Short Telomeres are Sufficient to Cause the Degenerative Defects Associated with Aging

Armanios, Mary; Alder, Jonathan K.; Parry, Erin M.; Karim, Baktiar O.; Strong, Margaret A.; Greider, Carol W.

doi:10.1016/j.ajhg.2009.10.028

Cited by 223 publications

(211 citation statements)

References 49 publications

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“…When Tert +/− CAST/EiJ mice were intercrossed to generate Tert +/+ CAST/EiJ mice, successive intercrosses of these genotypically wild-type mice resulted in telomere elongation. Taken together, the results of Armanios et al (28) and those which we have reported here are consistent with our proposed model, in which telomere length is inherited as a stable phenotype, with elongation of telomeres in the presence of wild-type telomerase occurring only when telomeres are recognized as critically short. Thus, functionally critical levels of telomere shortening may have been generated by haploinsufficiency in CAST/EiJ mice but not yet in the B6 mice that we have studied.…”

Section: Discussionsupporting

confidence: 81%

“…In contrast, the Tert mutation used in the study of Meznikova et al (27) involved the replacement of a portion of the Tert gene extending from within exon 4 to a point within exon 7 (10), an alteration that might be expected to allow transcription of a truncated Tert mRNA, although it was reported that no transcripts were detected by quantitative RT-PCR (12). Also after submission of our paper, Armanios et al (28) reported studies of heterozygous Tert +/− mice that had been backcrossed to a CAST/EiJ background with telomeres substantially shorter than those of B6 mice. They reported that successive generations of Tert +/− CAST/EiJ breeding resulted in progressive telomere shortening, in this case sufficient to result in telomere dysfunction.…”

Section: Discussionmentioning

confidence: 68%

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Telomere length is inherited with resetting of the telomere set-point

Chiang

Calado

Hathcock

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. Analysis of these findings was complicated by heterogeneity of telomere length among individuals, as well as by the admixing of telomeres inherited from affected parents with those inherited from unaffected ("wild-type" TERT) parents. To understand further the inheritance of telomere length, we established a shortened-telomere mouse model. When Tert +/− heterozygous mice were successively cross-bred through 17 generations, telomere length shortened progressively. The late-generation Tert +/− mice were intercrossed to produce genotypically wild-type Tert +/+ mice, for which telomere length was characterized. Strikingly, telomere length in these Tert +/+ mice was not longer than that of their Tert +/− parents. Moreover, when successive crosses were carried out among these short-telomere Tert +/+ offspring mice, telomere length was stable, with no elongation up to six generations. This breeding strategy therefore has established a mouse strain, B6.ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.T elomerase is an RNA-dependent DNA polymerase that consists of two essential components, a template RNA (TERC) and a catalytic reverse transcriptase (TERT). The telomerase holoenzyme adds telomeric DNA repeats at the termini of eukaryotic chromosomes, thus maintaining telomere length and function despite telomere attrition that normally occurs during chromosomal replication. Telomeric DNA repeats and specific associated proteins are assembled to form telomere structures that distinguish normal chromosome ends from DNA damage-induced double-strand breaks and thus subserve a critical function in maintaining chromosomal stability (1-3). The functional importance of telomere integrity and telomerase activity has been addressed in a variety of experimental model systems, notably including genetic alterations of telomerase and telomeric proteins in multiple eukaryotic species. Evidence for a physiologically important role of telomerase in humans first emerged from analysis of the genetic syndrome dyskeratosis congenita (DKC), characterized by failure of bone morrow and other rapidly dividing cell lineages. An X-linked form of DKC was the first human disease recognized to be related to telomerase deficiency and is c...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 68%

Telomere length is inherited with resetting of the telomere set-point

Chiang

Calado

Hathcock

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…It is therefore possible that although the telomerase genes may account for a small subset, other mutant telomere pathway genes will collectively explain a larger proportion of susceptibility. Even when telomerase is wild-type, telomere length is genetically determined, and short telomeres are sufficient to predispose to degenerative disease in the lung and elsewhere (28,29). The prevalence of telomerase and telomere gene mutations in smokers with emphysema will require future confirmation in other cohorts.…”

Section: Resultsmentioning

confidence: 99%

Telomerase mutations in smokers with severe emphysema

Stanley¹,

Chen²,

Podlevsky³

et al. 2014

J. Clin. Invest.

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140

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“…The data we present here highlight a contrast in the response to telomere dysfunction between high-and lowturnover tissues. In the hematopoietic system, telomere dysfunction causes stem cell failure because of replicative exhaustion, and this phenotype is clinically evident in mice and limits their survival (32)(33)(34)(35). In contrast, when telomere dysfunction is restricted to AEC2s, a population with a comparatively slow turnover, the clinical phenotype is fairly well tolerated de novo.…”

Section: Senescence Is a Preferred Response To Telomere Dysfunction Inmentioning

confidence: 99%

Telomere dysfunction causes alveolar stem cell failure

Alder

Barkauskas²,

Limjunyawong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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273

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Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

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Short Telomeres are Sufficient to Cause the Degenerative Defects Associated with Aging

Cited by 223 publications

References 49 publications

Telomere length is inherited with resetting of the telomere set-point

Telomere length is inherited with resetting of the telomere set-point

Telomerase mutations in smokers with severe emphysema

Telomere dysfunction causes alveolar stem cell failure

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