Longer Leukocyte Telomere Length Research Articles

Association of leukocyte telomere length with cardiac conduction disease and sick sinus syndrome

Abstract Background Cardiac conduction disease (CCD) and sick sinus syndrome (SSS) may be related to a degenerative process. Leukocyte telomere length (LTL) is associated with the aging process and age-related degenerative diseases. We aimed to investigate the association between LTL and the risks of CCD/SS, and to explore whether LTL is related with cardiovascular imaging and electrocardiographic (ECG) changes. Methods This is a population-based cross-sectional study of UK Biobank participants without history of CCD/SSS recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging and ECG measurements and incident CCD/SSS were evaluated by multivariable regression models. Results Among the 412,452 white participants, 188,891 (45.8%) were male, with a mean age of 57.3 years. Longer LTL was independently associated with positive cardiac remodeling, including higher left ventricular mass, larger atrial volume, and increased atrial stroke volumes. However, no significant associations were observed with ECG findings including PR interval and P-wave duration. 11991 (2.6%) participants developed CCD and 984 (0.2%) developed SSS. Longer LTL was not associated with younger age. However, longer LTL was not associated with a lower risk of incident CCD (LTL fourth quartile vs. first quartile: hazard ratio, 0.98; 95% CI, 0.97-1.0; P = 0.057) or SSS (LTL fourth quartile vs. first quartile: hazard ratio, 0.98; 95% CI, 0.92-1.05; P = 0.554). Conclusions In this cross-sectional study, longer LTL was associated with a larger atrial size with better atrial function in middle age, but not with ECG changes. However, longer LTL was not associated with a lower risk of incident CCD and SSS.

Association Between Ultraprocessed Foods Consumption and Leucocyte Telomere Length: A Cross-Sectional Study of UK Biobank

Background□ ObjectivesThis study aimed to investigate the association between consumption of ultraprocessed foods and leucocyte telomere length (LTL). MethodsThis cross-sectional study utilized data from the UK Biobank, including a total of 64,690 participants. LTL was measured using qPCR with natural logarithmic conversion and z-score normalization. Dietary data were collected through a 24-h recall questionnaire from 2009 to 2010. Ultraprocessed foods (UPFs) were identified using the NOVA food classification as either a continuous or a categorical variable. Multiple linear regression models were employed to analyze the association between UPF consumption and LTL. ResultsThe included participants had an average age of 56.26 y, of whom 55.2% were female. After adjusting for demographic and health-related variables, LTL exhibited a decrease of 0.005 (95% CI: −0.007, −0.002) with 1 UPF serving increase. Compared with participants consuming ≤3.5 servings/d, those consuming 3.5 to <6 servings showed a shortening of LTL by 0.025 (95% CI: −0.046, −0.003). Participants consuming 6 to ≤8 servings/d and >8 servings/d had LTL shortening of 0.032 (95% CI: −0.054, −0.011) and 0.037 (95% CI: −0.060, −0.014), respectively (P for trend = 0.002). Subgroup analyses by UPF subclasses revealed that the consumption of ready-to-eat/heated food (β: −0.010; 95% CI: −0.016, −0.004), beans and potatoes (β: −0.027; 95% CI: −0.043, −0.012), animal-based products (β: −0.012; 95% CI: −0.020, −0.005), artificial sugar (β: −0.014; 95% CI:−0.025,−0.003), and beverages (β: −0.005; 95% CI: −0.009, −0.001) showed negative associations with LTL. Conversely, breakfast cereals (β: 0.022; 95% CI: 0.006, 0.038) and vegetarian alternatives (β: 0.056; 95% CI:0.026,0.085) showed positive correlations with LTL. ConclusionsOur study found that a higher consumption of total UPF was associated with a shorter LTL. However, some UPFs may be associated with longer LTL, depending on their nutritional composition.

Influence of breed and environment on leukocyte telomere length in cattle.

High milk yield is associated with reduced longevity in high-producing dairy cattle breeds. Pre-term culling leads to high replacement heifer demand and economic losses for the dairy industry. Selection for this trait is limited because of low heritability and difficulties in phenotype measurement. Telomeres are elements found at the ends of chromosomes, consisting of repetitive DNA sequences, several thousand base pairs in length, coupled with nucleoprotein complexes. Eventually, in humans and most other animals, telomere length reduces with age. When telomeric DNA is truncated to a critical length, cell ageing, cell cycle arrest, and apoptosis are induced. As a result, telomere length can be considered as a predictor of health risks and an individual's lifespan. The leukocyte telomere length may be used as a proxy phenotype of productive lifespan to improve cattle selection. Our objectives were to assess the effects of breed and breed group (dairy vs. beef) on the leukocyte telomere length and to estimate the effect of cold climate on this trait in Kalmyk cattle populations from the South (Rostov Oblast) and Far North (Republic of Sakha) regions of Russia. The leukocyte telomere lengths were estimated computationally from whole-genome resequencing data. We leveraged data on leukocyte telomere length, sex, and age of 239 animals from 17 cattle breeds. The breed factor had a significant effect on leukocyte telomere length across our sample. There was no difference in leukocyte telomere length between dairy and beef groups. The population factor had a significant effect on leukocyte telomere length in Kalmyk animals. In conclusion, we found that breed, but not breed group (dairy vs. beef), was significantly associated with leukocyte telomere length in cattle. Residence in colder climates was associated with longer leukocyte telomere length in Kalmyk breed cattle.

Obesity contributes to telomere shortening in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a multifactorial disorder and obesity occurs in 38% to 88% of these women. Although hyperandrogenism may contribute to telomere lengthening, increased body mass index (BMI) is associated with telomere erosion. We sought to compare leukocyte telomere length (LTL) in PCOS women with normal, overweight, and obese BMI. We evaluated the relationship between LTL and clinical variables of PCOS and inflammatory biomarkers independent of BMI. A total of 348 women (243 PCOS and 105 non-PCOS) were evaluated for anthropometric measures, total testosterone, androstenedione, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting insulin and glycemia, lipid profile, homocysteine, C-reactive protein (CRP) and homeostatic model of insulin resistance (HOMA-IR). LTL was measured by qPCR. The PCOS group presented higher weight, waist circumference, BMI, testosterone, LH, fasting insulin, FAI, and HOMA-IR, and lower E2, SHBG, and fasting glycemia measures compared with the non-PCOS. When stratified by BMI, LTL was increased in all subgroups in PCOS compared to non-PCOS. However, in the PCOS group, LTL was lower in overweight (P = 0.0187) and obese (P = 0.0018)compared to normal-weight women. The generalized linear model showed that BMI, androstenedione, homocysteine, and CRP were associated with telomere biology. Women with PCOS had longer LTL, however, overweight or obesity progressively contributes to telomere shortening and may affect reproductive outcomes of PCOS, while androstenedione may increase LTL.

Oxidative Damage and Telomere Length as Markers of Lung Cancer Development among Chronic Obstructive Pulmonary Disease (COPD) Smokers.

Lung cancer (LC) constitutes an important cause of death among patients with Chronic Obstructive Pulmonary Disease (COPD). Both diseases may share pathobiological mechanisms related to oxidative damage and cellular senescence. In this study, the potential value of leucocyte telomere length, a hallmark of aging, and 8-OHdG concentrations, indicative of oxidative DNA damage, as risk biomarkers of LC was evaluated in COPD patients three years prior to LC diagnosis. Relative telomere length measured using qPCR and serum levels of 8-OHdG were determined at the baseline in 99 COPD smokers (33 with LC and 66 age-matched COPD without LC as controls). Of these, 21 COPD with LC and 42 controls had the biomarkers measured 3 years before. Single nucleotide variants (SNVs) in TERT, RTEL, and NAF1 genes were also determined. COPD cases were evaluated, which showed greater telomere length (p < 0.001) and increased serum 8-OHdG levels (p = 0.004) three years prior to LC diagnosis compared to the controls. This relationship was confirmed at the time of LC diagnosis. No significant association was found between the studied SNVs in cases vs. controls. In conclusion, this preliminary study shows that longer leucocyte telomere length and increased 8-OHdG serum levels can be useful as early biomarkers of the risk for future lung cancer development among COPD patients.

The Relationship between Dietary Macronutrient Composition and Telomere Length Among US Adults.

The role of dietary macronutrients and energy intake in the aging process has been well-established. However, previous research has mainly focused on the association between leukocyte telomere length (LTL) and individual macronutrients, while the effects of macronutrient composition on LTL remain unclear. This cross-sectional analysis involved 4130 US adults (44.8±17.0years; 51% female) from the National Health and Nutrition Examination Survey during 1999-2002. A single 24-h dietary recall is used to collect dietary data. The relationship between dietary macronutrient composition and LTL is examined using three-dimensional generalized additive models. After adjustment for age, sex, ethnicity, education, physical activity, BMI, and dietary quality, a three-dimensional association of macronutrient composition with LTL (P=0.02) is revealed. Diets lower in protein (5-10%), higher in carbohydrates (75%), and lower in fat (15-20%) are associated with the longest LTL corresponding to 7.7years of slower biological aging. Diets lowest in protein (5%) and carbohydrate (40%), while highest in dietary fat (55%) are associated with the shortest LTL, corresponding to accelerated biological aging of 4.4years. The associations appeared magnified with higher energy intake. These findings support a complex relationship between dietary macronutrients and biological aging independent of diet quality.

A sex-specific association of leukocyte telomere length with thigh muscle mass.

Telomeres are DNA-protein complexes at the ends of linear chromosomes that protect against DNA degradation. Telomeres shorten during normal cell divisions and therefore, telomere length is an indicator of mitotic-cell age. In humans, telomere shortening is a potential biomarker for disease risk, progression and premature death. Physical activity has been associated with longer leukocyte telomere length (LTL) in some studies. In the current study the relationship between LTL, thigh muscle mass and adipose tissue distribution was explored. We performed anthropometric measurements and magnetic resonance imaging (MRI) measurements of the thigh in 149 healthy subjects (77 male, 72 female). LTL was measured using qPCR. Additionally, the subjects answered a questionnaire concerning their training behaviour. In male subjects, LTL was significantly associated with thigh muscle mass, independent of age and body mass index (p=0.006). In addition, a slight association of LTL with weekly endurance units in the male group was found. These relations could not be observed in females. In conclusion, we observed a sex-specific association of LTL and thigh muscle mass in healthy males. The reason of this sex-specific association is currently unclear, but could be related to different training effects and/or hormonal pathways in men and women.

Associations between Longer Leukocyte Telomere Length and Increased Lung Cancer Risk among Never Smokers in Urban China.

The complex relationship between measured leukocyte telomere length (LTL), genetically predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology. To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's Health Studies (798 cases and 792 controls) and Shanghai Men's Health Studies (161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the ORs and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. In addition, we conducted Mendelian randomization (MR) using MR-PRESSO. We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (P trendLTL = 4×10-6; P trendgTL = 3×10-4). Similarly, among never-smoking men, longer measured LTL was associated with over triple the risk compared with those with the shortest (OR, 3.48; 95% CI, 1.85-6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL, 1.19; 95% CI, 1.03-1.37; P = 0.03). Longer pre-diagnostic LTL is associated with increased lung cancer risk among never smokers. Our findings firmly support the role of longer telomeres in lung carcinogenesis.

The causal relationship between genetically determined telomere length and meningiomas risk.

Studies have shown that longer leukocyte telomere length (LTL) is significantly associated with increased risk of meningioma. However, there is limited evidence concerning the causal association of LTL with benign and malignant meningiomas or with the location of benign tumors. We used three LTL datasets from different sources, designated by name and sample size as LTL-78592, LTL-9190, and LTL-472174. The linkage disequilibrium score (LDSC) was used to explore the association between LTL and meningioma. We utilized two-sample bidirectional Mendelian randomization (TSMR) to evaluate whether LTL is causally related to meningioma risk. We adjusted for confounders by conducting multivariable Mendelian randomization (MVMR). In the LTL-78592, longer LTL was significantly associated with increased risk of malignant [odds ratio (OR) = 5.14, p = 1.04 × 10-5], benign (OR = 4.81, p < 0.05), benign cerebral (OR = 5.36, p < 0.05), and benign unspecified meningioma (OR = 8.26, p < 0.05). The same results were obtained for the LTL-9190. In the LTL-472174, longer LTL was significantly associated with increased risk of malignant (OR = 4.94, p < 0.05), benign (OR = 3.14, p < 0.05), and benign cerebral meningioma (OR = 3.59, p < 0.05). Similar results were obtained in the MVMR. In contrast, only benign cerebral meningioma displayed a possible association with longer LTL (OR = 1.01, p < 0.05). No heterogeneity or horizontal pleiotropy was detected. In brief, genetically predicted longer LTL may increase the risk of benign, malignant, and benign cerebral meningiomas, regardless of the LTL measure, in European populations.

The relationship between longer leukocyte telomeres and dNCR in non-cardiac surgery patients: a retrospective analysis

BackgroundCognitive decline following surgery is a common concern among elderly individuals. Leukocyte telomere length (LTL) can be assessed as a biological clock connected to an individual lifespan. However, the mechanisms causing this inference are still not fully understood. As a result of this, LTL has the potential to be useful as an aging-related biomarker for assessing delayed neurocognitive recovery (dNCR) and related diseases.MethodsFor this study, 196 individuals over 60 who were scheduled due to major non-cardiac surgical operations attended neuropsychological testing before surgery, followed by additional testing one week later. The finding of dNCR was based on a measured Z-score ≤ -1.96 on two or more separate tests. The frequency of dNCR was presented as the primary outcome of the study. Secondly, we evaluated the association between dNCR and preoperative LTL.ResultsOverall, 20.4% [40/196; 95% confidence interval (CI), 14.7–26.1%] of patients exhibited dNCR 1-week post-surgery. Longer LTL was identified as a predictor for the onset of early cognitive impairment resulting in postoperative cognitive decline [odds ratio (OR), 14.82; 95% CI, 4.01–54.84; P < 0.001], following adjustment of age (OR, 12.33; 95% CI, 3.29–46.24; P < 0.001). The dNCR incidence based on LTL values of these patients, the area under the receiver operating characteristic (ROC) curve was 0.79 (95% CI, 0.722–0.859; P < 0.001). At an optimal cut-off value of 0.959, LTL values offered respective specificity and sensitivity values of 64.7% and 87.5%.ConclusionsIn summary, the current study revealed that the incidence of dNCR was strongly associated with prolonged LTL. Furthermore, this biomarker could help identify high-risk patients and offer insight into the pathophysiology of dNCR.

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.

Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5days (n = 54,180). Relative mean LTL at baseline (5-6years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity > 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant (P = .171).

Association of Longer Leukocyte Telomere Length With Cardiac Size, Function, and Heart Failure

Longer leukocyte telomere length (LTL) is associated with a lower risk of adverse cardiovascular outcomes. The extent to which variation in LTL is associated with intermediary cardiovascular phenotypes is unclear. To evaluate the associations between LTL and a diverse set of cardiovascular imaging phenotypes. This is a population-based cross-sectional study of UK Biobank participants recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging measurements and incident heart failure (HF) were evaluated by multivariable regression models. Genetic associations between LTL and significantly associated traits were investigated by mendelian randomization. Data were analyzed from January to May 2023. LTL. Cardiovascular imaging traits and HF. Of 40 459 included participants, 19 529 (48.3%) were men, and the mean (SD) age was 55.1 (7.6) years. Longer LTL was independently associated with a pattern of positive cardiac remodeling (higher left ventricular mass, larger global ventricular size and volume, and higher ventricular and atrial stroke volumes) and a lower risk of incident HF (LTL fourth quartile vs first quartile: hazard ratio, 0.86; 95% CI, 0.81-0.91; P = 1.8 × 10-6). Mendelian randomization analysis suggested a potential causal association between LTL and left ventricular mass, global ventricular volume, and left ventricular stroke volume. In this cross-sectional study, longer LTL was associated with a larger heart with better cardiac function in middle age, which could potentially explain the observed lower risk of incident HF.

Leukocyte telomere length predicts subsequent infectious morbidity among Colombian schoolchildren.

Telomere length (TL) attrition is related to chronic disease risk. However, less is known on whether TL predicts infectious outcomes, especially in childhood. We examined whether leukocyte TL (LTL) was associated with subsequent infectious morbidity in schoolchildren. We assessed LTL in 717 Colombian children 5-12 years-old at the beginning of a school year and followed them through the year for daily occurrence of common infection symptoms and doctor visits. We estimated adjusted incidence rate ratios (IRR) with 95% confidence intervals (CI) of gastrointestinal and respiratory syndromes for quartiles of standardized LTL Z score and per unit LTL Z score. A longer LTL was associated with increased incidence of all infectious morbidity syndromes considered. Adjusted IRR (95% CI) per unit LTL Z score were 1.55 (1.20, 2.00) for diarrhea with vomiting, 1.34 (1.13, 1.60) for cough with fever, 1.70 (1.28, 2.28) for ear infection, and 1.66 (1.36, 2.02) for doctor visits with symptoms. Longer LTL is related to increased incidence of common infectious morbidities in middle childhood.

Investigating the impact of metabolic syndrome traits on telomere length: a Mendelian randomization study.

Observational studies have reported bidirectional associations between metabolic syndrome (MetS) traits and short leukocyte telomere length (LTL), a TL marker in somatic tissues and a proposed risk factor for age-related degenerative diseases. However, in Mendelian randomization studies, longer LTL has been paradoxically associated with higher MetS risk. This study investigated the hypothesis that shorter LTL might be a consequence of metabolic dysfunction. This study undertook univariable and multivariable Mendelian randomization. As instrumental variables for MetS traits, all of the genome-wide significant independent signals identified in genome-wide association studies for anthropometric, glycemic, lipid, and blood pressure traits conducted in European individuals were used. Summary-level data for LTL were obtained from a genome-wide association study conducted in the UK Biobank. Higher BMI was associated with shorter LTL (β = -0.039, 95% CI: -0.058 to -0.020, p = 5 × 10-5 ) equivalent to 1.70 years of age-related LTL change. In contrast, higher low-density lipoprotein cholesterol was associated with longer LTL (β = 0.022, 95% CI: 0.007 to 0.037, p = 0.003) equivalent to 0.96 years of age-related LTL change. Mechanistically, increased low-grade systemic inflammation, as measured by circulating C-reactive protein, and lower circulating linoleic acid levels might link higher BMI to shorter LTL. Overweight and obesity might promote the development of aging-related degenerative diseases by accelerating telomere shortening.

Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank

Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank. In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A1c (HbA1c), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA1c lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA1c on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design. GPD1-induced HbA1c lowering was associated with younger PhenoAge (β -5·26, 95% CI -6·69 to -3·83) and longer leukocyte telomere length (β 0·28, 0·03 to 0·53), and AMPKγ2 (PRKAG2)-induced HbA1c lowering was associated with younger PhenoAge (β -4·88, -7·14 to -2·62) but not with longer leukocyte telomere length. Genetically predicted HbA1c lowering was associated with younger PhenoAge (β -0·96 per SD lowering of HbA1c, 95% CI -1·19 to -0·74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (β -0·36, 95% CI -0·59 to -0·13) but not with leukocyte telomere length. This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity. Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.

Dietary Patterns and Practices and Leucocyte Telomere Length: Findings from the UK Biobank.

Shorter telomere length (TL) is associated with risk of several age-related diseases and decreased life span, but the extent to which dietary patterns and practices associate with TL is uncertain. This study aimed to investigate the association of dietary patterns and practices and leucocyte TL (LTL). This was a cross-sectional study. Data collected voluntarily from up to 422,797 UK Biobank participants, during 2006-2010. LTL was measured as a ratio of the telomere repeat number to a single-copy gene and was loge-transformed and standardized (z-LTL). Adherence a priori to a Mediterranean-style diet was assessed through the MedDietScore. Principal component analysis was used to a posteriori extract the "Meat" and "Prudent" dietary patterns. Additional dietary practices considered were the self-reported adherence to "Vegetarian" diet, "Eating 5-a-day of fruit and vegetables" and "Abstaining from eggs/dairy/wheat/sugar." Associations between quintiles of dietary patterns or adherence to dietary practices with z-LTL were investigated through multivariable linear regression models (adjusted for demographic, lifestyle, and clinical characteristics). Adherence to the "Mediterranean" and the "Prudent" patterns, was positively associated with LTL, with an effect magnitude in z-LTL of 0.020 SD and 0.014 SD, respectively, for the highest vs the lowest quintile of adherence to the pattern (both P values < 0.05). Conversely, a reversed association between quintile of the "Meat" pattern and LTL was observed, with z-LTL being on average shorter by 0.025 SD (P= 6.12×10-05) for participants in the highest quintile of the pattern compared with the lowest quintile. For adherents to "5-a-day" z-LTL was on average longer by 0.027 SD (P= 5.36×10-09), and for "abstainers," LTL was shorter by 0.016 SD (P= 2.51×10-04). The association of LTL with a vegetarian diet was nonsignificant after adjustment for demographic, lifestyle, and clinical characteristics. Several dietary patterns and practices associated with beneficial health effects are significantly associated with longer LTL. However, the magnitude of the association was small, and any clinical relevance is uncertain.

Association between Residential Exposure to Air Pollution and Incident Coronary Heart Disease Is Not Mediated by Leukocyte Telomere Length: A UK Biobank Study.

Higher air pollution exposure and shorter leukocyte telomere length (LTL) are both associated with increased risk of coronary heart disease (CHD), and share plausible mechanisms, including inflammation. LTL may serve as a biomarker of air pollution exposure and may be intervened with to reduce the risk of CHD. To the best of our knowledge, we are the first to test the mediation effect of LTL in the relationship between air pollution exposure and incident CHD. Using the UK Biobank (UKB) data (n = 317,601), we conducted a prospective study linking residential air pollution exposure (PM2.5, PM10, NO2, NOx) and LTL to incident CHD during a mean follow-up of 12.6 years. Cox proportional hazards models and generalized additive models with penalized spline functions were used to model the associations of pollutant concentrations and LTL with incident CHD. We found non-linear associations of air pollution exposure with LTL and CHD. Pollutant concentrations in the lower range were decreasingly associated with longer LTL and reduced risk of CHD. The associations between lower pollutant concentrations and reduced risk of CHD, however, were minimally mediated by LTL (<3%). Our findings suggest that air pollution influences CHD through pathways that do not involve LTL. Replication is needed with improved measurements of air pollution that more accurately assesses personal exposure.

Association between genetically determined telomere lengthand health-related outcomes: A systematic review andmeta-analysis of Mendelian randomization studies.

Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta-analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length.

Abstract 3009: Measured and genetically-predicted leukocyte telomere length and lung cancer risk in the prospective UK Biobank

Abstract Telomere length is a biomarker reflective of aging and genomic instability. We previously found associations between longer measured leukocyte telomere length (LTL) and increased lung cancer risk in a pooled nested case-control study with 847 cases. Additionally, we reported that longer genetically-predicted telomere length (gTL) using a polygenic risk score (PRS) with 7 single nucleotide polymorphisms (SNPs) was associated with increased lung cancer risk among never-smoking Asian women. To investigate further, we conducted prospective cohort analyses of pre-diagnostic LTL and gTL in relation to risk of overall lung cancer and its subtypes in the UK Biobank. With over triple the number of cases, we had expanded statistical power to investigate lung cancer, adenocarcinoma (LUAD), and squamous cell carcinoma (SCC) among subgroups defined by smoking status and sex in this predominantly European study population. We analyzed 371,890 participants at baseline. Over the 12.36±1.64SD year follow-up, 2829 incident lung cancer cases were diagnosed, including 1078 LUAD and 487 SCC. LTL was measured using qPCR. Using European data, we calculated a weighted PRS for gTL. The PRS was derived from 130 linkage disequilibrium pruned SNPs (r2 &amp;gt; 0.01) associated with longer LTL in the UK Biobank. Multivariable Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of lung cancer in relation to log-transformed continuous and quartiles (Q) of LTL and gTL separately. Associations were estimated in the overall analytic sample and among smoking-sex subgroups. We conducted Mendelian Randomization (MR) analyses using MR-PRESSO with 130 genetic instruments to assess causal associations between LTL and lung cancer among Europeans.We found a strong dose-response relationship between longer LTL and increased lung cancer risk (p-trend= 2.6E-05), with the highest quartile being statistically significant (HRQ4vs.Q1=1.27, 95%CI: 1.15-1.42). The association was apparent for LUAD (p-trend=6.6E-10; HRQ4vs.Q1=1.78, 95%CI: 1.50-2.12), but not SCC. The lung cancer associations were prominent among never-smoking women (p-trend=4.0E-05) and never-smoking men (p-trend=2.0E-03). We also found dose-response relationships between longer gTL and risk of lung cancer (p-trend=4.2E-06) and LUAD (p-trend=2.1E-08). Additionally, we found evidence for causal associations between longer LTL and risk of lung cancer (HRper 1 SD gTL=1.87, 95%CI: 1.49-2.36, p=4.0E-07) and LUAD (HRper 1 SD gTL=2.45, 95%CI: 1.69-3.57, p=6.5E-06). Longer leukocyte telomere length potentially reflects biological processes relevant to the pathogenesis of lung cancer, particularly LUAD. Citation Format: Jason Yat-Yang Wong, Batel Blechter, Aubrey K. Hubbard, Jianxin Shi, Wei Hu, Mohammad Rahman, Shahinaz Gadalla, Mitchell Machiela, Nathaniel Rothman, Qing Lan. Measured and genetically-predicted leukocyte telomere length and lung cancer risk in the prospective UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3009.

Abstract 4220: Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study

Abstract Background: Previous epidemiologic studies have reported increased risks of certain cancers in relation to specific pesticide exposures, although the mechanisms underlying many of these associations remain poorly understood. Within the Biomarkers of Exposure and Effect in Agriculture (BEEA) study, a molecular epidemiologic investigation of pesticide applicators in Iowa and North Carolina, we examined whether occupational use of pesticides is associated with alterations in leukocyte telomere length. Telomeres are essential in maintaining chromosomal stability and altered telomere length has been linked to various malignancies. Methods: Relative telomere length (RTL) was measured using quantitative PCR in leukocytes from 1,539 male pesticide applicators ≥50 years of age. Using self-reported information on pesticide use, we characterized lifetime use of specific pesticides in terms of ever use and intensity-weighted lifetime days (IWLDs), a metric integrating total lifetime days of use and other factors influencing exposure. Multivariable linear regression models were used to estimate differences in geometric mean RTL (and corresponding 95% confidence intervals) by ever vs. never use of 48 pesticides and in exposure-response analyses for IWLDs of use of 46 pesticides, adjusting for age, state of residence, race/ethnicity, body mass index, and cigarette smoking status and pack-years. Results: Among ever users of the insecticides lindane and aldicarb, mean RTL was significantly longer compared to never users (p=0.01 and 0.03, respectively); in exposure-response analyses, we also observed a suggestive but non-statistically significant trend between increasing IWLDs of lindane use and longer RTL (p-trend=0.07). Higher IWLDs of use of the insecticide diazinon was also associated with longer RTL (p-trend=0.03) while increasing IWLDs of the insecticide heptachlor and the herbicide 2,4,5-TP were associated with shorter RTL (p-trends=0.04 and 0.03, respectively). Conclusions: This is, to our knowledge, the largest investigation of occupational pesticide use and RTL to date. Our findings provide novel evidence suggesting that use of certain pesticides could be associated with altered leukocyte telomere length. Notably, diazinon and lindane have previously been associated with increased risks of lung and lymphoid malignancies, respectively, and longer leukocyte telomere length has been implicated in the development of these cancers. Citation Format: Patricia A. Erickson, Vicky C. Chang, Casey L. Dagnall, Kedest Teshome, Mitchell J. Machiela, Kathryn H. Barry, Shahinaz M. Gadalla, Laura E. Beane Freeman, Gabriella Andreotti, Jonathan N. Hofmann. Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4220.