The DOI matches its Crossref record; 128 of the 128 references it cites were found in a registry or an index; 5 of the 123 sources its claims cite were checked for support.
The telomere syndromes
Open accessAbstract
There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders. Their manifestations encompass common disease states such as idiopathic pulmonary fibrosis and bone marrow failure. Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect. Here we review the manifestations and unique genetics of telomere syndromes. We also discuss their underlying molecular mechanisms and significance for understanding common age-related disease processes.
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61 Not checked yet · 26 Own interpretation · 3 No basis given · 1 Partly supported · accuracy not yet measured
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“There has been mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders.”
- Also stated in: § Abstract · boosted
“This Review highlights how recent discoveries in human genetics have synergized with the field of telomere biology to unequivocally establish a causal role for telomere dysfunction in several specific, common and recognizable disease contexts.”
§ The telomere syndromes > Abstract
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“Among these, the lung disease idiopathic pulmonary fibrosis (IPF) — best known until recently by its ‘idiopathic’ adjective — is the most common manifestation of telomere-mediated disease12.”
§ The telomere syndromes > Abstract
What the sources say
- Not checked yetcites [12] Armanios, M. Telomerase and idiopathic pulmonary fibrosis. Mutat. Res. 730, 52–58 (2012). source
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“Because, as we discuss, telomere length is heritable, the unique inheritance patterns that distinguish these syndromes from other Mendelian disorders are also discussed.”
- Also stated in: § Heritability of telomere length in humans · plain
“These observations collectively support that telomere length is a genetically determined trait and that short telomeres are probably sufficient to cause disease phenotypes within similar thresholds to those seen in monogenic disorders.”
§ The telomere syndromes > Abstract
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“These observations collectively support that telomere length is a genetically determined trait and that short telomeres are probably sufficient to cause disease phenotypes within similar thresholds to those seen in monogenic disorders.”
§ The telomere syndromes > Telomere length is a heritable trait > Heritability of telomere length in humans
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“Mutations in TERT and TR are the most commonly identifiable defects in monogenic telomere syndromes.”
§ The telomere syndromes > Genotype–phenotype correlations > Telomere length is a modifier of disease severity
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“Although these disorders seem to be clinically diverse, collectively they comprise a single syndrome spectrum defined by the short telomere defect.”
- Also stated in: § Abstract · hedged
“Because of their overlapping clinical features, it has been proposed to consider them as a single syndrome spectrum13, and here we refer to them as ‘the telomere syndromes.’”
§ The telomere syndromes > Abstract
What the sources say
- Not checked yetcites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source
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- Rests on an assumption: The short telomere defect in affected individuals is present in germ cells and thus simultaneously affects multiple organs even when one disease presentation predominates.
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In the paper
“As described below, mutations in the genes that encode the essential telomerase components — namely, TERT, TR and DKC1 — are a common cause of human telomere syndromes.”
§ The telomere syndromes > Telomeres and telomerase > Telomerase structure
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“We propose that at least three primary mechanisms explain the diverse telomere-mediated disease phenotypes.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
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“Clinically, this is most apparent in the high penetrance of pulmonary disease in telomerase mutation carriers, even though the lung has a slow mitotic rate56,99.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
What the sources say
- Not checked yetcites [56] Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007). References 54–56 showed that lymphocyte telomere length using flow cytometry and fluorescence in situ hybridization could be a useful diagnostic marker in identifying individuals with telomere-related disease. source
- Not checked yetcites [99] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 183, 904–912 (2011). source
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In the paper
“Altogether, mutations in four genes — DKC1, TINF2, TERT and TR — account for most dyskeratosis congenita cases with an identifiable genetic defect.”
§ The telomere syndromes > The monogenic telomere disorders > Childhood-onset telomere disorders
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“In addition, both dyskeratosis congenita and IPF patients are prone to developing haematological malignancies, commonly manifesting as myelodysplasia or acute myeloid leukaemia70,75,76.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
What the sources say
- Not checked yetcites [70] Diaz de Leon, A. et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE 5, e10680 (2010). source
- Not checked yetcites [75] Alter, B. P., Giri, N., Savage, S. A. & Rosenberg, P. S. Cancer in dyskeratosis congenita. Blood 113, 6549–6557 (2009). source
- Not checked yetcites [76] Alder, J. K. et al. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet. 7, e1001352 (2011). source
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“Patients with telomere syndromes are cancer-prone.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
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“although in most mouse studies, short telomeres have been found to be cancer-protective rather than cancer-promoting80.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
What the sources say
- Not checked yetcites [80] Deng, Y., Chan, S. S. & Chang, S. Telomere dysfunction and tumour suppression: the senescence connection. Nature Rev. Cancer 8, 450–458 (2008). source
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“Aside from trinucleotide repeat expansion, telomere shortening is the only other characterized molecular mechanism of genetic anticipation in autosomal-dominant disorders.”
§ The telomere syndromes > Genotype–phenotype correlations > Telomere length is a modifier of disease severity
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“In classic dyskeratosis congenita, where it has been studied, cancer diagnoses have been estimated to occur at an 11-fold increased incidence relative to the population in one series75.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
What the sources say
- Not checked yetcites [75] Alter, B. P., Giri, N., Savage, S. A. & Rosenberg, P. S. Cancer in dyskeratosis congenita. Blood 113, 6549–6557 (2009). source
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“This anticipation closely parallels the progressive telomere shortening with each successive generation and occurs because telomeres shorten in germ cells, and the shortened telomeres are transmitted to progeny along with the mutant telomerase gene (Fig. 3a).”
§ The telomere syndromes > Genotype–phenotype correlations > Telomere length is a modifier of disease severity
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“Dyskeratosis congenita is characterized by the short telomere defect11,38,55.”
§ The telomere syndromes > The monogenic telomere disorders > Childhood-onset telomere disorders
What the sources say
- Not checked yetcites [11] Mitchell, J. R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999). This study showed that dyskerin is essential for telomerase RNA stability and that dyskeratosis congenita cell lines have a short telomere length, linking this disease with defects in telomere maintenance. source
- Not checked yetcites [38] Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001). source
- Not checked yetcites [55] Alter, B. P. et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 110, 1439–1447 (2007). source
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“and this immunodeficiency in turn may lead to a failure of cancer surveillance.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
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In the paper
“The most compelling evidence for the causal role of telomere shortening as a primary modifier of disease is that families with mutant telomerase genes display genetic anticipation39,83.”
§ The telomere syndromes > Genotype–phenotype correlations > Telomere length is a modifier of disease severity
What the sources say
- Not checked yetcites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. source
- Not checked yetcites [83] Vulliamy, T. et al. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nature Genet. 36, 447–449 (2004). References 83 and 39 (above) showed that mutations in the essential telomerase genes cause genetic anticipation in autosomal-dominant dyskeratosis congenita. source
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“In ~40% of cases, dyskeratosis congenita remains genetically uncharacterized.”
§ The telomere syndromes > The monogenic telomere disorders > Childhood-onset telomere disorders
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“more recently it has been recognized that telomere dysfunction causes prominent phenotypes in slow-turnover tissues97,99,100,103 (Table 2).”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
What the sources say
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
- Not checked yetcites [99] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 183, 904–912 (2011). source
- Not checked yetcites [100] 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
- Not checked yetcites [103] Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011). References 97 and 103 implicate short telomeres as a cause of mitochondrial dysfunction, a pathogenic mechanism that highlights a role for telomere dysfunction in slow-turnover tissues. source
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“The short, dysfunctional telomeres trigger a DNA damage response that resembles the response elicited by DNA double-strand breaks91–94.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
What the sources say
- Not checked yetcites [91] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source
- Not checked yetcites [92] Enomoto, S., Glowczewski, L. & Berman, J. MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae. Mol. Biol. Cell 13, 2626–2638 (2002). source
- Not checked yetcites [93] IJpma, A. & Greider, C. W. Short telomeres induce a DNA damage response in Saccharomyces cerevisiae. Mol. Biol. Cell 14, 987–1001 (2003). source
- Not checked yetcites [94] Nautiyal, S., DeRisi, J. L. & Blackburn, E. H. The genome-wide expression response to telomerase deletion in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 99, 9316–9321 (2002). source
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“In IPF patients with telomerase mutations, the mean age of onset is 51 years, although IPF can manifest as late as the ninth decade of life70,71.”
§ The telomere syndromes > The monogenic telomere disorders > Adult-onset manifestations of telomere-mediated disease
What the sources say
- Not checked yetcites [70] Diaz de Leon, A. et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE 5, e10680 (2010). source
- Not checked yetcites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source
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“On the basis of their overlapping clinical findings, Hoyeraal–Hreidarsson and Revesz syndromes (and probably Coats plus syndrome) represent the same spectrum of disease because retinopathy, intracranial calcifications and bone marrow abnormalities can be seen in all three disorders and occur in the setting of very short telomere length.”
§ The telomere syndromes > The monogenic telomere disorders > Childhood-onset telomere disorders
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“The cancer spectrum in dyskeratosis congenita has a predilection for high-turnover tissues with an increased incidence of squamous cell carcinomas of the skin, upper aerodigestive and anogenital tracts75.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
What the sources say
- Not checked yetcites [75] Alter, B. P., Giri, N., Savage, S. A. & Rosenberg, P. S. Cancer in dyskeratosis congenita. Blood 113, 6549–6557 (2009). source
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“Telomere length limits the long-term proliferative capacity of the adaptive immune system in patients with telomere syndromes81”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
What the sources say
- Not checked yetcites [81] Knudson, M., Kulkarni, S., Ballas, Z. K., Bessler, M. & Goldman, F. Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita. Blood 105, 682–688 (2005). source
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“Acute myeloid leukaemia is a known complication of aplastic anaemia, but it may possibly be a first presentation of a germline mutation in TERT or TR in a subset of familial leukaemia cases (20%)77 and, at a much lower frequency, sporadic cases78.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
What the sources say
- Not checked yetcites [77] Kirwan, M. et al. Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum. Mutat. 30, 1567–1573 (2009). source
- Not checked yetcites [78] Calado, R. T. et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc. Natl Acad. Sci. USA 106, 1187–1192 (2009). source
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“It is therefore not surprising that telomere-associated disease manifests so prominently in the bone marrow.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Stem cell failure in highly proliferative tissues
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In the paper
“Although short telomeres cause similar cellular responses (namely, apoptosis and senescence) in different tissues, telomere-mediated disease manifests as apparently diverse disease processes.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
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“Even in somatic human cells that are naturally enriched for telomerase activity, such as haematopoietic stem cells (HSCs), telomeres typically become shorter with each cell division and with age42,43.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
What the sources say
- Not checked yetcites [42] Chiu, C. P. et al. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells 14, 239–248 (1996). source
- Not checked yetcites [43] Vaziri, H. et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc. Natl Acad. Sci. USA 91, 9857–9860 (1994). source
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In the paper
“For example, in the intestinal epithelium, it manifests as villous atrophy due to a loss of crypt stem cells36,101,118.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Stem cell failure in highly proliferative tissues
What the sources say
- Not checked yetcites [36] Hao, L. Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005). In reference 36, using CAST/EiJ mice that have telomere length similar to humans, this paper established that telomerase haploinsufficiency is sufficient to cause dyskeratosis-congenita-like phenotypes. It also showed that telomere length is inherited and can cause degenerative phenotypes even when telomerase is wild-type. source
- Not checked yetcites [101] Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999). source
- Not checked yetcites [118] Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2007). source
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In the paper
“Cell turnover is remarkably high in the haematopoietic compartment, where an estimated 109 cells are produced every hour113.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Stem cell failure in highly proliferative tissues
What the sources say
- Not checked yetcites [113] Metcalf, D. The Molecular Control of Blood Cells 1–22 (Harvard Univ. Press, 1988).
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In the paper
“In addition, 3–5% of aplastic anaemia patients carry mutant TERT and TR genes41,72,73.”
§ The telomere syndromes > The monogenic telomere disorders > Adult-onset manifestations of telomere-mediated disease
What the sources say
- Not checked yetcites [41] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). This study identified TERT mutations in patients with aplastic anaemia. source
- Not checked yetcites [72] Du, H. Y. et al. TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements. Blood 113, 309–316 (2008). source
- Not checked yetcites [73] Yamaguchi, H. et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 102, 916–918 (2003). This study identified TR mutations in patients with bone marrow failure. source
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In the paper
“Even at wild-type levels, telomerase generally elongates only a few telomeres in any given cell cycle or generation34,36.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
What the sources say
- Not checked yetcites [34] Teixeira, M. T., Arneric, M., Sperisen, P. & Lingner, J. Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell 117, 323–335 (2004). source
- Not checked yetcites [36] Hao, L. Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005). In reference 36, using CAST/EiJ mice that have telomere length similar to humans, this paper established that telomerase haploinsufficiency is sufficient to cause dyskeratosis-congenita-like phenotypes. It also showed that telomere length is inherited and can cause degenerative phenotypes even when telomerase is wild-type. source
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In the paper
“The telomerase-knockout mouse has provided an important model for understanding telomere-mediated disease mechanisms because there is a remarkable convergence with human disease phenotypes (an overview is shown in Table 2)36,82,84,85,97,99–111.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
What the sources say
- Not checked yetcites [36] Hao, L. Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005). In reference 36, using CAST/EiJ mice that have telomere length similar to humans, this paper established that telomerase haploinsufficiency is sufficient to cause dyskeratosis-congenita-like phenotypes. It also showed that telomere length is inherited and can cause degenerative phenotypes even when telomerase is wild-type. source
- Not checked yetcites [82] Armanios, M. et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85, 823–832 (2009). source
- Not checked yetcites [84] Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997). source
- Not checked yetcites [85] Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998). References 84 and 85 are two landmark papers that established that telomerase itself is not essential and that short telomeres cause apoptosis and cell loss in high-turnover tissues. source
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
- Not checked yetcites [99] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 183, 904–912 (2011). source
- Not checked yetcites [100] 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
- Not checked yetcites [101] Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999). source
- Not checked yetcites [102] Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N. & DePinho, R. A. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 287, 1253–1258 (2000). source
- Not checked yetcites [103] Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011). References 97 and 103 implicate short telomeres as a cause of mitochondrial dysfunction, a pathogenic mechanism that highlights a role for telomere dysfunction in slow-turnover tissues. source
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In the paper
“Responding to cis-regulatory mechanisms mediated through the telomere DNA–protein complex, telomerase preferentially elongates the shortest telomeres, so only a subset of telomeres may be elongated in any cell cycle34.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
What the sources say
- Not checked yetcites [34] Teixeira, M. T., Arneric, M., Sperisen, P. & Lingner, J. Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell 117, 323–335 (2004). source
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In the paper
“The shortest telomeres hence have a genetically dominant role in determining cellular phenotypes.”
§ The telomere syndromes > Telomere length measurement
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In the paper
“For human fibroblasts, a threshold of five dysfunctional short telomeres seems to be needed to trigger a senescence response in vitro50.”
§ The telomere syndromes > Telomere length measurement
What the sources say
- Not checked yetcites [50] Kaul, Z., Cesare, A. J., Huschtscha, L. I., Neumann, A. A. & Reddel, R. R. Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep. 13, 52–59 (2011). source
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In the paper
“but deletion of cyclin-dependent kinase inhibitor 1a (Cdkn1a), which encodes p21, a transcriptional target of p53, partially rescues the HSC self-renewal defect in mice118.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Stem cell failure in highly proliferative tissues
What the sources say
- Not checked yetcites [118] Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2007). source
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In the paper
“In humans, the aplastic anaemia phenotype can be reversed with allogeneic stem cell transplant, indicating that this telomere-related stem cell failure state is primarily cell-autonomous.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Stem cell failure in highly proliferative tissues
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- Rests on an assumption: Allogeneic stem cell transplantation can reverse aplastic anaemia in humans.
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In the paper
“However, affected individuals often have subclinical disease concurrently in other organs, even when symptoms related to a single disorder predominate13,39.”
§ The telomere syndromes > The monogenic telomere disorders > The telomere syndrome concept
What the sources say
- Not checked yetcites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source
- Not checked yetcites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. source
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In the paper
“Moreover, as we will discuss, they probably represent the most prevalent monogenic premature ageing disorders.”
§ The telomere syndromes > Abstract
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In the paper
“In human male germ cells, telomere lengths remain stable or even elongate with age3.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
What the sources say
- Not checked yetcites [3] Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992). References 2 and 3 showed that telomere length shortens in human cells with age and limits their in vitro replicative potential. source
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In the paper
“Moreover, the telomere defect alone is not sufficient to induce spontaneous lung disease in mice99.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
- Not checked yetcites [99] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 183, 904–912 (2011). source
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In the paper
“In contrast to the bone marrow, in the lung, cell turnover is very slow (2% per week in murine alveolar epithelial cells)99.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
- Not checked yetcites [99] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 183, 904–912 (2011). source
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In the paper
“Studies in mice and yeast have shown that it is not the average but the shortest telomeres that determine cell responses, suggesting that only one, or a few, overtly short telomeres trigger the DNA damage response and the consequent checkpoint cascade34,48,49.”
§ The telomere syndromes > Telomere length measurement
What the sources say
- Not checked yetcites [34] Teixeira, M. T., Arneric, M., Sperisen, P. & Lingner, J. Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell 117, 323–335 (2004). source
- Not checked yetcites [48] Hemann, M. T., Strong, M. A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001). This study established that the shortest telomeres have a genetically dominant influence on cellular phenotypes. source
- Not checked yetcites [49] McEachern, M. J. & Blackburn, E. H. Cap-prevented recombination between terminal telomeric repeat arrays (telomere CPR) maintains telomeres in Kluyveromyces lactis lacking telomerase. Genes Dev. 10, 1822–1834 (1996). source
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In the paper
“Although it was initially clear that high-turnover tissues are particularly sensitive to telomere length85,101,112”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
What the sources say
- Not checked yetcites [85] Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998). References 84 and 85 are two landmark papers that established that telomerase itself is not essential and that short telomeres cause apoptosis and cell loss in high-turnover tissues. source
- Not checked yetcites [101] Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999). source
- Not checked yetcites [112] Herrera, E. et al. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 18, 2950–2960 (1999). source
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In the paper
“In both humans and mice, there is clear evidence that short telomeres cause quantitative and qualitative defects in HSCs, which manifest as stem cell exhaustion36,41,71,114–117 (Fig. 4).”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Stem cell failure in highly proliferative tissues
What the sources say
- Not checked yetcites [36] Hao, L. Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005). In reference 36, using CAST/EiJ mice that have telomere length similar to humans, this paper established that telomerase haploinsufficiency is sufficient to cause dyskeratosis-congenita-like phenotypes. It also showed that telomere length is inherited and can cause degenerative phenotypes even when telomerase is wild-type. source
- Not checked yetcites [41] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). This study identified TERT mutations in patients with aplastic anaemia. source
- Not checked yetcites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source
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In the paper
“The constitutional telomere length in humans and mice is likely to be set early in embryonic development, when telomerase activity is transiently upregulated44.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
What the sources say
- Not checked yetcites [44] Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996). source
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In the paper
“For example, patients with IPF who have mutant telomerase genes are at an increased risk of developing bone marrow failure and liver disease54,71.”
§ The telomere syndromes > The monogenic telomere disorders > The telomere syndrome concept
What the sources say
- Not checked yetcites [54] Alder, J. K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl Acad. Sci. USA 105, 13051–13056 (2008). source
- Not checked yetcites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source
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In the paper
“Conversely, individuals with telomere-related aplastic anaemia have an increased incidence of fatal pulmonary fibrosis when they are exposed to pulmonary toxic drugs in the bone marrow transplant setting, even though they may have previously had no symptoms58,71.”
§ The telomere syndromes > The monogenic telomere disorders > The telomere syndrome concept
What the sources say
- Not checked yetcites [58] de la Fuente, J. & Dokal, I. Dyskeratosis congenita: advances in the understanding of the telomerase defect and the role of stem cell transplantation. Pediatr. Transplant 11, 584–594 (2007). source
- Not checked yetcites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source
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In the paper
“Indeed, in mouse models, short telomeres have been shown to lower the disease threshold to other exogenous and endogeneous damage, such as γ-irradiation119 and endoplasmic reticulum stress due to protein misfolding97 (Fig. 5a).”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
- Not checked yetcites [119] Wong, K. K. et al. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nature Genet. 26, 85–88 (2000). source
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
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In the paper
“In this setting, the cigarette smoke causes additive damage to dysfunctional telomeres in lung epithelial cells.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
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In the paper
“Differential secretory profiles have also been detected in sera from mice with short telomeres121.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
- Not checked yetcites [121] Jiang, H. et al. Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc. Natl Acad. Sci. USA 105, 11299–11304 (2008). source
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In the paper
“The cumulative effect is likely to reach a threshold of cellular damage that develops into an airspace destruction phenotype recognized as emphysema.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
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In the paper
“In these tissues, the metabolic dysfunction appears to be due to the effect of downregulation of PGC1α, which is a transcriptional co-activator that is important for mitochondrial biogenesis103.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [103] Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011). References 97 and 103 implicate short telomeres as a cause of mitochondrial dysfunction, a pathogenic mechanism that highlights a role for telomere dysfunction in slow-turnover tissues. source
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In the paper
“Therefore, telomere dysfunction in epithelial cells, or perhaps another cell type, might cause parenchymal organ remodelling, which manifests as fibrosis and/or emphysema46,54,99.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
- Not checked yetcites [46] Zhou, J., Monson, E. K., Teng, S. C., Schulz, V. P. & Zakian, V. A. Pif1p helicase, a catalytic inhibitor of telomerase in yeast. Science 289, 771–774 (2000). source
- Not checked yetcites [54] Alder, J. K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl Acad. Sci. USA 105, 13051–13056 (2008). source
- Not checked yetcites [99] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 183, 904–912 (2011). source
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In the paper
“Shortened dysfunctional telomeres in other mouse cell types, such as cardiac myocytes and hepatocytes, have also been associated with decreased mitochondrial copy number and defective oxidative metabolism103.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [103] Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011). References 97 and 103 implicate short telomeres as a cause of mitochondrial dysfunction, a pathogenic mechanism that highlights a role for telomere dysfunction in slow-turnover tissues. source
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In the paper
“These additional phenotypes now extend the scope of telomere-mediated disease into clinical contexts of prevalent conditions, such as IPF and diabetes.”
§ The telomere syndromes > Summary and implications
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In the paper
“Short telomeres cause spontaneous insulin secretion defects in vivo and in vitro, even when the β-cell mass is intact97 (Fig. 5b).”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
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In the paper
“Indeed, some types of cellular senescence, including the telomere-induced replicative type, are associated with an in vitro senescence-associated secretory phenotype (SASP), where cytokines and proteases are detected in culture media120.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
- Not checked yetcites [120] Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010). source
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In the paper
“The dysregulation of gene expression affects pathways that are essential for insulin secretion signalling and exocytosis, including mitochondrial function and Ca2+ handling97.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
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In the paper
“Gene expression changes due to telomere shortening also occur in vitro in fibroblasts undergoing replicative senescence122.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [122] Zhang, H., Pan, K. H. & Cohen, S. N. Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc. Natl Acad. Sci. USA 100, 3251–3256 (2003). source
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In the paper
“Although telomere dysfunction causes obvious histopathology in the bone marrow and parenchymal organs, there is evidence that in some settings, short dysfunctional telomeres compromise organ homeostasis even when cell mass is preserved.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
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In the paper
“The requirement for a ‘second hit’ in the lung may be related to the fact that its basal proliferation rate is very slow, and therefore replicative exhaustion is delayed.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
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In the paper
“Notably, impairment of insulin secretion in the presence of an intact β-cell mass also occurs in the early stages of human age-related diabetes123.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [123] Prentki, M. & Nolan, C. J. Islet β cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 (2006). source
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In the paper
“Instead, a second insult is required, and when mice with short telomeres are experimentally exposed to cigarette smoke, which is known to accelerate disease onset in human telomerase mutation carriers, they develop lung disease99.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
- Not checked yetcites [99] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 183, 904–912 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Smoking hastens disease onset in people who carry telomerase mutations.
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In the paper
“A model that requires multiple additional hits for phenotypes to manifest in slow-turnover tissues could explain why telomere-mediated lung disease represents an attenuated, adult-onset phenotype that is commonly seen after middle age12,99.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Multiple hits are additive to telomere dysfunction in slow-turnover tissues
What the sources say
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- It may state two separate claims as one. 23
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Eight mutant genes have been identified in dyskeratosis congenita9,38,39,60–64, and all of them encode telomerase or telomere protein components (summarized in Table 1).”
§ The telomere syndromes > The monogenic telomere disorders > Childhood-onset telomere disorders
What the sources say
- Not checked yetcites [9] Heiss, N. S. et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature Genet. 19, 32–38 (1998). This study identified mutations in the X-linked DKC1 gene as a first cause of dyskeratosis congenita. source
- Not checked yetcites [38] Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001). source
- Partly supportedcites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. sourceExperimental — accuracy not yet measured
The paper’s Abstract and background passage identify mutations in DKC1 and telomerase RNA in dyskeratosis congenita, and report a disease-associated mutation in hTERT, a telomerase component. They do not establish that eight genes had been identified or that all eight encode telomerase or telomere protein components. (LLM, conf=0.88)
- Partly supportedcites [60] Vulliamy, T. et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc. Natl Acad. Sci. USA 105, 8073–8078 (2008). sourceExperimental — accuracy not yet measured
The Discussion identifies mutations in telomerase components DKC1, TERC, TERT, NOP10 and NHP2, and in the telomere-associated shelterin component TIN2. This supports the connection between the genes discussed and telomere maintenance, but the paper does not establish the claimed total of eight mutant genes. (LLM, conf=0.86)
- Partly supportedcites [61] Walne, A. J. et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum. Mol. Genet. 16, 1619–1629 (2007). sourceExperimental — accuracy not yet measured
The Introduction identifies DC-associated mutations in DKC1, TERC and TERT and describes their roles in telomerase; the Discussion adds NOP10. These passages support the telomerase connection for the genes the paper discusses, but the paper does not establish that eight genes had been identified or that all eight encode telomerase or telomere components. No page numbers are available in our copy. (LLM, conf=0.88)
- Not checked yetcites [62] Savage, S. A. et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82, 501–509 (2008). This paper was the first to show that mutations in a shelterin component are a cause of dyskeratosis congenita. source
- Partly supportedcites [63] Zhong, F. et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25, 11–16. sourceExperimental — accuracy not yet measured
The paper’s introductory passage (labeled Abstract in our copy; page not provided) identifies mutations in five telomerase-component genes and the telomere-binding protein TIN2. It also reports DC-causing mutations in TCAB1, a telomerase holoenzyme protein. These passages support the link to telomerase or telomere proteins, but identify seven genes in total, not the claimed eight. (LLM, conf=0.86)
- Partly supportedcites [64] Keller, R. B. et al. CTC1 mutations in a patient with dyskeratosis congenita. Pediatr. Blood Cancer 59, 311–314 (2012). sourceExperimental — accuracy not yet measured
The Introduction lists seven dyskeratosis congenita genes involved in maintaining telomere integrity, and the Molecular and cellular studies section reports CTC1 mutations in a patient with the disorder, supporting an eighth gene. The paper does not establish the more specific claim that every listed gene encodes a telomerase or telomere protein component. (LLM, conf=0.83)
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In the paper
“They manifest in an autosomal-dominant inheritance pattern because complete or partial loss-of-function of one allele is sufficient to perturb telomere maintenance38,39,41.”
§ The telomere syndromes > Genotype–phenotype correlations > Telomere length is a modifier of disease severity
What the sources say
- Not checked yetcites [38] Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001). source
- Not checked yetcites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. source
- Not checked yetcites [41] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). This study identified TERT mutations in patients with aplastic anaemia. source
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“In addition to studies in families, a number of population-based twin and non-twin studies have shown that parental telomere length (especially the paternal) influences offspring telomere length with heritability estimates ranging from 0.36–0.84 (reviewed in Ref. 90).”
§ The telomere syndromes > Telomere length is a heritable trait > Heritability of telomere length in humans
What the sources say
- Not checked yetcites [90] Aviv, A. Genetics of leukocyte telomere length and its role in atherosclerosis. Mutat. Res. 730, 68–74 (2012). source
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In the paper
“When quantified, telomere length is short in wild-type offspring of parent M. castaneus mice that have short telomeres, indicating that telomere length is inherited36,82”
- Also stated in: § Evidence from mouse studies · plain
“Therefore, telomere length is inherited as a unique genotype, and its inheritance can be uncoupled from the telomerase and telomere gene loci.”
§ The telomere syndromes > Telomere length is a heritable trait > Evidence from mouse studies
What the sources say
- Not checked yetcites [36] Hao, L. Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005). In reference 36, using CAST/EiJ mice that have telomere length similar to humans, this paper established that telomerase haploinsufficiency is sufficient to cause dyskeratosis-congenita-like phenotypes. It also showed that telomere length is inherited and can cause degenerative phenotypes even when telomerase is wild-type. source
- Not checked yetcites [82] Armanios, M. et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85, 823–832 (2009). source
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- Also stated in: § Evidence from mouse studies · plain
In the paper
“In earlier generations, pulmonary fibrosis is usually the primary manifestation, whereas in later generations, bone marrow failure in younger individuals is seen as a first complication71.”
§ The telomere syndromes > Genotype–phenotype correlations > Telomere length is a modifier of disease type
What the sources say
- Not checked yetcites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source
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In the paper
“Telomere disorders most commonly manifest as adult-onset disease and as a consequence of germline TERT or TR loss-of-function mutations13.”
§ The telomere syndromes > The monogenic telomere disorders > Adult-onset manifestations of telomere-mediated disease
What the sources say
- Not checked yetcites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source
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In the paper
“The consequent signalling cascades activate checkpoints that induce either cellular senescence or apoptosis, and in at least some contexts both processes occur simultaneously82,85,91,95.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
What the sources say
- Not checked yetcites [82] Armanios, M. et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85, 823–832 (2009). source
- Not checked yetcites [85] Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998). References 84 and 85 are two landmark papers that established that telomerase itself is not essential and that short telomeres cause apoptosis and cell loss in high-turnover tissues. source
- Not checked yetcites [91] d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source
- Not checked yetcites [95] Hemann, M. T. et al. Telomere dysfunction triggers developmentally regulated germ cell apoptosis. Mol. Biol. Cell 12, 2023–2030 (2001). source
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In the paper
“However, the cancer-related mortality is limited to approximately 10% of dyskeratosis congenita cases, with the remaining mortality attributable to the degenerative disease phenotypes described above.”
§ The telomere syndromes > The monogenic telomere disorders > Telomere syndromes predispose to cancer
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In the paper
“The frequency of these mutations is highest in individuals with the progressive disorder IPF, which accounts for 8–15% of familial and 1–3% of sporadic cases54,56,68,69.”
§ The telomere syndromes > The monogenic telomere disorders > Adult-onset manifestations of telomere-mediated disease
What the sources say
- Not checked yetcites [54] Alder, J. K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl Acad. Sci. USA 105, 13051–13056 (2008). source
- Not checked yetcites [56] Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007). References 54–56 showed that lymphocyte telomere length using flow cytometry and fluorescence in situ hybridization could be a useful diagnostic marker in identifying individuals with telomere-related disease. source
- Not checked yetcites [68] Tsakiri, K. D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl Acad. Sci. USA 104, 7552–7557 (2007). References 56 and 68 identified mutations in the essential telomerase genes in familial pulmonary fibrosis. source
- Not checked yetcites [69] Cronkhite, J.T. et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 729–737 (2008). source
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In the paper
“Hence, the degree of telomere shortness is a determinant of both disease severity and type.”
§ The telomere syndromes > Genotype–phenotype correlations > Telomere length is a modifier of disease type
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In the paper
“The downstream effector pathways of telomere-induced senescence are largely p53-dependent96, but there may be involvement of the retinoblastoma protein (RB) pathway in some settings97.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease
What the sources say
- Not checked yetcites [96] Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999). source
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
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In the paper
“When examining telomere measurements within a mixed cell population, it is important to note that this is a surrogate marker of the mean in a heterogeneous cell population and that telomere length is mosaic, reflecting the telomere length regulation and replicative history of each cell type51,52.”
§ The telomere syndromes > Telomere length measurement
What the sources say
- Not checked yetcites [51] Lin, J. et al. Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance. J. Immunol. Methods 352, 71–80 (2010). source
- Not checked yetcites [52] Rufer, N. et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J. Exp. Med. 190, 157–167 (1999). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The limitation on the telomerase synthesis reaction on human telomeres favours telomere shortening as a general default state and means that telomere shortening generally accompanies cell proliferation.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
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In the paper
“This idea is consistent with the fact that telomerase activity is upregulated in most human cancers, which probably contributes to sustaining their immortality7.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
What the sources say
- Not checked yetcites [7] Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994). In this study, telomerase activity was found to be enriched in cancer and germ cells, suggesting that telomerase has a role in extending replicative potential. source
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In the paper
“The telomere syndromes are highly relevant for understanding age-related disease because the short telomere defect that they share is acquired with age.”
§ The telomere syndromes > Abstract
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- Rests on an assumption: The short telomere defect shared by telomere syndromes is acquired with age.
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In the paper
“The shared underlying telomere defect in aplastic anaemia and IPF brings together clinical entities that were previously considered to be disparate and defines a recognizable syndrome complex that predominantly manifests in adults, in contrast to dyskeratosis congenita.”
§ The telomere syndromes > The monogenic telomere disorders > The telomere syndrome concept
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In the paper
“Telomere elongation is cell-cycle-regulated; telomerase elongates telomeric DNA by adding telomere repeats during S phase and into M phase32,33.”
§ The telomere syndromes > Telomeres and telomerase > Elongation of telomeres by telomerase is tightly regulated
What the sources say
- Not checked yetcites [32] Diede, S. J. & Gottschling, D. E. Telomerase-mediated telomere addition in vivo requires DNA primase and DNA polymerases α and δ. Cell 99, 723–733 (1999). source
- Not checked yetcites [33] Marcand, S., Brevet, V., Mann, C. & Gilson, E. Cell cycle restriction of telomere elongation. Curr. Biol. 10, 487–490 (2000). source
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In the paper
“Indeed, the co-occurrence of IPF and bone marrow failure, along with liver cirrhosis, is specific to and highly predictive of a germline telomere maintenance defect13,39,71.”
§ The telomere syndromes > The monogenic telomere disorders > The telomere syndrome concept
What the sources say
- Not checked yetcites [13] Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genom. Hum. Genet. 10, 45–61 (2009). source
- Not checked yetcites [39] Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005). References 38 and 39 identified mutations in the essential telomerase genes, TERT and TR , in dyskeratosis congenita. source
- Not checked yetcites [71] Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011). source
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In the paper
“Therefore, it seems that telomere-induced senescence represents more than a loss of replicative potential and can limit cellular function even when cells appear morphologically intact97.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Telomere syndromes represent an archetype of premature-ageing syndromes because the short telomere defect they share is progressively acquired with age in humans.”
§ The telomere syndromes > Summary and implications
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In the paper
“Beyond its canonical phenotypes in high-turnover tissues, telomere dysfunction is sufficient to cause — and indeed commonly causes — degenerative phenotypes in slow-turnover tissues.”
§ The telomere syndromes > Summary and implications
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In the paper
“Although they appear morphologically normal, mouse β-cells with dysfunctional telomeres show the hallmarks of senescence. They have an activated DNA damage response, impaired proliferation, p16INK4A upregulation and altered gene expression97.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
What the sources say
- Not checked yetcites [97] Guo, N. et al. Short telomeres compromise β-cell signaling and survival. PLoS ONE 6, e17858 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The fact that the gene expression changes that occur during telomere-induced senescence cause functional changes in the absence of structural tissue disruption highlights a novel mechanism by which senescence and its associated gene expression changes cause disease.”
§ The telomere syndromes > Mechanisms of telomere-mediated disease > Exocytosis defects in pancreatic β-cells
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The paper relies on this without support.
The short telomere defect shared by telomere syndromes is acquired with age.
“The telomere syndromes are highly relevant for understanding age-related disease because the short telomere defect that they share is acquired with age.”
The paper relies on this without support.
The short telomere defect in affected individuals is present in germ cells and thus simultaneously affects multiple organs even when one disease presentation predominates.
“Their grouping together as a syndrome spectrum is crucial for clinical decisions because the short telomere defect in affected individuals is present in germ cells and thus simultaneously affects multiple organs even when one disease presentation predominates.”
The paper relies on this without support.
Allogeneic stem cell transplantation can reverse aplastic anaemia in humans.
“In humans, the aplastic anaemia phenotype can be reversed with allogeneic stem cell transplant, indicating that this telomere-related stem cell failure state is primarily cell-autonomous.”
The paper relies on this without support.
Smoking hastens disease onset in people who carry telomerase mutations.
“Instead, a second insult is required, and when mice with short telomeres are experimentally exposed to cigarette smoke, which is known to accelerate disease onset in human telomerase mutation carriers, they develop lung disease99.”
The paper relies on this without support.
β-cells in adult mouse pancreatic islets turn over slowly, roughly 4% each week.
“This mechanism has been elucidated in adult mouse β-cells of the pancreatic islets, which have a fairly slow turnover (4% per week).”
The paper relies on this without support.
Blood formation depends on a small set of stem cells that can self-renew and differentiate.
“Haematopoiesis relies on the self-renewal and differentiation capacity of a well-characterized oligoclonal stem cell compartment.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Telomerase deficiency in humans is associated with premature development of diseases, such as pulmonary fibrosis, dyskeratosis congenita and aplastic anemia, which involve the loss of the regenerative capacity of different tissues (Armanios and Blackburn, 2012).”
From The Hallmarks of Aging (2013) · cites this paper as Armanios and Blackburn, 2012
Experimental — accuracy not yet measuredIn the citing paper
“Progerias or premature aging, or the short telomere syndromes include genetic diseases associated with short telomeres and premature senescence [59].”
From Markers of cellular senescence. Telomere shortening as a marker of cellular senescence (2016) · cites this paper as [59]
In the citing paper
“Rare Mendelian human mutations compromising telomere maintenance or protection genes cause early death and diseases involving a wide variety of tissues and organ systems (Armanios and Blackburn, 2012).”
From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Armanios and Blackburn, 2012
In the citing paper
“The ribonucleoprotein enzyme telomerase provides the major mechanism for telomere preservation and length replenishment (Armanios and Blackburn, 2012; Chakhparonian and Wellinger, 2003) (Fig 1).”
From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Armanios and Blackburn, 2012
In the citing paper
“Inherited telomerase deficiencies resulting in a two-fold drop in gene dosage are directly linked to malignancies and several other diseases in humans (Armanios and Blackburn, 2012).”
From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Armanios and Blackburn, 2012
In the citing paper
“Short telomeres have been linked to numerous diseases of aging and in many but not all cases, to all-cause and disease-specific mortality (12–17).”
From Determinants of telomere attrition over 1 year in healthy older women: stress and health behaviors matter (2015) · cites this paper as [12]
In the citing paper
“stress appears to augment replicative TL shortening, perhaps by promoting nonenzymatic hydrolysis of telomere base pairs (11,18).”
From Social disadvantage, genetic sensitivity, and children's telomere length (2014) · cites this paper as [18]
Citations
Cites
Specific Association of Human Telomerase Activity with Immortal Cells and Cancer
Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C. B., West, M. D., Ho, P. L. C., Coviello, G. M., Wright, W. E., Weinrich, S. L., & Shay, J. W. (1994) · Science · doi:10.1126/science.7605428 · Cited by 7,091
Telomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750
The senescence-associated secretory phenotype: the dark side of tumor suppression
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Identification of a specific telomere terminal transferase activity in tetrahymena extracts
Greider, C. W., & Blackburn, E. H. (1985) · Cell · doi:10.1016/0092-8674(85)90170-9 · Cited by 3,400
Self-citationShelterin: the protein complex that shapes and safeguards human telomeres
de Lange, T. (2005) · Genes & Development · doi:10.1101/gad.1346005 · Cited by 3,056
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,917
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379
Moyzis, R. K., Buckingham, J. M., Cram, L. S., Dani, M. A. C., Deaven, L. L., Jones, M. D., Meyne, J., Ratliff, R. L., & Wu, J. R. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.18.6622 · Cited by 2,326
The RNA Component of Human Telomerase
Feng, J., Funk, W. D., Wang, S.-S., Weinrich, S. L., Avilion, A. A., Chiu, C.-P., Adams, R. R., Chang, E., Allsopp, R. C., Yu, J., et al. (1995) · Science · doi:10.1126/science.7544491 · Cited by 2,227
Telomere length predicts replicative capacity of human fibroblasts.
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López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
Senescence in Health and Disease
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Self-citationTelomeres and telomerase: three decades of progress
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Metadata
- Authors
- Armanios, M., & Blackburn, E. H.
- Affiliations
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- Corresponding author
- Armanios, Mary
- Venue
- Nature Reviews Genetics
- Published
- 2012-09-11
- Volume
- 13
- Issue
- 10
- Pages
- 693-704
- ISSN
- 1471-0056 (ISSN-L)
- 1471-0064
- PMC
- PMC3548426
- OpenAlex
- W1981775109
- Cited by
- 982
- References
- 128
- Citations by year
- 2026: 41 · 2025: 46 · 2024: 50 · 2023: 63 · 2022: 68 · 2021: 92 · 2020: 74 · 2019: 79 · 2018: 81 · 2017: 84 · 2016: 82 · 2015: 80 · 2014: 71 · 2013: 59 · 2012: 8
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-02-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R21HL104345)
- National Cancer Institute (R01CA160433)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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 maintenance, short telomeres, cellular aging, idiopathic pulmonary fibrosis, bone marrow failure, degenerative diseases, mode of inheritance, age-related diseases, telomere biology
- MeSH terms
- Animals, Humans, Models, Biological, Syndrome, Telomere, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Genetic Diseases, Inborn, Genetic Association Studies
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.
A language model drew the claims from the paper on 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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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