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Short telomere length in IPF lung associates with fibrotic lesions and predicts survival.

ABSTRACT: Telomere maintenance dysfunction has been implicated in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). However, the mechanism of how telomere length is related to fibrosis in the lungs is unknown. Surgical lung biopsies of IPF patients typically show a heterogeneous pattern of non-fibrotic and fibrotic areas. Therefore, telomere length (TL) in both lung areas of patients with IPF and familial interstitial pneumonia was compared, specifically in alveolar type 2 (AT2) cells. Fluorescent in situ hybridization was used to determine TL in non-fibrotic and fibrotic areas of 35 subjects. Monochrome multiplex quantitative polymerase chain reaction (MMqPCR) was used for 51 whole lung biopsies and blood TL measurements. For sporadic IPF subjects, AT2 cell TL in non-fibrotic areas was 56% longer than in fibrotic areas. No such difference was observed in the surrounding lung cells. In subjects carrying a telomerase reverse transcriptase (TERT) mutation, AT2 cell TL was significantly shorter than in sporadic subjects. However, no difference in surrounding cell TL was observed between these subject groups. Finally, using biopsy MMqPCR TL measurements, it was determined that IPF subjects with shortest lung TL had a significantly worse survival than patients with long TL. This study shows that shortening of telomeres critically affects AT2 cells in fibrotic areas, implying TL as a cause of fibrogenesis. Furthermore, short lung telomere length is associated with decreased survival.

SUBMITTER: Snetselaar R

PROVIDER: S-EPMC5744955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Short lung transplant donor telomere length is associated with decreased CLAD-free survival.

Project description:Telomere length (TL) decreases with cellular ageing and biological stressors. As advanced donor and recipient ages are risk factors for chronic lung allograft dysfunction (CLAD), we hypothesised that decreased age-adjusted donor TL would predict earlier onset of CLAD. Shorter donor TL was associated with increased risk of CLAD or death (HR 1.26 per 1 kb TL decrease, 95% CI 1.03 to 1.54), particularly for young donors. Recipient TL was associated with cytopenias but not CLAD. Shorter TL was also seen in airway epithelium for subjects progressing to CLAD (p=0.02). Allograft TL may contribute to CLAD pathogenesis and facilitate risk stratification.

| S-EPMC6550329 | biostudies-literature

Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome.

Project description:Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.

| S-EPMC7770569 | biostudies-literature

Short Leukocyte Telomere Length Predicts Albuminuria Progression in Individuals With Type 2 Diabetes.

Project description:IntroductionTelomere length, a marker for biological aging, is implicated with diabetic kidney disease (DKD); however, the association between telomere length and albuminuria progression among Asian patients with type 2 diabetes (T2D) is not well understood. Here, we aim to study whether leukocyte telomere length (LTL) may independently predict albuminuria progression in patients with T2D with preserved renal filtration function (estimated GFR >60 ml/min per 1.73 m2 and urine albumin-to-creatinine ratio [uACR] <300 mg/g).MethodsThe baseline LTL was measured by real-time polymerase chain reaction in the SMART2D cohort (n = 691) with a median follow-up of 3 years. Albuminuria progression was defined as a change in albuminuria category to a higher category and at least 30% increase in uACR from baseline in 3 years.ResultsProgressors (n = 123) had significantly shorter median LTL compared with nonprogressors (n = 568) (0.58 [0.38-0.79] vs. 0.62 [0.45-0.88], P = 0.039). Compared with subjects with longer LTL (fourth quartile), subjects with shorter LTL (first quartile) had 1.93-fold (1.04-3.60, P = 0.038) increased risk for albuminuria progression after adjustment for traditional risk factors. The association of LTL with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria (odds ratio [OR]: 1.54; 95% confidence interval [CI]: 1.02-2.32; P = 0.042 vs. OR: 1.13; 95% CI: 0.91-1.40; P = 0.263 per 1-SD decrement in natural log-transformed LTL).ConclusionTherefore, our results demonstrated that in patients with T2D with preserved renal filtration function, LTL predicts albuminuria progression beyond traditional risk factors, suggesting LTL may be novel biomarker for DKD progression.

| S-EPMC5976822 | biostudies-literature

Newborn telomere length predicts later life telomere length: Tracking telomere length from birth to child- and adulthood.

Project description:BackgroundTelomere length (TL) is considered a biological marker of aging and may indicate age-related disease susceptibility. Adults and children show a fixed ranking and tracking of TL over time. However, the contribution of an individual's initial birth TL to their later life TL is unknown. We evaluated change and tracking of TL from birth to child- and adulthood.MethodsTelomere length at birth was measured using qPCR in two independent prospective birth cohorts. After a median follow-up period of 4 years in ENVIRONAGE (n = 273) we assessed leukocyte telomere length (LTL) and after 23 years in EFPTS (n = 164) buccal TL was assessed. Correlations and multivariable regression models were applied to study telomere tracking and determinants of TL change from birth onwards.FindingsIn children, LTL at the age of 4 correlates with TL at the start of life both in cord blood (r = 0.71, P < 0.0001;) and placenta (r = 0.60, P < 0.0001) and was -11.2% and -33.1% shorter, respectively. In adulthood, buccal TL at the age of 23 correlates with placental TL (r = 0.46, P < 0.0001) and was -35.9% shorter. TL attrition was higher in individuals with longer birth TL. However, based on TL ranking, individuals do not tend to change dramatically from TL rank after 4 or 23 years of follow-up. Finally, longer maternal TL associates with lower telomere attrition in the next generation.InterpretationThe high prediction of newborn TL for later life TL, and stable TL ranking from birth onwards underscores the importance of understanding the initial setting of newborn TL and its significance for later life.FundingEuropean Research Council (ERC-StG310898) and Flemish Scientific Fund (12X9620N).

| S-EPMC7808927 | biostudies-literature

Leukocyte telomere length predicts overall survival in hepatocellular carcinoma treated with transarterial chemoembolization.

Project description:Previous studies have reported that telomere length in peripheral blood leukocytes can predict the clinical outcome of several cancers. However, whether leukocyte telomere length is associated with the prognosis of hepatocellular carcinoma (HCC) remains to be determined. In this study, relative telomere length (RTL) in peripheral blood leukocytes was measured using a real-time PCR-based method for 269 HCC patients treated with transarterial chemoembolization (TACE) from two independent hospitals. The association between RTL and the overall survival (OS) of HCC was analyzed. The immunological function of the HCC patients with different leukocyte RTLs was evaluated. Multivariate analyses indicated that long leukocyte RTL was significantly associated with poor OS of HCC patients, with a hazard ratio of 2.04 (95% confidence interval, 1.46-2.86; P < 0.001). Kaplan-Meier analyses showed a significant difference of median survival time between patients with long and short RTL (log rank P < 0.001). Fluorescence-activated cell sorting analyses showed that the long RTL group had a significantly increased percentage of CD4(+)CD25(+)FOXP3(+) Treg in CD4(+) T cells compared with short RTL group (P = 0.002). In conclusion, our results suggest that leukocyte RTL may serve as an independent prognostic marker for HCC patients treated with TACE.

| S-EPMC6276896 | biostudies-literature

Telomere length in early life predicts lifespan.

Project description:The attrition of telomeres, the ends of eukaryote chromosomes, is thought to play an important role in cell deterioration with advancing age. The observed variation in telomere length among individuals of the same age is therefore thought to be related to variation in potential longevity. Studies of this relationship are hampered by the time scale over which individuals need to be followed, particularly in long-lived species where lifespan variation is greatest. So far, data are based either on simple comparisons of telomere length among different age classes or on individuals whose telomere length is measured at most twice and whose subsequent survival is monitored for only a short proportion of the typical lifespan. Both approaches are subject to bias. Key studies, in which telomere length is tracked from early in life, and actual lifespan recorded, have been lacking. We measured telomere length in zebra finches (n = 99) from the nestling stage and at various points thereafter, and recorded their natural lifespan (which varied from less than 1 to almost 9 y). We found telomere length at 25 d to be a very strong predictor of realized lifespan (P < 0.001); those individuals living longest had relatively long telomeres at all points at which they were measured. Reproduction increased adult telomere loss, but this effect appeared transient and did not influence survival. Our results provide the strongest evidence available of the relationship between telomere length and lifespan and emphasize the importance of understanding factors that determine early life telomere length.

| S-EPMC3277142 | biostudies-other

Telomere attrition predicts reduced survival in a wild social bird, but short telomeres do not.

Project description:Attempts to understand the causes of variation in senescence trajectories would benefit greatly from biomarkers that reflect the progressive declines in somatic integrity (SI) that lead to senescence. While telomere length has attracted considerable interest in this regard, sources of variation in telomere length potentially unrelated to declines in SI could, in some contexts, leave telomere attrition rates a more effective biomarker than telomere length alone. Here, we investigate whether telomere length and telomere attrition rates predict the survival of wild white-browed sparrow-weaver nestlings (Plocepasser mahali). Our analyses of telomere length reveal counterintuitive patterns: telomere length soon after hatching negatively predicted nestling survival to fledging, a pattern that appears to be driven by differentially high in-nest predation of broods with longer telomeres. Telomere length did not predict survival outside this period: neither hatchling telomere length nor telomere length in the mid-nestling period predicted survival from fledging to adulthood. Our analyses using within-individual telomere attrition rates, by contrast, revealed the expected relationships: nestlings that experienced a higher rate of telomere attrition were less likely to survive to adulthood, regardless of their initial telomere length and independent of effects of body mass. Our findings support the growing use of telomeric traits as biomarkers of SI, but lend strength to the view that longitudinal assessments of within-individual telomere attrition since early life may be a more effective biomarker in some contexts than telomere length alone.

| S-EPMC6772082 | biostudies-other

Telomere length and genetic variant associations with interstitial lung disease progression and survival.

Project description:Leukocyte telomere length (LTL), MUC5B rs35705950 and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year versus -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The MUC5B rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 versus -0.01±0.23; p=0.00055) and higher MUC5B MAF (34.6, 95% CI 24.4-46.3 versus 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B MAF have different associations with lung function progression and survival for IPAF and CTD-ILD.

| S-EPMC6612265 | biostudies-literature

Reduced telomere length is associated with fibrotic joint disease suggesting that impaired telomere repair contributes to joint fibrosis.

Project description:ObjectiveJoint fibrosis affects many synovial joints (including hip, knee and shoulder) causing stiffness and pain. The mechanism of joint fibrosis remains unknown, although genetic factors may contribute. Defects in maintenance of telomere length resulting from impaired telomere repair have been shown to cause lung and liver fibrotic disease. Here we tested the hypothesis that joint fibrosis and other soft tissue fibrotic conditions are also associated with telomere length.Patients and methods5,200 participants in the TwinsUK registry had data on telomere length (measured by qPCR) and the traits of interest (hip and knee stiffness, total joint replacement (TJR, hip or knee) and fibrotic conditions (Dupuytren's disease, frozen shoulder).ResultsMultivariable logistic regression analyses showed a significant association between telomere length and fibrotic conditions (hip stiffness, knee stiffness and frozen shoulder, p = ≤0.002) even after taking age into account. No association was found between TJR and telomere length.ConclusionThese findings suggest that defects in telomere repair contribute to joint fibrosis, and that fibrosis shares a common mechanistic pathway in different organs. Therapeutic strategies to combat telomere shortening may offer novel treatments for fibrotic joint disease.

| S-EPMC5749754 | biostudies-literature

Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival.

Project description:BACKGROUND:Prior studies have shown that patients with pulmonary fibrosis with mutations in the telomerase genes have a high rate of certain complications after lung transplantation. However, few studies have investigated clinical outcomes based on leukocyte telomere length. METHODS:We conducted an observational cohort study of all patients with pulmonary fibrosis who underwent lung transplantation at a single center between January 1, 2007, and December 31, 2014. Leukocyte telomere length was measured from a blood sample collected before lung transplantation, and subjects were stratified into 2 groups (telomere length <10th percentile vs ?10th percentile). Primary outcome was post-lung transplant survival. Secondary outcomes included incidence of allograft dysfunction, non-pulmonary organ dysfunction, and infection. RESULTS:Approximately 32% of subjects had a telomere length <10th percentile. Telomere length <10th percentile was independently associated with worse survival (hazard ratio 10.9, 95% confidence interval 2.7-44.8, p = 0.001). Telomere length <10th percentile was also independently associated with a shorter time to onset of chronic lung allograft dysfunction (hazard ratio 6.3, 95% confidence interval 2.0-20.0, p = 0.002). Grade 3 primary graft dysfunction occurred more frequently in the <10th percentile group compared with the ?10th percentile group (28% vs 7%; p = 0.034). There was no difference between the 2 groups in incidence of acute cellular rejection, cytopenias, infection, or renal dysfunction. CONCLUSIONS:Telomere length <10th percentile was associated with worse survival and shorter time to onset of chronic lung allograft dysfunction and thus represents a biomarker that may aid in risk stratification of patients with pulmonary fibrosis before lung transplantation.

| S-EPMC5515686 | biostudies-literature

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