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Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies.

Significance Idiopathic pulmonary fibrosis and emphysema are leading causes of mortality, but there are no effective therapies. Mutations in telomerase are the most common identifiable risk factor for idiopathic pulmonary fibrosis. They also predispose to severe emphysema in smokers, occurring at a frequency similar to α-1 antitrypsin deficiency. The work shown here points to alveolar stem cell senescence as a driver of these pathologies. Epithelial stem cell failure was associated with secondary inflammatory recruitment and exquisite susceptibility to injury from “second hits.” The findings suggest that efforts to reverse the stem cell failure state directly, rather than its secondary consequences, may be an effective therapy approach in telomere-mediated lung disease. 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.

Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1, in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.

Mutations affecting both components of the telomerase enzyme, hTERT and hTR, are associated with familial idiopathic pulmonary fibrosis, and carriers of such mutations have shorter telomeres than do noncarrier family members. This finding suggests that the disease may be triggered by a loss of alveolar cells, the progenitors of which may be limited by short telomeres. Mutations affecting both components of the telomerase enzyme, hTERT and hTR, are associated with familial idiopathic pulmonary fibrosis, and carriers of such mutations have shorter telomeres than do noncarrier family members. Idiopathic pulmonary fibrosis has a predictable, progressive clinical course that ultimately leads to respiratory failure. Irreversible fibrosis is the hallmark of the disease, which has a characteristic radiographic appearance most often associated with the pathological lesion of usual interstitial pneumonia. Although both genetic and environmental factors have been implicated, the cause of idiopathic pulmonary fibrosis is unknown — as, indeed, its name implies. Treatment approaches that target the immune system have not proved to be successful. 1 From 2 to 20% of patients with idiopathic pulmonary fibrosis have a family history of the disease; inheritance appears to be autosomal dominant with . . .

Dyskeratosis congenita is a rare inherited disorder characterized by abnormal skin manifestations. Morbidity and mortality from this disease is usually due to bone marrow failure, but idiopathic pulmonary fibrosis and an increased cancer predisposition also occur. Families with autosomal dominant dyskeratosis congenita display anticipation and have mutations in the telomerase RNA gene. We identified a three-generation pedigree with autosomal dominant dyskeratosis congenita, anticipation, and telomere shortening. We show that a null mutation in motif D of the reverse transcriptase domain of the protein component of telomerase, hTERT, is associated with this phenotype. This mutation leads to haploinsufficiency of telomerase, and telomere shortening occurs despite the presence of telomerase. This finding emphasizes the importance of telomere maintenance and telomerase dosage for maintaining tissue proliferative capacity and has relevance for understanding mechanisms of age-related changes.

The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca(2+) influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16(INK4a). Specifically, we identified gene expression changes in pathways which are essential for Ca(2+)-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis.

Recent discoveries have extended the reach of telomere biology from the basic sciences into the heart of clinical medicine.1 Telomeres were discovered in a pond protozoan; their basic biology has been dissected in model systems like maize, yeast, and mice.2 In cultured human cells, telomere length predicts the onset of the Hayflick limit, the finite replicative potential of cells before they senesce, and the exogeneous expression of the telomerase catalytic component, TERT, can bypass senescence.3,4 These early discoveries have led to a hypothesized role for telomeres in processes related to aging and cancer, but the exact clinical contexts in which telomere biology matters for patient care have not until recently been elucidated. The strongest evidence supporting that telomeres play a causal role in human disease comes from observations that mutations in genes that encode telomerase components and other telomere maintenance genes cause disease. Because these diseases have systemic features that matter for clinical management, we have referred to them as the telomere syndromes.1 Mutations in 13 telomerase and telomere maintenance genes cause the short telomere syndrome phenotype; the most common of these are mutations in TERT.1 Gain-of-function TERT mutation, in contrast, up-regulates telomerase expression and manifests as familial melanoma,5 likely related to excessively long telomere length. The latter has been hypothesized to be a manifestation of long telomere syndromes.1 Lessons from recent work highlight that short telomeres, at clinically relevant thresholds, cause recognizable disease patterns and not generic forms of premature aging.6 In children and young adults, a severe form of short telomere syndromes manifests as bone marrow failure, immunodeficiency, and abnormalities in the skin and gastrointestinal tract.1,6 This form primarily affects high turnover tissues. Mutant telomerase and telomere genes are the most common cause of inherited bone marrow failure, and recognizing these patients in the hematopoietic stem cell transplant evaluation alters decisions about donor and ablative regimens.6 Similarly, there is growing evidence that identifying patients with telomere-mediated lung disease could aid in the management of lung transplant, both for anticipating and averting complications.12 These examples, and others, support the measurement of telomere length, using clinically validated methods, as a precision medicine tool.6 The retrospective experience presented by Mangaonkar et al13 and a review from the same group14 published in this issue of the Proceedings represent Mayo Clinic's efforts to ensure meeting the clinical demands in this new area of medicine.

Key Points Mutations in telomerase and telomere gene components manifest as diverse clinical syndromes that vary in severity but share a single common molecular defect of shortened telomeres. Telomere length determines disease severity and type in the monogenic telomere syndromes. This is most evidently seen in the pattern of genetic anticipation in families with autosomal-dominant inheritance because mutant telomerase genes cause haploinsufficiency and progressive telomere shortening across generations. Telomere length is a heritable genetic trait even when the telomerase genes are wild-type. Because it is polymorphic, it may influence disease risk across populations. Short telomere length limits the replicative potential of stem cells in high-turnover tissues, such as the bone marrow. This is seen clinically in a failure of haematopoiesis known as aplastic anaemia, which is a common complication of telomere syndromes. Even in tissues of slow turnover, short telomere length causes degenerative disease, as seen in the high prevalence of pulmonary disease in telomerase mutation carriers. In these tissues, short telomere length lowers the threshold to acquired injuries, such as cigarette smoke in the lung. Telomeres have long been implicated in processes of cellular ageing. This Review discusses how a diverse range of human diseases are now known to be caused by mutations that result in defective telomere maintenance and shortened telomeres. It describes the unique inheritance patterns of telomere defects and how telomere biology sheds light into several disease mechanisms. 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.

Purpose DNA Ligase 4 (LIG4) is a key factor in the non-homologous end-joining (NHEJ) DNA double-strand break repair pathway needed for V(D)J recombination and the generation of the T cell receptor and immunoglobulin molecules. Defects in LIG4 result in a variable syndrome of growth retardation, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and developmental delay. Methods We diagnosed a patient with LIG4 syndrome by radiosensitivity testing on peripheral blood cells, and established that two of her four healthy siblings carried the same compound heterozygous LIG4 mutations. An extensive analysis of the immune phenotype, cellular radiosensitivity, telomere length, and T and B cell antigen receptor repertoire was performed in all siblings. Results In the three genotypically affected individuals, variable severities of radiosensitivity, alterations of T and B cell counts with an increased percentage of memory cells, and hypogammaglobulinemia, were noticed. Analysis of T and B cell antigen receptor repertoires demonstrated increased usage of alternative microhomology-mediated end-joining (MHMEJ) repair, leading to diminished N nucleotide addition and shorter CDR3 length. However, overall repertoire diversity was preserved. Conclusions We demonstrate that LIG4 syndrome presents with high clinical variability even within the same family, and that distinctive immunologic abnormalities may be observed also in yet asymptomatic individuals.