The highly proliferative gut tissue exhibits rapid telomere shortening with systemic effects on the host organism. Recent studies have demonstrated a bidirectionality in interactions between intestinal telomere length dynamics and the composition and activity of the gut microbiome thus linking processes of inflammation, dysbiosis and aging across different vertebrate species.

UNASSIGNED: Telomere has been recognized as a biomarker of accelerating aging, and telomere length (TL) shortening is closely related to diverse chronic illnesses. Human serum metabolites have demonstrated close correlations with TL maintenance or shortening in observational studies. Nevertheless, little is known about the underlying pathological mechanisms, and Mendelian randomization (MR) analysis of serum metabolites may provide a more comprehensive understanding of the potential biological process.
UNASSIGNED: We employed a two-sample MR analysis method to assess the causal links between 486 serum metabolites and TL. We applied the inverse-variance weighted (IVW) approach as our primary analysis, and to assure the stability and robustness of our results, additional analysis methods including the weighted median, MR-Egger, and weighted mode were conducted. MR-Egger intercept test was utilized to detect the pleiotropy. Cochran\'s Q test was implemented to quantify the extent of heterogeneity. Furthermore, the pathway analysis was conducted to identify potential metabolic pathways.
UNASSIGNED: We identified 11 known blood metabolites associated with TL. Among these metabolites, four were lipid (taurocholate, dodecanedioate, 5,8-tetradecadienoate, and 15-methylpalmitate), one amino acid (levulinate (4-oxovaleate)), one carbohydrate (lactate), one nucleotide (pseudouridine), one energy (phosphate), and three xenobiotics (2-hydroxyacetaminophen sulfate, paraxanthine, and ergothioneine). The known protective metabolites included levulinate (4-oxovaleate), dodecanedioate, 5,8-tetradecadienoate, lactate, phosphate, paraxanthine, and ergothioneine. Multiple metabolic pathways have been identified as being implicated in the maintenance of telomere length.
UNASSIGNED: Our MR analysis provided suggestive evidence supporting the causal relationships between 11 identified blood metabolites and TL, necessitating further exploration to clarify the mechanisms by which these serum metabolites and metabolic pathways may affect the progression of telomeres.

UNASSIGNED: Leukocyte telomere length (LTL) shortens with age and may be related to multiple sclerosis (MS).
UNASSIGNED: We hypothesize that chronologically young people with MS (pwMS) with short LTL behave similarly to older MS subjects.
UNASSIGNED: Prospective 2-year study including two cohorts of young (18-35 years) and elderly (⩾50 years) pwMS with similar disease duration. Physical and cognitive evaluation, 3 T brain magnetic resonance imaging (MRI) and retinal nerve fiber layer (RNFL) measurement by optical coherence tomography were performed. LTL was measured by quantitative polymerase chain reaction assay.
UNASSIGNED: Around 105 patients were included, 57 young and 48 elderly. LTL was shorter in older patients (0.61 versus 0.57, p = 0.0081) and in males (female, 0.60; male, 0.59; p = 0.01335). For every 10-year increase in age, LTL was 0.02 U shorter. In elderly, LTL correlated with disease duration (p = 0.05), smoking (p = 0.03), Expanded Disability Status Scale (EDSS; p = 0.004), 9HPT (p = 0.00007), high-efficacy therapies (p = 0.001), brain lesion volume (BLV) (p = 0.011), and number of T2 lesions (p = 0.01). In young patients, LTL did not correlate with clinical or radiological variables. For every 0.1 U shorter LTL, gray matter volume decreased 1.75 cm3 and white matter volume 1.78 cm3.
UNASSIGNED: LTL correlated with disability and BLV in elderly. Besides LTL shortening, other variables should be considered as mechanisms of neurodegeneration that might be involved in aging pwMS.

OBJECTIVE: Several studies demonstrated potential associations between the telomere length (TL) in leukocytes and psoriasis or psoriatic arthritis (PsA). This study aimed to investigate whether there was the causal genetic relationship between TL and psoriatic diseases bidirectionally.
METHODS: Two-sample univariable MR (UVMR) analysis was applied to explore the bidirectional causal association of TL with overall psoriasis, psoriasis vulgaris (PV) and PsA. Multivariable MR (MVMR) and the mediation effects analysis were applied to test whether the bidirectional associations between TLs and psoriasis were mediated by body mass index (BMI), alcohol, and smoking status.
RESULTS: According to the UVMR results, a negative causal impact of TL on the risk of overall psoriasis was found (OR = 0.775; 95% CI: 0.646-0.931; P = 6.36 × 10-3), and a similar trend was observed in the reversed direction for psoriasis-TL (IVW-β = -0.0097; 95% CI: -0.0170 to -0.0024; P = 9.12 × 10-3). There were also negative genetic associations between TL and PV bidirectionally. The independent association of genetically predicted TL and overall psoriasis persisted in the MVMR results controlled for BMI, smoking, and alcohol consumption (ORMVMR = 0.736; 95% CI: 0.597 to 0.907; P = 0.004). An independent significant association of genetic predisposition to PsA with TL was also found (βMVMR = 0.006; 95% CI: 0.001 to 0.012; P = 0.033). The mediation analysis showed that BMI partially mediated the reverse association between PSO and TL.
CONCLUSIONS: This MR study revealed an association between genetic indicators of shortened TL and risk of overall psoriasis and PV, and genetic predisposition to PsA was associated with longer TL. Key message What is already known on this topic?  Telomere length (TL) is acknowledged to reflect an individual\'s biological age but is also associated with dysregulated immune function and immunosenescence. The impact of aging on psoriasis is controversial. Existing evidence suggests that aging may influence pathological changes and clinical course but whether aging is an independent risk factor remains unclear. What this study adds?  The current study found an association between genetic indicators of shortened TL and the risk of overall psoriasis and psoriasis vulgaris (PV). There was a bidirectional link between genetically indicated overall psoriasis and shortened TL. A possible positive genetic association between PsA and TL was also found. How this study might affect research, practice, or policy?  Our study may provide evidence for TL as new diagnostic and therapeutic strategies in clinical practices for psoriasis. Greater efforts to psoriasis management may substantially reduce the aging attributable to TL shortening. Future large-scale GWAS and experimental studies are warranted to examine the mechanistic basis for links between TL and psoriasis to improve understanding and illuminate possible therapeutic targets for psoriatic disease.

UNASSIGNED: The purpose of this study is to investigate the causal effect and potential mechanisms between telomere length and abdominal aortic aneurysm (AAA).
UNASSIGNED: Summary statistics of telomere length and AAA were derived from IEU open genome-wide association studies and FinnGen R9, respectively. Bi-directional Mendelian randomization (MR) analysis was conducted to reveal the causal relationship between AAA and telomere length. Three transcriptome datasets were retrieved from the Gene Expression Omnibus database and telomere related genes was down-loaded from TelNet. The overlapping genes of AAA related differentially expressed genes (DEGs), module genes, and telomere related genes were used for further investigation. Telomere related diagnostic biomarkers of AAA were selected with machine learning algorisms and validated in datasets and murine AAA model. The correlation between biomarkers and immune infiltration landscape was established.
UNASSIGNED: Telomere length was found to have a suggestive negative associations with AAA [IVW, OR 95%CI = 0.558 (0.317-0.701), P < 0.0001], while AAA showed no suggestive effect on telomere length [IVW, OR 95%CI = 0.997 (0.990-1.004), P = 0.4061]. A total of 40 genes was considered as telomere related DEGs of AAA. PLCH2, PRKCQ, and SMG1 were selected as biomarkers after multiple algorithms and validation. Immune infiltration analysis and single cell mRNA analysis revealed that PLCH2 and PRKCQ were mainly expressed on T cells, while SMG1 predominantly expressed on T cells, B cells, and monocytes. Murine AAA model experiments further validated the elevated expression of biomarkers.
UNASSIGNED: We found a suggestive effect of telomere length on AAA and revealed the potential biomarkers and immune mechanism of telomere length on AAA. This may shed new light for diagnosis and therapeutics on AAA.

BACKGROUND: Clinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear.
METHODS: This work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes.
RESULTS: Combining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70-3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06-3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88-3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %.
CONCLUSIONS: Our study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.

Cystic fibrosis (CF) is characterized by chronic airway inflammation and premature aging. The link with leukocyte telomere length (LTL) as a marker of biological aging is unclear. We studied disease severity and LTL in 168 CF patients of which 85 patients had a second retrospective LTL assessment. A higher FEV1 was associated with longer LTL, with a stronger effect in men (5.08% longer LTL) compared to women (0.41% longer LTL). A higher FEV1/FVC ratio was associated with 7.05% (P=0.017) longer LTL in men. CF asthma, as defined by the treatment with inhaled corticosteroids, was associated with -6.65% shorter LTL (P=0.028). Men homozygous for the ΔF508 genotype showed a -10.48% (P=0.026) shorter LTL compared to heterozygotes. A genotype-specific non-linear association between LTL shortening and chronological age was observed. Stronger age-related LTL shortening was observed in patients homozygous for the ΔF508 genotype (P-interaction= 0.044). This work showed that disease severity in CF patients negatively influences LTL, with slightly more pronounced effects in men. The homozygous genotype for ΔF508 may play a role in LTL attrition in CF patients. Understanding factors in CF patients that accelerate biological aging provides insights into mechanisms that can extend the overall life quality in CF-diseased.

Telomeres play a crucial role in maintaining chromosomal integrity and regulating the number of cell divisions and have been associated with cellular aging. Telomere length (TL) has been widely studied in manifold cancer types; however, the results have been inconsistent. This systematic review and meta-analysis aims to analyze the evidence on the association between TL and head and neck cancer (HNC) risk. We comprehensively searched the literature in PubMed, Cochrane Library, and Scopus and identified nine eligible studies, which yielded 11 datasets. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to ascertain the strength of the association. On the basis of the median TL, we defined two groups, short TL and long TL, with the latter being the reference group. Our analysis found a significant relationship between short TL and increased HNC risk (OR 1.38, 95% CI: 1.10-1.73, p = 0.005), while significant heterogeneity among the studies was noted. The subgroup analysis on HNC subtypes revealed a significant association between short TL and oral cancers (OR 2.08, 95% CI: 1.23-3.53, p = 0.007). Additionally, subgroup analysis indicates that adjustments for age, sex, and smoking did not affect the significance of our findings. In conclusion, our meta-analysis found evidence for an association between short TL and HNC risk, which could indicate that TL might act as a potential biomarker for HNC risk, but high-quality prospective studies are imperative to validate our findings.

BACKGROUND: Age plays a primary role in the development of age-related macular degeneration (AMD). Telomere length (TL) is one of the most relevant biomarkers of aging. In our study, we aimed to determine the association of TL with T lymphocytes, B lymphocytes, NK cells or monocytes with different forms of AMD.
METHODS: Our study included 62 patients with AMD: geographic atrophy (GA), neovascular AMD (NVAMD) with and without macular atrophy and 22 healthy controls. Each leukocyte subtype was isolated from peripheral blood by immunomagnetic separation, and the DNA was purified. The TL in the genomic DNA was determined using qPCR by amplifying the telomere region with specific oligonucleotide primers and normalizing to the control gene. Statistical analysis was performed using R version 4.5.1.
RESULTS: We observed a statistically significant increase in TL in the T cells between the control and NVAMD groups but not for the GA group. The B cells and monocytes showed a significant decrease in TL in all AMD groups. The TL in the NK cells did not decrease in any of the AMD groups.
CONCLUSIONS: The TL in the monocytes had the strongest association with AMD. It reflects a person\'s \"telomeric status\" and may become a diagnostic hallmark of these degenerative processes.

This study employed a two-step Mendelian randomization analysis to explore the causal relationship between telomere length, as a marker of aging, and anorexia nervosa and to evaluate the mediating role of changes in the white matter microstructure across different brain regions. We selected genetic variants associated with 675 diffusion magnetic resonance imaging phenotypes representing changes in brain white matter. F-statistics confirmed the validity of the instruments, ensuring robust causal inference. Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, and leave-one-out tests, validated the results. The results show that telomere length is significantly negatively correlated with anorexia nervosa in a unidirectional manner (p = 0.017). Additionally, changes in specific white matter structures, such as the internal capsule, corona radiata, posterior thalamic radiation, left cingulate gyrus, left longitudinal fasciculus, and left forceps minor (p < 0.05), were identified as mediators. These findings enhance our understanding of the neural mechanisms, underlying the exacerbation of anorexia nervosa with aging; emphasize the role of brain functional networks in disease progression; and provide potential biological targets for future therapeutic interventions.