Shorter Telomere Length Research Articles

Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways.

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta = - 1.167, PAdj = 2.75 × 10-4). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.

Early-life conditions impact juvenile telomere length, but do not predict later life-history strategies or fitness in a wild vertebrate.

Environmental conditions experienced during early life may have long‐lasting effects on later‐life phenotypes and fitness. Individuals experiencing poor early‐life conditions may suffer subsequent fitness constraints. Alternatively, individuals may use a strategic “Predictive Adaptive Response” (PAR), whereby they respond—in terms of physiology or life‐history strategy—to the conditions experienced in early life to maximize later‐life fitness. Particularly, the Future Lifespan Expectation (FLE) PAR hypothesis predicts that when poor early‐life conditions negatively impact an individual's physiological state, it will accelerate its reproductive schedule to maximize fitness during its shorter predicted life span. We aimed to measure the impact of early‐life conditions and resulting fitness across individual lifetimes to test predictions of the FLE hypothesis in a wild, long‐lived model species. Using a long‐term individual‐based dataset, we investigated how early‐life conditions are linked with subsequent fitness in an isolated population of the Seychelles warbler Acrocephalus sechellensis. How individuals experience early‐life environmental conditions may vary greatly, so we also tested whether telomere length—shorter telomers are a biomarker of an individual's exposure to stress—can provide an effective measure of the individual‐specific impact of early‐life conditions. Specifically, under the FLE hypothesis, we would expect shorter telomeres to be associated with accelerated reproduction. Contrary to expectations, shorter juvenile telomere length was not associated with poor early‐life conditions, but instead with better conditions, probably as a result of faster juvenile growth. Furthermore, neither juvenile telomere length, nor other measures of early‐life conditions, were associated with age of first reproduction or the number of offspring produced during early life in either sex. We found no support for the FLE hypothesis. However, for males, poor early‐life body condition was associated with lower first‐year survival and reduced longevity, indicating that poor early‐life conditions pose subsequent fitness constraints. Our results also showed that using juvenile telomere length as a measure of early‐life conditions requires caution, as it is likely to not only reflect environmental stress but also other processes such as growth.

RELATION BETWEEN TELOMERE DYNAMICS AND METABOLIC DISORDERS IN EARLY AGE

Objective: In adults, short leukocyte telomere length (LTL) is associated with metabolic disorders such as diabetes and obesity. The causality remains unclear since longitudinal studies do not show influence of metabolic disorders on LTL attrition. These associations could stem from early life interactions between telomere dynamics and metabolic disorders. To test this hypothesis, we measured, in obese children and their controls, LTL and its evolution over time and their associations with metabolic parameters. Design and method: 73 children aged 2–10 years (mean 7.6 ± 2.0) at inclusion were followed between 2 and 4 years (one visit/year). Anthropometric measurements (weight, height, waist and hip circumferences), a body composition analysis and a complete biology were performed annually. LTL was measured by Southern blot and LTL attrition was calculated. Scores for metabolic parameters were created based on the mean value of the parameter throughout the study. Results: Mean LTL attrition was 67 ± 8 bp/year. Baseline LTL correlated negatively with BMI score (p = 0.02), fat percentage score (p = 0.01), glycemia score (p = 0.0007), and insulinemia score (p = 0.02). These associations persisted after adjustment for age and sex. Trends for negative associations were observed between baseline LTL and waist/hip score (p = 0.07), and Hb1Ac score (p = 0.07). No association was found between LTL attrition and any of the metabolic parameters. Conclusions: In young children, metabolic parameters are negatively associated with LTL but not with LTL attrition. These results indicate that either short TL is the cause of metabolic disorders or that these metabolic disorders increased LTL attrition very early in life probably before the age of 5 years.

Associations between circadian misalignment and telomere length in BD: an actigraphy study

BackgroundLife expectancy is significantly decreased in bipolar disorder (BD). This is associated with accelerated cellular aging which can be estimated by telomere length (TL). However, specific determinants of shorter TL in BD are under-explored. This study examines whether circadian misalignment (i.e. mismatch between preferred and actual phase of circadian activity rhythms) is associated with shorter TL in BD.MethodsEuthymic individuals with BD (n = 101) undertook 21 consecutive days of actigraphy recording and completed the Composite Scale of Morningness (CSM) to assess phase preference for activities (chronotype). Polymerase chain reaction was used to measure TL in blood. Cluster analysis identified circadian aligned/misaligned subgroups as defined by preferred (CSM score) and actual phases of activity (actigraphically determined onset of active and inactive periods). We tested for any associations between TL and clusters, with adjustments for between-cluster differences in socio-demographic and illness factors.ResultsWe identified three clusters: an "Aligned Morning" cluster (n = 31) with preferred and actual timing of activity in the morning, an "Aligned Evening" cluster (n = 37) with preferred and actual timing of activity in the evening and a "Misaligned" cluster (n = 32) with an evening chronotype, but an earlier objective onset of active periods. After adjustment for confounders, we found that TL was significantly associated with circadian misalignment and older age.ConclusionsCircadian misalignment may partly explain shorter TL in BD and could contribute to accelerated aging in these individuals.

Obesity Accelerates Leukocyte Telomere Length Shortening in Apparently Healthy Adults: A Meta-Analysis.

BackgroundShorter telomere length is associated with numerous comorbidities. Several studies have investigated the role of obesity in telomere shortening. In the current systematic review and meta-analysis, we summarized the results of studies that evaluated the association between obesity and telomere length.MethodsA systematic search from Scopus, PubMed, Embase, and ProQuest electronic databases up to 19 March 2021 without language restriction was performed and after data extraction and screening, 19 manuscripts were eligible to be included in the final meta-synthesis.ResultsThe highest category of telomere length was associated with an approximate 0.75 kg/m2 reduction in body mass index (BMI; WMD = −0.75 kg/m2; CI = −1.19, −0.31; p < 0.001; I2 = 99.4%). Moreover, overweight/obese individuals had 0.036 kbp shorter telomere length compared with non-overweight/obese adults (WMD = −0.036; CI = −0.05, −0.02; p = 0.030; I2 = 100%). According to the results of subgroupings, continent, age, and sample size could be possible sources of heterogeneity.ConclusionFrom the results, it was clear that obesity was associated with shorter telomere length. Because of the observational design of included studies, the causality inference of results should be done with caution; thus, further longitudinal studies are warranted for better inference of causal association.

0059 Does Discrimination Moderate the Relationship between Insomnia and Telomere Length in Older Adults from Three Racial/Ethnic Groups?

Abstract Introduction Both insomnia and discrimination have been associated with adverse physical and mental health outcomes. Evidence suggests that discrimination may moderate the effects of sleep on telomeres, DNA sequences at the end of chromosomes that protect them from degradation. The purpose of this study was to determine the relationship between insomnia and telomere length among older non-latinx white, black, and latinx individuals and whether discrimination moderated this relationship differently based on race or ethnicity. Methods This study is a secondary analysis from the Health and Retirement Study, a longitudinal project sponsored by the National Institute on Aging. Our analysis consisted of 3,205 US participants who provided information on sleep problems as well as salivary samples from which telomere data were assayed. We computed a linear regression to examine the relationship between insomnia symptoms and telomere length in each racial/ethnic group, including interaction terms to assess moderating effects of discrimination. Results Insomnia symptoms were associated with shortened telomere length among non-latinx white participants (β -0.046, p=0.015, [-0.06, -0.01]). Discrimination had a moderating effect between insomnia symptoms and telomere length among black participants (β -0.28, p=0.045, [-0.33, -0.00]). Analyses remained significant after adjusting for age, medical co-morbidities, smoking status, and a history of depression. Conclusion Our results suggest that symptoms of insomnia may contribute to telomere erosion, with potentially adverse effects on genomic integrity. For black individuals, those who experienced discrimination were at greater risk of telomere damage associated with insomnia. Support (If Any) Funding has been made available by the NIH, granted to UCSF School of Nursing Biobehavioral Research Training Program in Symptom Science (NIH: T32 NRO16920).

Telomere Length and COVID-19 Outcomes: A Two-Sample Bidirectional Mendelian Randomization Study.

Observational studies have found a relationship between directly measured short leukocyte telomere length (LTL) and severe coronavirus disease 19 (COVID-19). We investigated the causal association between genetically predicted LTL and COVID-19 susceptibility or severity. A previous genome-wide association study (GWAS) of 78,592 European-ancestry participants identified single nucleotidepolymorphisms (SNPs) that can be utilized to genetically predict LTL. Summary-level data for COVID-19 outcomes were analyzed from the COVID-19 Host Genetics Initiative. A two-sample bidirectional Mendelian randomization (MR) study was designed to evaluate these causal relationships. Using an inverse-weighted MR analysis and population-based controls, genetically predicted LTL did not reveal any significant association with COVID-19 susceptibility (odds ratio (OR): 0.94; 95% CI: 0.85–1.04; p = 0.202) or severity (OR: 0.85; 95% CI: 0.70–1.03; p = 0.099). Similar results were found for five other definitions of cases/controls and/or COVID-19 outcomes. Six additional MR methods and sensitivity analyses were conducted after removing variants with potential horizontal pleiotropy and including variants at a liberal significance level, which produced similar results. Using SNPs identified for the prediction of LTL from another GWAS study, we found a non-significant association for COVID-19 susceptibility or severity with narrower CIs toward the null hypothesis. No proof of genetically predicted COVID-19 phenotypes remained causally associated with genetically predicted LTL, and the null association was consistent with a lack of significant genetic correlation. Genetic evidence does not support shorter LTL as a causal risk factor for COVID-19 susceptibility or severity.

Telomere length and stroke recurrence after ischemic stroke and TIA.

Shortening telomere length (TL), as an indicator of aging, has been associated with increased risk of cardiovascular disease and incident stroke. However, there are limited data relating to the association between TL and recurrent stroke. Patients from the Third China National Stroke Registry who had whole genome sequencing (WGS) were selected. TL was estimated using TelSeq based on binary sequence alignment/map files derived from WGS data. Cox proportional hazards regression models were performed to assess the association of TL with recurrent stroke. A total of 8041 patients with ischemic stroke (IS) or transient ischemic attack (TIA) were included. Mean TL was 2.14 ± 0.82 kb. Patients in the lowest tertile of TL had higher incidence of stroke recurrence compared to those in the middle and highest tertile (6.4% vs 5.9% vs 5.2%), but the difference was not longer significant after adjusting for age, sex, cardiovascular risk factors and stroke severity. Similarly, when analyzing TL as a continuous variable, the HR per 1000 bp increase in TL was significant 0.88 (0.79-0.98), but after adjusting for co-variates, was no longer significant (0.91; 95% confidence interval (CI), 0.81-1.02). In patients aged > 65 years, but not in younger patients, after adjusting for co-variates, TL was significantly associated with stroke recurrence. Compared to the lowest tertile, HRs (95% CI) after adjustment for all co-variates for the middle and highest tertiles were 0.78 (0.55-1.10) and 0.67 (0.46-0.98), respectively, with p for trend of 0.03. In analyses using TL as a continuous variable, adjusted HR (95% CI) per 1000 bp increase in TL was 0.80 (0.66-0.96). However, there was no significant interaction between TL and age on risk of stroke recurrence (p for interaction = 0.09). In Chinese IS or TIA patients, no independent association was found between TL and risk of stroke recurrence after adjusting for co-variates. We found a possible association in older patients but this needs replicating.

Shorter Telomeres Related to Posttraumatic Stress Disorder Re-experiencing Symptoms in Sexually Assaulted Civilian Women.

Telomeres are short tandem repeats of “TTAGGG” that protect the chromosome ends from deterioration or fusion of chromosomes. Their repeat length shortens with cell division acting as a biomarker of cellular aging. Traumatic stress events during adulthood or childhood have been associated with posttraumatic stress disorder (PTSD) and short leukocyte telomere length (LTL). This study investigated whether LTL was associated with PTSD in a Brazilian sample of sexually assaulted civilian women at two time points: baseline and 1-year follow-up. At baseline, we assessed 64 women with PTSD following sexual assault (cases) and 60 women with no previous history of sexual trauma or mental disorders (healthy controls – HC). At follow-up visit, 13 persistent PTSD cases, 11 HCs, and 11 PTSD remitters patients were evaluated. PTSD diagnosis and severity were assessed using Mini International Neuropsychiatric Interview (Diagnostic and Statistical Manual of Mental Disorders III/IV criteria) and Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), respectively. LTL was measured using multiplex real-time polymerase chain reaction (PCR). In the baseline analysis, we observed that LTL was associated with re-experiencing symptoms (B = −0.16; confidence interval (CI) 95% = −0.027—−0.005; Bonferroni-adjusted p-value = 0.02), but no association was observed between other PTSD symptoms and LTL. In the longitudinal analysis, telomere shortening was no longer observed in patients with PTSD and PTSD remitters. In conclusion, our findings indicate that shorter baseline LTL is associated with early stage of PTSD re-experiencing symptoms in recently sexually assaulted women.

Telomere-mediated lung disease.

Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange.

Concomitant use of relative telomere length, biological health score and physical/social statuses in the biological aging evaluation of mustard-chemical veterans

Sulfur mustard (SM) is a toxic gas that has been used as a chemical weapon in wars. After many years, SM-exposed people are still suffering from its side effects such as biological and premature aging. This study was aimed to evaluate biological aging rate via involving biological health scoring (BHS), relative telomere length (TL) and different physical/social variables i.e. marital and smoking statuses, body mass index, salary and educational levels. BHS was calculated according to measurement of 18 biomarkers related to function of four physiological systems (endocrine, inflammatory, cardiovascular and metabolic systems) and two organs (liver and kidney). The volunteers were 442 individuals exposed to SM gas in 1987 and 119 healthy individuals as non-exposed group. Each group was divided based on leukocyte relative TL (short, intermediate and long). Our data showed an inverse correlation between BHS and relative TL in two groups. The BHS was significantly higher in SM-exposed group than non-exposed group, especially in the participants with short and intermediate TL. The BHS had also a positive correlation with smoking and BMI parameters, and a negative correlation with salary and educational levels in the participants with shorter telomeres; and SM strengthened these correlations in the shorter telomeres. It is concluded that the higher BHS along with shorter relative TL that are indices for lower health quality and biological aging, could be used in the health evaluation of non- and SM-exposed people; and involving of BHS, TL and physical/social covariates could be useful to make this evaluation more accurate.

Relationship between Telomere Length, TERT Genetic Variability and TERT, TP53, SP1, MYC Gene Co-Expression in the Clinicopathological Profile of Breast Cancer.

The molecular mechanisms of telomerase reverse transcriptase (TERT) upregulation in breast cancer (BC) are complex. We compared genetic variability within TERT and telomere length with the clinical data of patients with BC. Additionally, we assessed the expression of the TERT, MYC, TP53 and SP1 genes in BC patients and in BC organoids (3D cell cultures obtained from breast cancer tissues). We observed the same correlation in the blood of BC patients and in BC organoids between the expression of TERT and TP53. Only in BC patients was a correlation found between the expression of the TERT and MYC genes and between TP53 and MYC. We found associations between TERT genotypes (rs2735940 and rs10069690) and TP53 expression and telomere length. BC patients with the TT genotype rs2735940 have a shorter telomere length, but patients with A allele rs10069690 have a longer telomere length. BC patients with a short allele VNTR-MNS16A showed higher expression of the SP1 and had a longer telomere. Our results bring new insight into the regulation of TERT, MYC, TP53 and SP1 gene expression related to TERT genetic variability and telomere length. Our study also showed for the first time a similar relationship in the expression of the above genes in BC patients and in BC organoids. These findings suggest that TERT genetic variability, expression and telomere length might be useful biomarkers for BC, but their prognostic value may vary depending on the clinical parameters of BC patients and tumor aggressiveness.

TELOMERE LENGTH AS A BIOLOGICAL MARKER FOR ASSESSING THE SERIOUSNESS OF PNEUMONIA OF VARIOUS ETIOLOGIES

Abstract. The results of the features of the clinical course of pneumonia of various etiologies are presented, taking into account the epigenetic indicator of the human body, such as telomere length. We examined 102 male military personnel who were treated at the hospital therapy clinic of the Military Medical Academy named after S. M. Kirov. The patients were divided into two groups: group I of 63 people aged 37,3±6,7 years with pneumonia caused by a new coronavirus infection; Group II - 39 men aged 41.4±5.3 years with bacterial pneumonia of various etiologies. Patients were examined and treated according to the standard scheme. In the group of severe viral pneumonia, a significantly larger volume of lung parenchymal damage was determined, a decrease in saturation to 91,3±1,6% (p=0,003); myocardial damage: an increase in troponin T up to 15,6±5,3 ng/l (p=0.001), an increase in total CPK, AST and ALT compared with patients of group II. In group I, evaluating the results of hemogram parameters, attention is drawn to the tendency to thrombocytopenia (172±29x109/l, p=0,03), the tendency to leukopenia (4.1±1,2x109/l) in severe disease. There was a significant increase in CRP, D-dimer and ferritin in severe viral pneumonia in men of group I, which can be characterized as coagulopathy associated with the risk of developing arterial and venous thrombosis because of microthrombovasculitis. Telomeres are specialized functional complexes that are located at the ends of chromosomes and protect them from fusion with each other, which preserves the integrity of the eukaryotic cell genome. Telomere length is an important characteristic of a person’s overall health. It is associated with such characteristics as longevity or the affinity of the human body to various diseases, such as type 2 diabetes mellitus, hypertension, coronary heart disease, and others. In this scientific study, change in length lomer in patients with pneumonia of various etiologies. The most pronounced shortening of telomere length was found in patients with severe viral pneumonia (significant shortening of telomere length by more than 2000 base pairs), compared with bacterial pneumonia. The identified changes can be used to predict an unfavorable outcome of pneumonia caused by a new coronavirus infection, for example, the development of such a formidable complication as a “cytokine storm”. The obtained preliminary results make it possible to consider telomere length as a specific biological marker for assessing the severity of pneumonia caused by the SARS-CoV-2 virus.

Lung transplant recipients with idiopathic pulmonary fibrosis have impaired alloreactive immune responses.

Telomere dysfunction is associated with idiopathic pulmonary fibrosis (IPF) and worse outcomes following lung transplantation. Telomere dysfunction may impair immunity by upregulating p53 and arresting proliferation, but its influence on allograft-specific immune responses is unknown. We hypothesized that subjects undergoing lung transplantation for IPF would have impaired T cell proliferation to donor antigens. We analyzed peripheral blood mononuclear cells (PBMC) from 14 IPF lung transplant recipients and 12 age-matched non-IPF subjects, before and 2 years after transplantation, as well as PBMC from 9 non-transplant controls. We quantified T cell proliferation and cytokine secretion to donor antigens. Associations between PBMC telomere length, measured by quantitative PCR, and T cell proliferation to alloantigens were evaluated with generalized estimating equation models. IPF subjects demonstrated impaired CD8+ T cell proliferation to donor antigens pre-transplant (p < 0.05). IL-2, IL-7, and IL-15 cytokine stimulation restored T cell proliferation, while p53 upregulation blocked proliferation. IPF subjects had shorter PBMC telomere lengths than non-IPF subjects (p < 0.001), and short PBMC telomere length was associated with impaired CD8+ T cell proliferation to alloantigens (p=0.002). IPF as an indication for lung transplant is associated with short PBMC telomere length and impaired T cell responses to donor antigens. However, the rescue of proliferation following cytokine exposure suggests that alloimmune anergy could be overcome. Telomere length may inform immunosuppression strategies for IPF recipients.

Association between Physical Activity and Telomere Length in Women with Breast Cancer: A Systematic Review.

The association between physical activity and telomere length (TL) has been continuously reported. However, the interplay of physical activity and TL among women with breast cancer has not been elucidated. Thus, the purpose of this systematic review was to synthesize the evidence for the association of physical activity with TL in women with breast cancer. Systematic searches were conducted to identify quantified studies using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Clinical Trials.gov. Five studies were included in this systematic review. Three of the five studies reported that physical activity has a significant relationship in delaying TL shortening, but others observed no association between physical activity and TL in breast cancer survivors. Although the heterogeneous studies acted as limitations in drawing clear conclusions, physical activity strategies show encouraging impacts in delaying TL shortening. To understand the effects of physical activity on TL shortening in breast cancer survivors, further studies are needed considering the tissue site, treatments for breast cancer, DNA extraction methods, and tools for measuring physical activity.

The neuroprotective effects of oxygen therapy in Alzheimer’s disease: a narrative review

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Telomere length in individuals with and without major depression and adverse childhood experiences

Major depressive disorder (MDD) and adverse childhood experiences (ACE) are associated with poor physical and mental health in adulthood. One underlying mechanism might be accelerated cellular aging. For example, both conditions, MDD and ACE, have been related to a biological marker of cellular aging, accelerated shortening of telomere length (TL). Since MDD and ACE are confounded in many studies, we aimed with the current study to further disentangle the effects of MDD and ACE on TL using a full-factorial design including four carefully diagnosed groups of healthy participants and MDD patients with and without ACE (total N = 90, all without use of antidepressants). As dependent variable, TL was assessed in leukocytes. We found no group differences based on MDD and ACE exposure in TL. While TL was negatively associated with age and male sex, TL was not associated with any measure of severity of MDD, ACE or current stress. One possible explanation for our null result may be the comparatively good physical health status of our sample. Future research is needed to elucidate the relation of TL, MDD and ACE, taking potential effect modification by medication intake and physical health status into account.

Gestational exposure to NO2 aggravates placental senescence

Placental senescence is a normal physiological process of placenta, while premature placental senescence has been confirmed to be associated with some adverse pregnancy complications. Epidemiological studies indicate that NO2 exposure can aggravate placental senescence which is represented by fibrosis and abnormal telomere homeostasis, etc. In this study, pregnant C57BL/6 mice were exposed to NO2 (2.5 ppm, 5 h/day) daily in a dynamic exposure chamber throughout the gestation period, and were sacrificed at embryonic day 13.5 (E13.5), E15.5 and E18.5. Placenta were harvested and conducted for histopathological examination and telomere evaluation. Our results showed that gestational NO2 exposure significantly aggravated placental fibrosis and calcification, and up-regulated the related bio-markers (connective tissue growth factor (Ctgf) and transforming growth factor-β1 (Tgf-β1)) at E18.5. In addition, gestational exposure to NO2 also activated senescence related pathway (p53/p21) at E18.5. Furthermore, gestational NO2 exposure significantly shortened telomere length at E18.5, and the expression of telomere homeostasis regulation genes telomeric repeat binding factor 1 (Trf1), protection of telomeres 1a (Pot1a) and Pot1b were significantly increased while telomerase reverse transcriptase (Tert) was suppressed after NO2 exposure at E13.5 or E18.5, respectively. Importantly, DNA methylation status of the 22nd at E13.5 and 32nd at E18.5 site in sub-telomeric region of chromosome 1 was significantly altered. Based on the above results, our present study indicated that gestational NO2 exposure could lead to premature placental senescence during the late trimester of pregnancy via aggravation of fibrosis and telomere length shortening regulated by telomere regulatory enzyme and DNA methylation.

Extrapulmonary manifestations of a telomere syndrome in patients with idiopathic pulmonary fibrosis are associated with decreased survival.

Idiopathic pulmonary fibrosis (IPF) is a heterogenous disease with a median survival of 3-4 years. Patients with mutations in telomere-related genes exhibit extrapulmonary signs and symptoms. These patients represent a distinct phenotype of IPF with worse survival. As genetic analyses are not available for most patients with IPF, we sought to determine the predictive value of extrapulmonary signs and symptoms of a telomere syndrome in patients with IPF. We retrospectively studied 409 patients with IPF. Clinical characteristics, laboratory results and family history suggestive of a telomere syndrome were related to leukocyte telomere length measured by quantitative PCR and patient outcomes. The cohort included 293 patients with sporadic IPF and 116 patients with a background of familial pulmonary fibrosis. Any or a combination of a clinical history (haematological disease, liver disease, early greying of hair, nail dystrophy, skin abnormalities), a family history or haematological laboratory abnormalities (macrocytosis, anaemia, thrombopenia or leukopenia) suggestive of a telomere syndrome was present in 27% of IPF patients and associated with shorter leukocyte telomere length and shorter survival (p = 0.002 in a multivariate model). In sporadic IPF, having either a clinical history, family history or haematological laboratory abnormalities was not significantly associated with decreased survival (p = 0.07 in a multivariate model). Taking a careful clinical and family history focused on extrapulmonary manifestations of a telomere syndrome can provide important prognostic information in patients with IPF, as this is associated with shorter survival.

Shorter periconception maternal telomere length and the risk of congenital cardiac outflow defects in the offspring.

BackgroundCongenital cardiac outflow defects (COD) are the largest group of congenital heart defects, with ventricular septal defect (VSD) as the most prevalent phenotype. Increased maternal age, excessive oxidative stress and inflammation are involved in the pathophysiology of COD and enhance telomere length (TL) shortening. We investigated the association between periconception maternal TL and the risk of having a child with COD.MethodsFrom a multicentre case‐control trial, 306 case mothers of a child with COD and 424 control mothers of a child without a congenital malformation were selected. Relative TL was measured by qPCR. Multivariable logistic regression was used to compute crude and adjusted odds ratios, per standard deviation decrease, between maternal T/S ratio and COD and VSD risk. Adjustments were made for maternal age. Additional adjustments were made in a second model.ResultsShorter maternal relative TL was significantly associated with an OR of 1.29 (95% CI 1.04–1.61), p = .02, for the risk of VSD in offspring, which remained significant after an adjustment for maternal age (adjOR 1.25(95% CI 1.01–1.55), p = .04). No association between maternal TL and the risk of overall COD in offspring was observed.ConclusionShorter maternal relative TL is associated with an approximately 1.3‐OR for the risk, per SD in relative TL shortening, of VSD in the offspring. These findings need further confirmation in other studies on the predictive value of maternal TL.