Shorter Leukocyte Telomere Length Research Articles

Telomere Biology in Mood Disorders: An Updated, Comprehensive Review of the Literature

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell’s mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.

Association of Leukocyte Telomere Length with Mild Cognitive Impairment and Alzheimer’s Disease: Role of Folate and Homocysteine

Background: Leukocyte telomere length (LTL) is associated with the aging process and age-related degenerative diseases. The relation of peripheral blood LTL to mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and the role of folate and homocysteine (Hcy) in this relation remain unclear. Objectives: We aimed to investigate the association between LTL and the risks of MCI/AD, and to explore whether folate and Hcy may play a role in this association. Methods: This case-control study included 129 MCI subjects, 131 AD patients and 134 healthy controls. LTL was assessed using real-time polymerase chain reaction assay. Serum folate levels were tested by chemiluminescence enzyme immunoassay, and serum Hcy levels were measured using the enzymatic cycling method. Data were analyzed using multivariate logistic regression and multivariable linear regression with adjustment for potential confounders. Results: The mean LTL was 1.56 ± 0.25 in controls, 1.44 ± 0.23 in MCI, and 1.28 ± 0.28 in AD patients (p< 0.01). In multivariate logistic regression, subjects in the longest LTL tertile had lower OR for MCI (OR 0.246; 95% CI 0.101–0.597) and AD (OR 0.123; 95% CI 0.044–0.345) in comparison to subjects in the shortest tertile. Shorter LTL was dose-dependently related to the ORs of MCI and AD. Further, serum folate concentration was positively associated with LTL (p < 0.01), while serum Hcy level was negatively associated with LTL (p < 0.05). In stratified analyses, LTL-MCI/AD association varied by serum folate and Hcy level. Conclusions: Shorter LTL is associated with the risks of MCI/AD. Folate and Hcy might play an important role in this association.

Pre-transplant short telomeres are associated with high mortality risk after unrelated donor haematopoietic cell transplant for severe aplastic anaemia.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (<10th percentile-for-age) or very short (<5th or <1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age=20years). One hundred and twelve patients (22·86%) had pre-HCT RTL <10th percentile-for-age, with the majority below the 5th percentile (N=80, 71·43%). RTL <10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR]=1·78, 95% confidence interval [CI]=1·18-2·69, P=0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P>0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL <5th versus ≥5th percentile=1·38, P=0·15 for the first 12months after HCT, and HR=3·91, P<0·0001, thereafter, P-heterogeneity=0·008; the corresponding HRs for RTL <1st versus ≥1st percentile=1·29, P=0·41, and HR=5·18, P<0·0001, P-heterogeneity=0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.

Helicobacter pylori infection, serum pepsinogens as markers of atrophic gastritis, and leukocyte telomere length: a population-based study

BackgroundPersistent infections that induce prolonged inflammation might negatively affect the leukocyte telomere length (LTL); however, the role in LTL of Helicobacter pylori (H. pylori) infection, which persistently colonizes the stomach, remains unknown.The study objective was to examine associations of sero-prevalence of H. pylori immunoglobulin G (IgG) antibody and serum pepsinogens (PGs), as markers of atrophic gastritis, with LTL.A cross-sectional study was performed among 934 Arab residents of East Jerusalem, aged 27–78 years, randomly selected from Israel’s national population registry. Sera were tested for H. pylori IgG and PG levels by ELISA. LTL was measured by southern blots. Multiple linear regression models were fitted to adjust for sociodemographic and lifestyle factors.ResultsLTL decreased significantly with age (p < 0.001) and was shorter in men than women (p = 0.032). The mean LTL was longer in H. pylori sero-positive persons than negative ones: mean difference 0.13 kb (95% CI 0.02, 0.24), p = 0.016. Participants with atrophic gastritis (PGI < 30 μg/L or a PGI: PGII < 3.0) had shorter LTL than did those without: mean difference − 0.18 (95% CI − 0.32, − 0.04). The difference was of larger magnitude between persons who had past H. pylori infection (sero-negative to H. pylori IgG antibody) and atrophic gastritis, compared to those who were H. pylori sero-negative and did not have atrophic gastritis: mean difference − 0.32 kb (95% CI − 0.55, − 0.10). This association remained significant after adjustment for age, sex, and religiosity: beta coefficient − 0.21 kb (95% CI − 0.41, − 0.001), p = 0.049. The results were similar after further adjustment for lifestyle factors. In bivariate analysis, mean LTL was longer in physically active persons than non-active ones, and shorter in persons with than without obesity; however, these differences were diminished and were not significant in the multivariable model.ConclusionsH. pylori IgG sero-positivity per se was not related to reduced LTL. However, persons with past H. pylori infection (i.e., lacking H. pylori IgG serum antibody) and with serological evidence of atrophic gastritis, had a significantly shorter LTL than did those without atrophic gastritis.

Delayed sleep-onset and biological age: late sleep-onset is associated with shorter telomere length.

We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging. Data from the Netherlands Study of Depression and Anxiety (N = 2,936) were used at two waves 6 years apart, to measure LTL. Telomeres shorten during the life span and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analyzed the associations between LTL, sleep, and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity, and childhood trauma. Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B = -49.9, p = .004), late sleep-onset time (B = -32.4, p = .001), indication of DSPS (B = -73.8, p = .036), and moderately late chronotype in adulthood (B = -71.6, p = .003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B = 161.40, p = .037). No predictors showed accelerated LTL attrition over 6 years. Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.

Telomere Length: A Potential Biomarker for the Risk and Prognosis of Stroke.

Stroke is one of the leading causes of death and disability worldwide. Age is associated with increased risk of stroke, while telomere length shortening plays a pivotal role in the process of aging. Moreover, telomere length shortening is associated with many risk factors of stroke in addition to age. Accumulated evidence shows that short leukocyte telomere length is not only associated with stroke occurrence but also associated with post-stroke recovery in the elderly population. In this review, we aimed to summarize the association between leukocyte telomere length and stroke, and discuss that telomere length might serve as a potential biomarker to predict the risk and prognosis of stroke.

Re: Shorter Leukocyte Telomere Length is Associated with Risk of Nonobstructive Azoospermia.

Re: Shorter Leukocyte Telomere Length is Associated with Risk of Nonobstructive Azoospermia.

Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts.

Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr−1 faster in smokers than in non-smokers (95% CI: −2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr−1. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.

Re: Non-Obstructive Azoospermia and Shortened Leukocyte Telomere Length: Further Evidence Linking Poor Health and Infertility.

Re: Non-Obstructive Azoospermia and Shortened Leukocyte Telomere Length: Further Evidence Linking Poor Health and Infertility.

Shortened leukocyte telomere length is associated with reduced pulmonary function and greater subsequent decline in function in a sample of World Trade Center responders

The objective of this study was to examine whether shorter leukocyte telomere length (LTL) is associated with more rapid pulmonary function decline in a longitudinal study of World Trade Center (WTC) responders. WTC responders (N = 284) participating in a monitoring study underwent blood sampling and were followed prospectively for spirometric outcomes. A single blood sample was taken to measure LTL using southern blotting. Outcomes included percent-predicted one-second forced expiratory volume (FEV1%), forced vital capacity (FVC%), and the FEV1/FVC ratio. In a subset, percent-predicted diffusing capacity (DLCO%) was also measured. Longitudinal modeling examined prospectively collected information over five years since blood was banked was used to examine the rate of change in pulmonary functioning over time. Severity of WTC exposure was assessed. Shorter LTL was associated with lower FEV1% and FVC% at baseline. For example, 29.9% of those with LTL <6.5 kbps had FEV1% <80% whereas only 12.4% of those with LTL ≥6.5 had FEV1% <80% (RR = 2.53, 95%CI = [1.70–3.76]). Lower DLCO% was also significantly associated with shorter LTL. Longitudinal models identified a prospective association between shorter LTL and greater yearly rates of decline in FEV1% (0.46%/year, 95%CI = [0.05–0.87]) and in the FEV1/FVC ratio (0.19%/year, 95%CI = [0.03–0.36]). There were no associations between severity of exposure and either LTL or pulmonary function. Longitudinal analyses revealed that shorter LTL, but not severity of WTC exposures, was associated with poorer pulmonary functioning and with greater subsequent decline in pulmonary functioning over time. These findings are consistent with the idea that shortened LTL may act as a biomarker for enhanced pulmonary vulnerability in the face of acute severe toxic inhalation exposures.

Study on the relationship between telomere length changes and recurrence of atrial fibrillation after radiofrequency catheter ablation.

Advanced age is the foremost risk factor for atrial fibrillation (AF). Telomere length is a surrogate for biological aging, but the association between shortened leukocyte telomere length (LTL) and recurrence of AF (RAF) after ablation remains inconclusive. In this prospective analysis, 282 patients underwent an initial catheter ablation for paroxysmal or persistent AF. The association between RAF and LTL was analyzed by univariate and multivariate Cox regression, as well as time-dependent receiver operating characteristic (ROC) analysis and Kaplan-Meier analysis. After a mean follow-up of 14.20 ± 5.04 months, RAF was documented in 78 of the 277 patients who completed the study (28.16%). In Cox proportional hazards models, LTL, age, diagnosis to ablation time (DTAT), N-terminal pronatriuretic peptide, and CHA2DS2-VASc score were significantly associated with RAF. After multivariable adjustment, LTL and DTAT were predicted as independent risk factors for RAF with hazard ratio (HR) of 3.17 (95% confidence interval [CI]: 1.23-8.15, P = 0.017) and 1.43 (95% CI: 1.10-1.86, P = 0.007), respectively. In addition, ROC analysis indicated the potential diagnostic value of LTL with an area under the curve of 0.64 (P < 0.001; sensitivity = 60.3%, specificity = 57.8%), and an optimum cut-off value of 1.040. LTL less than or equal to 1.040 was defined as shortened LTL, while LTL greater than 1.040 nonshortened LTL. Kaplan-Meier analysis showed RAF rate curve was separated significantly between two groups (21.2% vs 35.9%, log-rank test result P = 0.007). Patients with shortened LTL might have a higher risk for RAF with HR = 1.84 (P = 0.008). Shortened LTL is an independent risk factor for AF recurrence. Shortened LTL could be a potential biomarker in predicting RAF after ablation.

Clinical implication of telomere length-related polymorphisms in gastric cardia adenocarcinoma.

e15502 Background: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. Methods: We systematically screened GWAS-identified candidate SNPs and tested the impact of thirty polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1,024 GCA patients and 1,118 controls. Results: We observed that CXCR4 rs6430612, TERT rs10069690 and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype ( P= 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers ( P= 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype ( P= 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients was 1.35 compared with the GG genotype ( P= 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers ( Pinteraction=9.7×10-5) and nondrinkers ( Pinteraction= 4.6×10-5). Conclusions: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.

Associations of smoking indicators and cotinine levels with telomere length: National Health and Nutrition Examination Survey.

The influence of smoking exposure on telomere length with a focus on the impact of race has rarely been discussed. We performed a cross sectional analysis into the associations of smoking indicators with leukocyte telomere length (LTL) by race among 5864 nationally representative sample of US adults (≥20 years). Data from 1999 to 2002 National Health and Nutrition Examination Survey was used for the analysis. Smoking indicators were assessed by interviews and serum cotinine levels. LTL was quantified by polymerase chain reaction. Multiple linear regressions were used to assess the association with adjustment for covariates, sample weights and design effects separately for Whites, Blacks and Mexican Americans. The intensity of smoking, measured by the average number of cigarettes consumed per day, was negatively associated with LTL among Whites (β: −3.87, 95% CI: −5.98 to −1.21) and among Blacks (β: −15.46, 95% CI: −29.79 to −2.12) participants. Compared with cotinine level < 0.05 ng/ml, cotinine level ≥3 ng/ml was associated with shorter LTL (β: −77.92, 95% CI = −143.05 to −11.70) among Whites, but not among Blacks. We found increased number of cigarette consumption to be associated with shorter LTL in both Blacks and Whites, indicating that the impact of smoking on life-shortening diseases could partly be explained by telomere biology. Increased cotinine concentration however, was associated with shorter LTL only among Whites, not among Blacks. This differential relationship that we observed may have implications in interpreting cotinine as an objective biomarker of smoking exposure across races and warrant additional prospective investigation.

Association between leukocyte telomere length and hostility in US army service members

Hostility is a common form of emotionally charged anger which can lead to maladaptive and unhealthy behaviors. Significant association between shortened telomeres and greater levels of hostility has been observed in civilian populations, but has not yet been comprehensively studied in military populations. Our study investigates the relationship between hostility, post-traumatic stress disorder (PTSD), and leukocyte telomere length (LTL) in a sample of United States Army Special Operations personnel (n = 474) who deployed to Iraq and/or Afghanistan as part of combat operations. Hostility was measured with five items from the Brief Symptom Inventory (BSI). PTSD was determined using the PTSD Checklist (PCL) total score. The LTL was assessed using quantitative polymerase chain reaction methods and regression analyses were conducted to determine the association of hostility and telomere length. PTSD subjects reported higher hostility scores compared with those without PTSD. Among the participants with PTSD, those with medium or high level of hostility had shorter LTL than those with low level hostility (P < 0.01). Stepwise regression indicated that hostility level and age, but not gender and PTSD, were negatively correlated with LTL. Univariate regression showed that total hostility score was negatively associated with LTL (CI= −0.06 to −0.002, Beta= −0.095, p < 0.039) as well as a significant correlation between LTL and hostility impulses (HI) (CI= −0.108 to −0.009, Beta= −0.106, p < 0.021) and hostility controlling (HC) (CI= −0.071 to −0.002, Beta= −0.095, p < 0.004). Multiple regression analyses revealed that, while HC has no significant association with LTL, HI was still negatively correlated with LTL (p = 0.021). Our data indicates that LTL is associated with HI levels. Prevention and treatment efforts designed to reduce hostility may help mitigate risk for LTL shortening, a process of cellular aging, and thus slow accelerated aged-related health outcomes.

Obstructive sleep apnea, nighttime arousals, and leukocyte telomere length: the Multi-Ethnic Study of Atherosclerosis.

Sleep disturbances and sleep apnea are associated with increased vulnerability to age-related disease, altering molecular pathways affecting biological aging. Telomere length captures one component of biological aging. We evaluated whether objectively assessed sleep and sleep apnea relate to leukocyte telomere length (LTL) in the Multi-Ethnic Study of Atherosclerosis (MESA). Men and women aged 44-84 years (n = 672) from the MESA Stress and MESA Sleep studies underwent polysomnography and 7 day actigraphy (at Exam 5) and assessment of LTL (at baseline [Exam 1] and about 10 years later [Exam 5]). General linear models adjusting for age, sex, race/ethnicity, BMI, physical activity, and smoking found that severe obstructive sleep apnea (OSA; apnea-hypopnea index > 30) was cross-sectionally associated with shorter LTL (p = 0.007). Modest associations of shorter LTL with less rapid eye movement sleep, more stage 1 sleep, wake after sleep onset >30 min, and long sleep duration were found, but these effects were diminished after adjusting for lifestyle and OSA. Exploratory analyses found that higher arousal index at Exam 5 was associated with greater LTL decline over the prior 10 years (p = 0.004). OSA was associated with shorter LTL. Individuals with high-arousal frequency had greater leukocyte telomere attrition over the prior decade. These findings suggest that sleep apnea and sleep fragmentation are associated with accelerated biological aging.

OR18-2 Higher Plasma Estradiol Concentration Is Independently Associated with Lower Biological Age, Assessed as Leucocyte Telomere Length, in Older Men

Telomeres are essential DNA-protein complexes comprising TTAGGG repeats binding specific proteins, which protect the physical ends of chromosomes from fusion and degradation. Attrition of telomeres results in cellular senescence. Leucocyte telomere length (LTL) reflects lengths of telomeres in various tissues, and shorter LTL is a marker of advancing biological age. Previous work has associated bioactive metabolites of T, dihydrotestosterone (DHT) and estradiol (E2) with LTL in a population of predominantly middle-aged men [1]. However, the relationship of these hormones to biological age in older men was unclear. We aimed to clarify associations of sex hormones with LTL in a cohort of 2,913 community-dwelling men aged 70-89 years. Early morning blood samples were assayed for T, DHT and E2 using mass spectrometry, and for sex hormone-binding globulin (SHBG) using immunoassay. LTL was measured using a multiplex quantitative PCR method and expressed as the amount of telomeric DNA relative to beta-globin, a single copy control gene (T/S ratio). Cross-sectional analyses utilised multivariable linear regression. Mean (±SD) age was 76.7±3.2 years. The average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L, and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r=0.038, p=0.039). After excluding highest and lowest 1% of values, the correlation between E2 and T/S ratio was largely unchanged (r=0.039, p=0.037). SHBG was inversely correlated with T/S ratio (r=-0.053, p=0.004), also unchanged in the trimmed analysis (r=-0.055, p=0.004.) After adjusting for age, BMI, cardiovascular disease, diabetes, alcohol, smoking, physical activity, lipids and hypertension, E2 remained associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, p=0.043). When E2 and SHBG were simultaneously included in the multivariate model, E2 remained positively associated with T/S ratio (coefficient 0.014, p=0.014) and SHBG inversely associated (coefficient -0.013, p=0.037). The magnitude of increase in T/S ratio associated with a 1 SD higher plasma E2 concentration was comparable with having a BMI 3.6 kg/m2 lower, and two thirds that associated with being 3.6 years younger. T, DHT and LH were not associated with LTL in multivariate analyses. To conclude, in older men, neither T nor DHT are associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated. These findings associate activity of the gonadal axis with lower biological age in older men. However, causality cannot be inferred from an observational, cross-sectional study, thus additional research is necessary to determine whether sex hormone exposure modulates male biological ageing. Reference: [1] Yeap BB, et al. J Clin Endocrinol Metab 2016; 101: 1299-1306.

An investigation of racial/ethnic and sex differences in the association between experiences of everyday discrimination and leukocyte telomere length among patients with coronary artery disease

Leukocyte telomere length (LTL) may be sensitive to psychosocial stressors such as discrimination. An inclusive examination of experiences of discrimination on LTL across racial/ethnic and sex groups is currently lacking. Baseline data were obtained from 369 White and African American patients with coronary artery disease (CAD) in the Mental Stress Ischemia Mechanisms and Prognosis Study. LTL was measured from peripheral blood leukocytes by quantitative polymerase chain reaction and calculated in kilobase pairs. Discrimination was measured using the 10-item Everyday Discrimination Scale (EDS). Responses were rated using 4-point Likert scales ranging from never = 1 to often = 4 and summed. Regression models were stratified by race/ethnicity and sex to estimate associations between discrimination and LTL. Each 10-unit increase in experiences of everyday discrimination was associated with an average of .20 fewer kilobase pairs (or 200 base pairs) among both African American women (β = -0.19; 95% CI: -0.35, -0.04; p-value: 0.02) and White women (β = -0.19; 95% CI: -0.37, -0.01; p-value: 0.04), after adjusting for basic demographic factors. Results were similar after further adjusting for behavioral, disease, and psychosocial risk factors (depression and stress). There were no significant associations between experiences of everyday discrimination and LTL for White men or African American men. Overall, experiences of discrimination were associated with shorter LTL among women and not in men. Discrimination may be a potential source of stress associated with shorter LTL among women with CAD. Future studies should explore longitudinal associations between everyday experiences of discrimination and telomere length and also with adverse cardiovascular outcomes.

Genetic variations associated with telomere length confer risk of gastric cardia adenocarcinoma.

Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single-nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. We systematically screened GWAS-identified candidate SNPs and tested the impact of 30 polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1024 GCA patients and 1118 controls. We observed that CXCR4 rs6430612, TERT rs10069690, and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype (P = 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers (P = 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype (P = 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients were 1.35 compared with the GG genotype (P = 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers (Pinteraction=9.7 × 10-5) and nondrinkers (Pinteraction=4.6 × 10-5). Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.

Cumulative lifetime stress exposure and leukocyte telomere length attrition: The unique role of stressor duration and exposure timing

BackgroundStress exposure occurring across the lifespan increases risk for disease, potentially involving telomere length shortening. Stress exposure during childhood and adulthood has been cross-sectionally linked with shorter telomere length. However, few longitudinal studies have examined telomere length attrition over time, and none have investigated how stressor duration (acute life events vs. chronic difficulties), timing (childhood vs. adulthood), and perceived severity may be uniquely related to telomere length shortening. MethodsTo address these issues, we administered a standardized instrument for assessing cumulative lifetime stress exposure (Stress and Adversity Inventory; STRAIN) to 175 mothers of children with Autism Spectrum Disorder or neurotypical children and measured their leukocyte telomere length (LTL) at baseline and 2 years later. ResultsGreater count of lifetime stressors was associated with shorter LTL at baseline and greater LTL attrition over time. When separating lifetime stressors into acute life events and chronic difficulties, only greater count of chronic difficulties significantly predicted shorter baseline LTL and greater LTL attrition. Similarly, when examining timing of stressor exposure, only greater count of chronic childhood difficulties (age < 18) significantly predicted shorter baseline LTL and greater LTL attrition over the 2-year period in mid-life. Importantly, these results were robust while controlling for stressors occurring during the interim 2-year period. Post-hoc analyses suggested that chronic difficulties occurring during earlier childhood (0–12 years) were associated with greater LTL attrition. Cumulative stressor severity predicted LTL attrition in a parallel manner, but was less consistently associated with baseline LTL. ConclusionsThese data are the first to examine the effects of different aspects of cumulative lifetime stress exposure on LTL attrition over time, suggesting that accumulated chronic difficulties during childhood may play a unique role in shaping telomere shortening in midlife.

Association between prenatal particulate air pollution exposure and telomere length in cord blood: Effect modification by fetal sex

IntroductionIn utero particulate matter exposure produces oxidative stress that impacts cellular processes that include telomere biology. Newborn telomere length is likely critical to an individual's telomere biology; reduction in this initial telomere setting may signal increased susceptibility to adverse outcomes later in life. We examined associations between prenatal particulate matter with diameter ≤2.5 µm (PM2.5) and relative leukocyte telomere length (LTL) measured in cord blood using a data-driven approach to characterize sensitive windows of prenatal PM2.5 effects and explore sex differences. MethodsWomen who were residents of Mexico City and affiliated with the Mexican Social Security System were recruited during pregnancy (n = 423 for analyses). Mothers’ prenatal exposure to PM2.5 was estimated based on residence during pregnancy using a validated satellite-based spatio-temporally resolved prediction model. Leukocyte DNA was extracted from cord blood obtained at delivery. Duplex quantitative polymerase chain reaction was used to compare the relative amplification of the telomere repeat copy number to single gene (albumin) copy number. A distributed lag model incorporating weekly averages for PM2.5 over gestation was used in order to explore sensitive windows. Sex-specific associations were examined using Bayesian distributed lag interaction models. ResultsIn models that included child's sex, mother's age at delivery, prenatal environmental tobacco smoke exposure, pre-pregnancy BMI, gestational age, birth season and assay batch, we found significant associations between higher PM2.5 exposure during early pregnancy (4–9 weeks) and shorter LTL in cord blood. We also identified two more windows at 14–19 and 34–36 weeks in which increased PM2.5 exposure was associated with longer LTL. In stratified analyses, the mean and cumulative associations between PM2.5 and shortened LTL were stronger in girls when compared to boys. ConclusionsIncreased PM2.5 during specific prenatal windows was associated with shorter LTL and longer LTL. PM2.5 was more strongly associated with shortened LTL in girls when compared to boys. Understanding sex and temporal differences in response to air pollution may provide unique insight into mechanisms.