Leukocyte telomere length (LTL) is associated with multiple conditions, including cardiovascular diseases and neoplasms, yet their differential associations across diverse individuals are largely unknown. We estimated LTL from blood-derived whole-genome sequences in the All of Us research program (n = 242,494) with diverse ancestries across the USA. LTL was associated with lifestyle, socioeconomic status, biomarkers, cardiometabolic diseases and neoplasms, with heterogeneity across genetic ancestries and sexes. Geographical analysis revealed that significantly longer LTL clustered in the West Coast and Central Midwest, while significantly shorter LTL clustered in the Southeast in the USA. Genome-wide association studies and meta-analyses with the UK Biobank (n = 679,972) found 234 nonoverlapping loci, of which 37 were novel. We identified six novel loci unique to non-European-like populations and one specific to women. Rare variant analysis uncovered nine novel genes, providing new functional insights. Our study highlighted underappreciated contextual heterogeneities of phenomic and genomic associations with LTL.

BACKGROUND:Major depressive disorder (MDD) is more prevalent in women and associated with shorter telomere length, a marker of biological ageing, and an increased risk of age-related disease. However, the precise influence of depression-related genetic and environmental risk factors on telomere dynamics remains a topic of debate. METHODS:We examined leukocyte relative telomere length (RTL) and longitudinal telomere attrition in 958 women (median age: 58 years) from the TwinsUK cohort. RTL was measured using quantitative PCR from up to four timepoints. Associations with self-reported depression, antidepressant use, lifestyle and socioeconomic factors, and polygenic risk scores (PGS) for MDD and comorbid age-related diseases were assessed using linear mixed models. RESULTS:Over a median 6-year follow-up, telomere length declined annually by 1.3 % of baseline RTL. Depression showed a borderline association with shorter RTL (p = 0.06), while a nominal association was observed between antidepressant use and shorter RTL (p = 0.02), replicating previous findings. No significant associations were observed for PGS related to MDD. PGS for coronary artery disease was associated with shorter RTL (p = 0.02), while other trait PGS showed inconsistent associations with RTL or attrition. Higher waist-to-hip ratio was associated with faster telomere attrition longitudinally (p = 0.01). CONCLUSIONS:Our findings suggest depression and its genetic liability are not directly associated with telomere length or attrition in older women. In contrast, waist-to-hip ratio, a modifiable factor, was linked to accelerated telomere shortening, pointing to central adiposity as a potential intervention target with relevance for both mental and physical health.

BACKGROUND:Infections may increase the risk of age-related diseases such as dementia. Accelerated immunological ageing, measurable by telomere length (TL), may be a potential mechanism. However, the relationship between different infections and TL or telomere attrition remains unclear. This systematic review synthesises existing evidence on whether infections contribute to TL or telomere attrition and highlights research gaps to inform future studies. OBJECTIVE:To summarise the literature on associations between infections and telomere length or attrition. METHODS:We conducted comprehensive searches across six databases (MEDLINE, EMBASE, Web of Science, Scopus, Global Health, Cochrane Library) from inception to 22 May 2025, using concepts of infections, TL, and study type. Two researchers independently screened studies, extracted data, and assessed risk of bias (ROB) using the ROBINS-E tool. Meta-analysis was unfeasible due to heterogeneity, so a narrative synthesis was conducted. Studies were grouped by infection type, telomere measurement assay, cell type, and statistical approach. A GRADE assessment was performed to evaluate evidence quality. RESULTS:Our searches identified 10,349 studies, of which 73 met eligibility criteria. Most (59) were cross-sectional and most were published after 2000, with the earliest from 1996. Most studies were from the USA (17). HIV was the most frequently studied infection (35 studies), with 79% (excluding overlapping samples) reporting an association between HIV and reduced TL or increased telomere attrition. Findings for other infections, including herpesviruses and Human Papillomavirus were more variable. Variation in infection type, measurement assay, cell type, and statistical approach made cross-study comparisons challenging. Most studies had a high ROB, mainly due to unmeasured confounding. The GRADE assessment rated evidence quality as very low. CONCLUSIONS:Our review highlights a potential link between HIV and TL and telomere attrition. More robust longitudinal studies with standardised measurements and better confounder control are needed, particularly for non-HIV infections. PROSPERO (ID:CRD42023444854).

Background Deterioration of the cardiac conduction system is an important manifestation of cardiac ageing. Cellular ageing is accompanied by telomere shortening and telomere length (TL) is often regarded as a marker of biological ageing, potentially adding information regarding conduction disease over and above chronological age. We therefore sought to evaluate the association between leucocyte telomere length (LTL) on two related, but distinct aspects of the cardiac conduction system: ECG measures of conduction (PR interval and QRS duration) and incident pacemaker implantation in a large population-based cohort.Methods In the UK Biobank, we measured PR interval and QRS duration from signal-averaged ECG waveforms in 59 868 and 62 266 participants, respectively. Incident pacemaker implantation was ascertained using hospital episode data from 420 071 participants. Associations with LTL were evaluated in (Cox) multivariable regression analyses adjusted for potential confounders. Putative causal effects of LTL were investigated by mendelian randomisation (MR).Results Mean PR interval and QRS duration were 144.2 ms (+/- 20.4) and 92.3 ms (+/- 7.8), respectively, and there were 7169 (1.7%) incident pacemaker implantations, during a median follow-up period of 13.6 (IQR 1.5) years. LTL was significantly associated with PR interval (0.19 ms (95% CI: 0.03 to 0.35), per 1 SD shorter LTL, p=0.021), but not QRS duration. After adjusting for age, sex and cardiovascular risk factors, shorter LTL remained associated with an increased risk for incident pacemaker implantation (HR per SD decrease in LTL: 1.03 (95% CI: 1.01 to 1.06), p=0.012). MR analysis showed a trend towards an association of shorter LTL with longer PR interval and higher risk of pacemaker implantation but was likely to be underpowered.Conclusions Shorter LTL was significantly, and possibly causally, associated with prolongation of atrioventricular conduction and pacemaker implantation, independent of traditional cardiovascular risk factors. Our findings support further research to explore the role of ageing on cardiac conduction beyond chronological age.

Telomere attrition is a biomarker of cellular aging, influenced by lifestyle and dietary exposures. The specific role of macronutrient composition, particularly polyunsaturated fatty acids (PUFAs), in telomere dynamics remains insufficiently explored. We hypothesized that higher intake of specific macronutrients, particularly PUFAs, would be positively associated with leukocyte telomere length (LTL). In this cross-sectional study of 143,553 UK Biobank participants aged 40-69 years, we examined associations between macronutrient intake and standardized LTL (z-LTL), measured as the log-transformed telomere repeat to single-copy gene ratio. Dietary intake was assessed using repeated 24-hour web-based dietary recalls. Multivariable linear regression models were used to estimate associations between macronutrients (% of total energy intake) and z-LTL, adjusting for demographic, lifestyle, and clinical covariates. Effect estimates were translated into age-equivalent changes in LTL. Carbohydrate and total fat intake were positively associated with z-LTL, corresponding to age-related LTL differences of approximately 30-40 days. In energy substitution models, n - 3 PUFA intake showed a stronger positive association with z-LTL than other fats, with adherence to recommended intake associated with differences equivalent to over 2 years (P < .0001) of age-related telomere shortening, whereas no evidence of an association for MUFA was observed. Energy-adjusted fibre intake was associated with an age-related change of LTL equivalent to 1 year (P < .0001). These findings suggest that dietary composition, particularly n - 3 PUFA intake, may be linked with LTL in a manner consistent with healthier cellular aging. Further longitudinal and experimental studies are needed to confirm these associations and explore their implications for dietary guidance.

Background: Leukocyte telomere length (LTL) is an age-related marker strongly associated with neoplasms and cardiometabolic disease. LTL is also intimately linked with clonal hematopoiesis of indeterminate potential (CHIP), a recently described risk factor for cardiovascular disease (CVD). However, population-scale investigations of LTL in diverse backgrounds are limited, and geolocational variance has not been studied. Method: LTL and CHIP were derived using blood-derived whole genome sequencing data from 244,819 diverse U.S. residents in the NIH All of Us Research Program (AoU). We performed association analyses of LTL with CHIP and other available health-related traits, Phecode, as well as geolocation data by ZIP code. Genome-wide association study (GWAS) of LTL in AoU and meta-analysis with UK Biobank were performed. All association tests were adjusted for age, sex, sequencing site, and the first 10 genetic principal components with multiple test corrections. Mediation analysis was adjusted for additional risk factors for CVD. Result: Among 244,819 AoU participants, 146,717 (59.9%) were female with mean (standard deviation) age 51.8 (±16) years. Estimated LTL correlated strongly with age, sex, and genetic ancestry in AoU. Socioeconomic status, lifestyle variables, anthropometry, blood biomarkers (e.g., lipids and glucose), and vital signs were associated with LTL in AoU. Phecode analysis showed LTL is associated with neoplasms and age-related conditions, including CVDs. LTL mediated some of the observed increased coronary artery disease risk among individuals with hematologic malignancies ( P < 2 × 10 -16 ). Significantly longer LTL clustered in the West Coast and Central Midwest ( P = 0.001 and 0.033, respectively), while significantly shorter LTL clustered in the Southeast ( P = 0.001) (Figure). GWAS meta-analyses identified 197 loci, of which 36 (18%) were novel, including ancestry-specific loci. Rare variant aggregation test found 9 novel associated genes. Conclusions: LTL is a marker of biological age that is associated and interacts with neoplasms, CVDs, and its various risk factors, with notable geographic variability within the U.S. Germline genetic analyses of LTL yield new insights into drivers of LTL.

Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis. Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.

To investigate whether micronutrient intake from food as well as the regular uptake of specific vitamins and/or minerals are associated with leucocyte telomere length (LTL). This is a cross-sectional study using data from 422,693 UK Biobank participants aged from 40 to 69 years old, during 2006–2010. LTL was measured as the ratio of telomere repeat number to a single–copy gene and was loge-transformed and z-standardized (z-LTL). Information concerning supplement use was collected at baseline through the touchscreen assessment, while micronutrient intake from food were self-reported through multiple web-based 24 h recall diaries. The association between micronutrient intake or supplement use and z-LTL was assessed using multivariable linear regression models adjusting for demographic, lifestyle and clinical characteristics. About 50

Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age -related changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration, and chemotaxis in human monocyte-derived macrophages (MDMs) from older (>50 years old) compared with younger (18-30 years old) donors, alongside downregulation of transcription factors MYC and USF1. In MDMs from young donors, knockdown of MYC or USF1 decreases phagocytosis and chemotaxis and alters the expression of associated genes, alongside adhesion and extracellular matrix remodeling. A concordant dysregulation of MYC and USF1 target genes is also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs leads to an increased cell size, altered morphology, and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age -related functional decline and identify downstream targets to improve macrophage function in aging.

Vasiliki Bountziouka,1,2 Anna L. Hansell,3,4 Christopher P. Nelson,1,2 Veryan Codd,1,2 and Nilesh J. Samani1,2 Department of Cardiovascular Sciences, University of Leicester, Leicester, UK National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK Centre for Environmental Health and Sustainability, University of Leicester, Leicester, UK NIHR Health Protection Research Unit in Environmental Exposures and Health, University of Leicester, Leicester, UK

Importance 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. Objective To evaluate the associations between LTL and a diverse set of cardiovascular imaging phenotypes Design, Setting, and Participants 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. Exposure LTL. Main Outcomes and Measures Cardiovascular imaging traits and HF. Results 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. Conclusions and Relevance 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.

Background 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. Objective This study aimed to investigate the association of dietary patterns and practices and leucocyte TL (LTL). Design This was a cross-sectional study. Participants and setting Data collected voluntarily from up to 422,797 UK Biobank participants, during 2006-2010. Main outcome measures LTL was measured as a ratio of the telomere repeat number to a single-copy gene and was loge-transformed and standardized (z-LTL). Statistical analyses performed Adherence a priori to a Mediterranean-style diet was assessed through the MedDietScore. Principal component analysis was used to a pos-teriori 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 be-tween 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). Results 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 = 6.12x10-05) 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 = 5.36x10-09), and for "abstainers," LTL was shorter by 0.016 SD (P = 2.51x10-04). The association of LTL with a vegetarian diet was nonsignificant after adjustment for de-mographic, lifestyle, and clinical characteristics. Conclusions Several dietary patterns and practices associated with beneficial health effects are significantly associated with longer LTL. However, the magnitude of the as-sociation was small, and any clinical relevance is uncertain. J Acad Nutr Diet. 2023;123(6):912-922.

Background:Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours.Methods:We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343).Results:Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity.Conclusions:This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.Funding:Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17‐022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).

Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized. Here we show that leucocyte telomere length (LTL) is associated with multi-modal MRI phenotypes in 31,661 UK Biobank participants. Longer LTL is associated with: i) larger global and subcortical grey matter volumes including the hippocampus, ii) lower T1-weighted grey-white tissue contrast in sensory cortices, iii) white-matter microstructure measures in corpus callosum and association fibres, iv) lower volume of white matter hyperintensities, and v) lower basal ganglia iron. Longer LTL was protective against certain related clinical manifestations, namely all-cause dementia (HR 0.93, 95% CI: 0.91–0.96), but not stroke or Parkinson’s disease. LTL is associated with multiple MRI endophenotypes of neurodegenerative disease, suggesting a pathway by which longer LTL may confer protective against dementia.

OBJECTIVE:Older men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men.DESIGN:Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years.METHODS:Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL.RESULTS:In 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001).CONCLUSIONS:Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.