impaired telomere length and telomerase activity in peripheral blood leukocytes and granulosa cells in patients with biochemical primary ovarian insufficiency. Hum. Reprod. 32, 201–207 (2017). source

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

    Premisecitation

    Antisense oligonucleotides are an emerging drug class targeting RNAs, with eight products on the market and many in advanced clinical trials.

    “Antisense oligonucleotides (ASOs) are an emerging class of drugs targeting RNAs, with eight products presently on the market and many more in advanced clinical trials197.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Crooke, S. T., Baker, B. F., Crooke, R. M. & Liang, X. H. Antisense technology: an overview and prospectus. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-021-00162-z (2021). source

  • May combine two claims.

    Interpretationnone given

    Limitations of tASO use may include tissue distribution, need for safety evaluations, and relatively less-studied mechanism of action.

    “Limitations of their use may lie in their tissue distribution, the need for safety evaluations and their relatively less-studied mechanism of action.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The tASO approach has broad activity independent of the genetic defects underlying telomere dysfunction, acts at both critically short and damaged telomeres and in non-proliferating cells, and uses nonviral delivery.

    “An advantage of this approach is its broad activity independent from the genetic defects underlying telomere dysfunction, its ability to act at both critically short and damaged telomeres and in non-proliferating cells, and its nonviral delivery.”
    Quote in the paperSubstantial claim
63 of 63

  • The paper relies on this without support.

    DNA is the only irreplaceable component of the cell.

    “the notion that DNA is the only irreplaceable component of the cell makes a strong argument in favour of an apical role of DNA integrity in ageing”

  • The paper relies on this without support.

    Leukocyte telomere length reflects telomere length or dysfunction in the relevant tissue or organ.

    “In a limited cohort, patients with atherosclerosis bear shorter telomeres in circulating leukocytes than healthy age-matched individuals114.”

  • The paper relies on this without support.

    Findings from mouse models of telomere dysfunction can be generalized to human age-related disease mechanisms.

    “A causal role of short and dysfunctional telomeres in cardiac diseases has been established in mice110.”

  • The paper relies on this without support.

    Clearance or senolytic elimination of senescent cells acts specifically by removing senescent cells and not through other mechanisms.

    “The clearance of senescent cells in aged mice improves heart functions and reduces the fraction of TAF-positive cardiomyocytes without a significant effect on mean telomere length36.”

  • The paper relies on this without support.

    Senescence markers such as p16, p21, and DDR activation indicate cellular senescence.

    “Chondrocytes, the cells that constitute the articular cartilage, show several senescence markers, including DDR activation, in osteoarthritis119,120.”

  • The paper relies on this without support.

    Telomere-associated foci indicate telomere dysfunction.

    “During physiological ageing in humans and mice, TAFs occur independently from telomere length in post-mitotic cardiomyocytes.”

  • The authors state this as an assumption.

    Mouse telomere biology differs from human telomere biology in ways relevant to translating therapies.

    “Of course, the different telomere biology of mice, the most commonly used animal model, with longer telomeres and widespread telomerase expression, compared with humans has to be considered when translating any potential therapy to the clinic.”
7 of 7

Claims other papers make about this one

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

  • The theory of telomere attrition is not able to explain senescence in non-proliferating, quiescent, or terminally differentiated cells, suggesting a more complicated pathway.

    “Nevertheless, despite the theory of telomere attrition seeming logical, it is not able to explain senescence in non-proliferating, quiescent, or terminally differentiated cells, suggesting a more complicated pathway [174].”

    From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [174]

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Related

Authors
Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F.
Affiliations
  • IFOM (IT)
  • Mayo Clinic (US)
Corresponding author
Passos, João F.
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2022-02
Volume
24
Issue
2
Pages
135-147
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-022-00842-x
PMC
PMC8985209
OpenAlex
W4213091566
Semantic Scholar
5f7700d000f5b025619477fe0350208ad1ac3566
Cited by
754
References
208
Citations by year
2026: 142 · 2025: 231 · 2024: 203 · 2023: 140 · 2022: 36 · 2020: 1 · 2013: 1
FWCI
20.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Ted Nash Long Life Foundation
  • European Commission (2014‐2020, HORIZON2020, POR FESR 2014-2020, 825575)
  • Associazione Italiana per la Ricerca sul Cancro (5×1000, 21762, 21091)
  • Regione Lombardia (POR FESR 20142020, 2014–2020, FESR 2014-2020)
  • Fondazione Regionale per la Ricerca Biomedica (825575)
  • National Institutes of Health (UL1TR002377)
  • Biotechnology and Biological Sciences Research Council (BB/K017314/1)
  • European Regional Development Fund (FESR 2014-2020, 2014-2020’, POR FESR 2014-2020)
  • National Institute on Aging (R01AG068182, R01AG068048, P01AG062413)
  • National Cancer Institute (UH3CA268103, UG3CA268103)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK084567)
  • National Center for Advancing Translational Sciences
  • H2020 European Research Council (835103, 875139)
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 › Nuclear Structure and Function
Keywords
telomere dysfunction, telomere shortening, cellular senescence, aging, age-related diseases, senolytics, telomere damage
MeSH terms
Noncommunicable Diseases, Age Factors, Aging, Animals, DNA Damage, Humans, Telomere, Cellular Senescence, Telomere Homeostasis, Telomere Shortening

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 under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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