Alterations In Telomere Length Research Articles

Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy

Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other’s efficacy, paving the way for promising future therapeutic advancements.

Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study.

Previous studies have demonstrated that various hematologic diseases (HDs) induce alterations in telomere length (TL). The aim of this study is to investigate whether genetically predicted changes in TL have an impact on the risk of developing HDs. GWAS data for TL and 11 HDs were extracted from the database. The R software package "TwoSampleMR" was employed to conduct a two-sample Mendelian randomization (MR) analysis, in order to estimate the influence of TL changes on the risk of developing the 11 HDs. We examined the effect of TL changes on the risk of developing the 11 HDs. The IVW results revealed a significant causal association between genetically predicted longer TL and the risk of developing acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MANTLE), and hodgkin lymphoma (HODGKIN). However, there was no significant causal relationship observed between TL changes and the risk of developing chronic myeloid leukemia (CML), diffuse large b-cell lymphoma (DLBCL), marginal zone b-cell lymphoma (MARGINAL), follicular lymphoma (FOLLICULAR), monocytic leukemia (MONOCYTIC), and mature T/NK-cell lymphomas (TNK). The MR analysis revealed a positive association between genetically predicted longer TL and an increased risk of developing ALL, AML, CLL, MANTLE, and HODGKIN. This study further supports the notion that cells with longer TL have greater proliferative and mutational potential, leading to an increased risk of certain HDs.

TERT-independent telomere elongation and shelterin dysregulation after pulmonary exposure to stainless-steel welding fume in-vivo

Telomeres are inert DNA sequences (TTAGGG) at the end of chromosomes that protect genetic information and maintain DNA integrity. Emerging evidence has demonstrated that telomere alteration can be closely related to occupational exposure and the development of various disease conditions, including cancer. However, the functions and underlying molecular mechanisms of telomere alteration and shelterin dysregulation after welding fume exposures have not been broadly defined. In this study, we analyzed telomere length and shelterin complex proteins in peripheral blood mononuclear cells (PBMCs) and in lung tissue recovered from male Sprague-Dawley rats following exposure by intratracheal instillation (ITI) to 2 mg/rat of manual metal arc-stainless steel (MMA-SS) welding fume particulate or saline (vehicle control). PBMCs and lung tissue were harvested at 30 d after instillation. Our study identified telomere elongation and shelterin dysregulation in PBMCs and lung tissue after welding fume exposure. Mechanistically, telomere elongation was independent of telomerase reverse transcriptase (TERT) activation. Collectively, our findings demonstrated that welding fume-induced telomere elongation was (a) TERT-independent and (b) associated with shelterin complex dysregulation. It is possible that an alteration of telomere length and its regulatory proteins may be utilized as predictive biomarkers for various disease conditions after welding fume exposure. This needs further investigation.

Effects of HSV-G47Δ Oncolytic Virus on Telomerase and Telomere Length Alterations in Glioblastoma Multiforme Cancer Stem Cells Under Hypoxia and Normoxia Conditions.

Due to the existence of tumor stem cells with tumorigenicity properties and resistance patterns, treatment of glioblastoma is not easy. Hypoxia is a major concern in glioblastoma therapy. Telomerase activity and telomere length alterations have been known to play a critical role in glioblastoma progression and invasion. This study aimed to investigate the effects of HSV-G47Δ oncolytic virus on telomerase and telomere length alterations in U251GBMCSCs (U251-Glioblastoma cancer stem cells) under hypoxia and normoxia conditions. U251-CSCs were exposed to the HSV-G47Δ virus in optimized MOI (Multiplicity of infection= 1/14 hours). An absolute telomere length and gene expression of telomerase subunits were determined using an absolute human telomere length quantification PCR assay. Furthermore, a bioinformatics pathway analysis was carried out to evaluate physical and genetic interactions between dysregulated genes with other potential genes and pathways. Data revealed that U251CSCs had longer telomeres when exposed to HSV-G47Δ in normoxic conditions but had significantly shorter telomeres in hypoxic conditions. Furthermore, hTERC, DKC1, and TEP1 genes were significantly dysregulated in hypoxic and normoxic microenvironments. The analysis revealed that the expression of TERF2 was significantly reduced in both microenvironments, and two critical genes from the MRN complex, MER11 and RAD50, were significantly upregulated in normoxic conditions. RAD50 showed a significant downregulation pattern in the hypoxic niche. Our results suggested that repair complex in the telomeric structure could be targeted by HSV-G47Δ in both microenvironments. In the glioblastoma treatment strategy, telomerase and telomere complex could be potential targets for HSV-G47Δ in both microenvironments.

Exposure to Ambient Particulate Matter during Pregnancy: Implications for Infant Telomere Length

Background: Growing evidence suggests that air pollution may influence fetal development, with potential consequences for later health. Alteration of telomere length (TL) is one possible mediating mechanism for the link between fetal exposure to air pollution and the development of disease. However, the few studies exploring associations between prenatal pollution and infant TL have assessed varied trimesters of pregnancy and shown mixed results. The aim of this study was to examine the differential relationships between prenatal exposure to air pollutant PM2.5 during the first, second, and third trimesters of pregnancy with infant TL at one month of age. Methods: Women (n = 74) were recruited in obstetric clinics during their third trimester. Data on PM2.5 exposure for each woman’s residential area during each trimester was acquired from the regional Air Quality Management District. At one month postnatal, a salivary sample was collected from the infant, which provided DNA for the telomere assay. Women completed questionnaires about stressors in their lives, perceived stress, depression, and sociodemographics for inclusion as covariates. Multiple linear regression was used to analyze the results. Results: PM2.5 exposure during the second (β = 0.31, p = 0.003) and third (β = 0.24, p = 0.02) trimesters was associated with longer infant TL. Exposure in the first trimester was not related to TL. Covariates of maternal depression and age and infant female sex were also associated with longer TL. Variables in the model contributed to 34% of the variance in TL (F = 10.58, p = 0.000). Discussion: Fetal programming of longer telomeres in response to pollution may have adaptive value in preparing the neonate for a postnatal environment that is less than optimal in terms of air quality. Alternatively, longer telomeres may forecast later health risks, considering established links between longer TL and diseases such as cancer. Future research needs to address how prenatal pollution interacts with TL to influence health over time.

Prenatal exposure to environmental heavy metals and newborn telomere length: A systematic review and meta-analysis

Exposure to environmental heavy metals is associated with telomere length (TL) alteration. Available information regarding the effect of prenatal exposure to environmental pollutants on newborn TL is controversial. The aim of this study is to systematically review and conduct a meta-analysis of the existing epidemiological studies on the associations between prenatal metal exposure and newborn TL. A comprehensive literature search was performed using the online databases of PubMed, Web of Science, and ScienceDirect from their inception to December 1, 2023. Thirteen eligible studies were included from the overall initial identification of 3559 records. The effect size was expressed as standardized beta coefficients with 95% confidence intervals (CIs) by the restricted maximum-likelihood approach with a weighted random-effects model. Prenatal exposure to environmental heavy metals was associated with a shorter newborn TL (standardized beta = −0.04; 95% CI: −0.08, 0.00; p = 0.05). Subgroup analysis showed that prenatal exposure to cadmium was significantly, negatively associated with TL in newborns (standardized beta = −0.05; 95% CI: −0.10, −0.01; p = 0.021). Heavy metal exposure during the third trimester was significantly associated with a shorter TL in newborns (standardized beta = −0.05; 95% CI: −0.11, −0.01; p = 0.045). No significant association was found between the newborn's sex and exposure sample type. This study provides evidence for the negative effect of prenatal exposure to heavy metals on newborn TL. In particular, cadmium exposure and exposure during the third trimester of pregnancy are critical factors associated with heavy metal-induced TL shortening.

The Relationship between Telomere Length and Epigenetic Aging with Hematologic Diseases Risk: A Multivariable Mendelian Randomisation Study

Introduction: Aging is a complex phenomenon that involves multifaceted changes, including significant alterations in telomere length and epigenetic aging. When aging affects the hematopoietic system, it leads to a gradual increase in mutations in hematopoietic stem cells, making individuals more susceptible to the development of hematologic diseases. However, due to the limitations of observational studies, such as potential confounding factors and reverse causality, the precise causal direction and magnitude of the relationship between telomere length, epigenetic aging, and the incidence of hematologic diseases remain uncertain. Therefore, we conducted an investigation to determine the causal relevance of telomere length and epigenetic aging in relation to hematologic diseases using Mendelian randomization (MR). Methods: Firstly, we conducted a 2-sample single-variable Mendelian randomization (SVMR) study to examine the genetically predicted effects of telomere length and epigenetic age acceleration, as measured by HannumAge, Horvath Intrinsic Age, PhenoAge, GrimAge, and DNAm PAI-1 (DNA methylation-estimated plasminogen activator inhibitor-1) levels, on multiple hematologic diseases, including anemia, lymphoma, leukemia, myeloproliferative diseases, and hemostasis and coagulation diseases. Additionally, we used lasso regression to exclude multicollinearity in SNPs and subsequently performed multivariable MR using the screened SNPs to adjust for statistically significant risk factors, and MR Bayesian model averaging was performed to rank the significant risk factors based on their genetic evidence (Figure A). Results: Summary data were available for 19 malignant hematological neoplasms and 35 non-malignant hematological disorders, corresponding to 70,813 cases and 12,253,012 controls. Increased telomere length due to germline genetic variation was generally associated with increased risk for hematologic diseases. The strongest associations were observed for lymphoma, lymphoid leukaemia, Hodgkin lymphoma, chronic lymphocytic leukaemia, essential thrombocythaemia, unspecified types of non-Hodgkin lymphoma, multiple myeloma, Non-follicular lymphoma, unspecified iron deficiency, leukaemia, while higher levels of telomere length was associated with a reduced risk of pernicious anaemia (Figure B). Meta-analyzed IVW MR findings suggested that higher PhenoAge acceleration was associated with increased risks of myeloid leukemia, chronic lymphocytic leukemia, and lymphoid leukemia. Conversely, higher PhenoAge acceleration was linked to reduced risks of unspecified disorders of white blood cells and unspecified coagulation defects. Similarly, SVMR showed genetic predisposition for GrimAge acceleration to be associated with increased risks of amyloidosis, unspecified anemias, and myeloid leukemia. Conversely, genetically predicted GrimAge acceleration was associated with reduced risks of hemorrhagic anemia, hemolytic anemias, and idiopathic thrombocytopenic purpura. Furthermore, our findings suggested that elevated HannumAge acceleration increased the risks of lymphoma, leukemia, and lymphoid leukemia.Conversely, higher HannumAge acceleration was associated with a reduced risk of chronic myeloid leukemia. Additionally, higher levels of DNAm PAI-1 were found to be associated with an increased risk of chronic myeloid leukemia. However, there was no evidence of causality between genetically predicted Intrinsic epigenetic age acceleration and the 19 malignant hematological neoplasms and 35 non-malignant hematological disorders mentioned (Figure C). We utilized MVMR-LASSO to estimate the combined effects of telomere length and five epigenetic clocks on hematologic diseases. After adjusting for epigenetic aging, we observed a significant positive association between telomere length and various hematologic diseases, including leukemia, lymphoid leukemia, chronic lymphocytic leukemia, lymphomas, Hodgkin lymphoma, non-follicular lymphoma, unspecified types of non-Hodgkin lymphoma, essential thrombocythemia, and multiple myeloma (Figure D&E). Conclusion: Longer telomeres and epigenetic aging may increase the risk of developing most hematologic malignancies, while simultaneously raising or decreasing the risk of certain non-malignant hematologic diseases.

Efficacy of a dietary supplement derived from five edible plants on telomere length in Thai adults: A randomized, double-blind, placebo-controlled trial.

Mylife/Mylife100® is a dietary supplement consisting of black sesame seed, guava fruit, mangosteen aril, pennywort leaves, and soy protein. These edible plants contain multiple high-potential bioactive compounds exerting various vital biological functions including antioxidants which contribute to delaying the rate of telomere shortening. Telomere length is associated with cellular aging and age-related diseases. This study aimed to assess the efficacy of Mylife/Mylife100® on telomere length through a randomized, double-blind placebo-controlled trial. The trial assessed the alteration of leukocyte telomere length after 32 adults aged 50-65 years received either Mylife/Mylife100® or placebo (five capsules/day) for 8-week supplementation. The results demonstrated a significant increase in mean telomere length from baseline (6313 bp) to the 8-week supplementation period (6655 bp; p < 0.05) in the group receiving the product, whereas no significant change was observed in the placebo group. Additionally, the product group exhibited a significant improvement in plasma total antioxidant capacity levels compared to the placebo group (mean change, +35 vs -38; p = 0.006). This study also showed a significant correlation between telomere length and % CD4 + T cells (r = +0.325; p = 0.00003), % CD8 + T cells (r = +0.156; p = 0.048), and visceral fat (r = - 0.349; p = 0.000006). The findings suggest that consuming this dietary supplement (Mylife/Mylife100®) for 8 weeks has a positive effect on cellular aging by lengthening telomeres possible through their antioxidant capacities. Oxidative stress and cellular aging are underlying predisease mechanisms that might be alleviated by supplementing with this product.

Alteration of relative telomere length and telomerase reverse transcriptase expression in the granulosa cells of women during aging and assessment of in vitro fertilization outcomes.

Telomere attrition plays a critical role in the reproductive aging process in humans. Telomere length (TL) is typically regulated by telomerase, the main component of which is telomerase reverse transcriptase (TERT). The aim of the present study was to investigate the changes of relative TL (RTL) and TERT expression in granulosa cells (GCs) during aging and its association with reproduction. Clinical data on the frozen‑thawed embryo transfer cycles of older (>35year old) and younger (≤35year old) women from a single center over a 3‑year period were retrospectively analyzed. Preimplantation genetic testing for chromosome aneuploidies in older women during the same period was also analyzed. Following the analysis of the data, several biological characteristics of senescent GCs were explored. In addition, a total of 160women who were undergoing their first fresh cycle of invitro fertilization (IVF) or intracytoplasmic sperm injection were included in the study. GCs were collected from all participants. The changes of RTL and TERT expression in GCs during aging were investigated using quantitative PCR and western blotting. The associations of RTL and TERT with IVF outcomes were also assessed. The clinical data demonstrated that the pregnancy and live birth rates of women aged >35years were ~20% lower than those of women aged ≤35years, and the number of embryos with aneuploidy was 7‑fold of that without euploidy in the older age group. An aging‑induced change in follicle stimulating hormone receptor expression was observed. A shorter TL and increased TERT expression were detected in the older women. A significant inverse correlation between the expression levels of TERT and oocyte yield was identified. However, no association of RTL and TERT with blastocyst formation rate and the probability of clinical pregnancy was detected. It may be concluded that RTL and TERT alterations in GCs are potential determinants of ovarian aging. TERT expression in GCs appears to be a potential biomarker for the prediction of ovarian response, which provides a novel strategy for the assessment of female fertility.

Mendelian randomization and colocalization analyses reveal an association between short sleep duration or morning chronotype and altered leukocyte telomere length

Observational studies suggest certain sleep traits are associated with telomere length, but the causal nature of these associations is unclear. The study aimed to determine the causal associations between 11 sleep-related traits and leukocyte telomere length (LTL) through two-sample Mendelian randomization and colocalization analyses using the summary statistics from large-scale genome-wide association studies. Univariable Mendelian randomization indicates that genetically determined short sleep is associated with decreased LTL, while morning chronotype is associated with increased LTL. Multivariable Mendelian randomization further supports the findings and colocalization analysis identifies shared common genetic variants for these two associations. No genetic evidence is observed for associations between other sleep-related traits and LTL. Sensitivity MR methods, reverse MR and re-running MR after removing potential pleiotropic genetic variants enhance the robustness of the results. These findings indicate that prioritizing morning chronotype and avoiding short sleep is beneficial for attenuating telomere attrition. Consequently, addressing sleep duration and chronotype could serve as practical intervention strategies.

The impact of childhood maltreatment on telomere length in cocaine use disorder

ABSTRACT Background Several studies suggest that child maltreatment (CM) is a risk factor for a wide range of adverse biological and psychological outcomes, such as cocaine use disorder (CUD). CM and CUD are independently associated with altered telomere length (TL), but the mechanisms that underpin this relationship remain unknown. The aim of this study was to examine TL changes in cocaine-addicted individuals with and without CM. Methods This study comprised 29 cocaine-addicted individuals with a DSM-5 diagnosis of CUD and 29 healthy controls. All subjects completed questionnaires to evaluate the presence of CM (CTQ-SF) and their perceived parental care quality (PBI). Based on the responses, the CUD sample was divided into subgroups, while the control group was selected based on the absence of CM. Blood was collected from all participants, DNA was extracted, and TL was measured using quantitative real-time PCR. Results CUD patients with a history of CM had the shortest TL among subgroups. Further, we observed a linear relationship between “paternal care” levels experienced in childhood and TL. Conclusion These results support the association between telomere shortening with CM and drug addiction and suggest that greater parental care is a protective factor against stressors that affect TL.

O019 Studying telomere biology and genomic instability in gliomas

Abstract Introduction Glioblastoma (GBM) is the most aggressive primary brain cancer. Identifying novel markers which stratify patients and predict response to targeted therapies is a priority. Telomeres are caps on chromosome ends protecting them from aberrant DNA damage response. Telomere length (TL) alterations and fusions are key markers for genomic instability and high-resolution telomere analysis provides powerful prognostic and predictive information in several tumour types. We therefore studied telomeric profiles and fusions in GBM patients and related this to clinical outcome. Methods Tumours from 151 adults with isocitrate dehydrogenase-wildtype GBMs were analysed for TL using the precision High-Throughput Single Telomere Length Analysis technique. 67 patients underwent further multiplex long-range polymerase chain reaction to identify fusions via Southern hybridisation using telomere-adjacent 33P radioisotope-labelled probes. Telomere fusions from 10 tumours that exhibited the highest frequency of fusions were characterised with long-read Nanopore sequencing. Results GBMs display short telomeres with a median length of 4.0kb. Shorter TLs in patients with unmethylated O6-methylguanine DNA methyltransferase status (commonest current biomarker) conferred worse survival (HR 2.13, p = 0.002). 66/67 (98.5%) patients analysed revealed telomeric fusions. Nanopore sequencing validated these events, while confirming the presence of microhomology and telomeric deletion. This mutational spectrum is consistent with utilisation of specific DNA repair pathways in mediating telomere fusion. Conclusion This study provides the first mechanistic evidence of dysfunctional telomeres in adult GBMs and suggests TL analysis may provide independent prognostic information. The presence of telomere fusions indicates significant genomic instability and may favour targeted therapies for patients exhibiting this signature.

Ethanol Preference Leads to Alterations in Telomere Length, Mitochondria Copy Number, and Antioxidant Enzyme Activity in Zebrafish Brains.

The motivations for and effects of ethanol consumption vary considerably among individuals, and as such, a significant proportion of the population is prone to substance abuse and its negative consequences in the physical, social, and psychological spheres. In a biological context, the characterization of these phenotypes provides clues for understanding the neurological complexity associated with ethanol abuse behavior. Therefore, the objective of this research was to characterize four ethanol preference phenotypes described in zebrafish: Light, Heavy, Inflexible, and Negative Reinforcement. To do this, we evaluated the telomere length, mtDNA copy number using real-time quantitative PCR (qPCR), and the activity of these antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the brain, and the interactions between these biomarkers. Changes observed in these parameters were associated with ethanol consumption and alcohol abuse. The Heavy, Inflexible, and Negative Reinforcement phenotypes showed ethanol preference. This was particularly the case with the Inflexible phenotype, which was the group with the greatest ethanol preference. These three phenotypes showed telomere shortening as well as high SOD/CAT and/or GPx activities, while the Heavy phenotype also showed an increase in the mtDNA copy number. However, the Light phenotype, containing individuals without ethanol preference, did not demonstrate any changes in the analyzed parameters even after being exposed to the drug. Additionally, the PCA analysis showed a tendency to cluster the Light and Control groups differently from the other ethanol preference phenotypes. There was also a negative correlation between the results of the relative telomere length and SOD and CAT activity, providing further evidence of the biological relationship between these parameters. Our results showed differential molecular and biochemistry patterns in individuals with ethanol preference, suggesting that the molecular and biochemical basis of alcohol abuse behavior extends beyond its harmful physiological effects, but rather is correlated with preference phenotypes.

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.

Cardiac telomere attrition following changes in the expression of shelterin genes in pulmonary hypertensive chickens

ABSTRACT 1. The alterations of relative telomere length and expression of shelterin genes (TRF1, TRF2, RAP1, POT1, and TPP1) were evaluated from the chickens’ right heart ventricle in the early and last stages of cold-induced pulmonary hypertension (PHS) at 21 and 42 d of age. 2. The relative telomere length in the right ventricular tissues was significantly shorter in the PHS group of broilers than in the control group at 42 d, but did not statistically change at 21 d of age. There was a significant negative correlation between relative telomere length and RV:TV ratio in the broilers at 42 d of age. 3. The relative expression of POT1, RAP1 and TPP1 genes in the right ventricular tissues was significantly lower in the PHS group than in the control group at 21 d. The relative expression of the TRF2 gene was only higher in the PHS group of broilers than control at 42 d. The mRNA level of the TRF2 gene exhibited a significant positive correlation with RV:TV ratio at 42 d. 4. It was concluded that most shelterin genes are dysregulated in the early stage of PHS (right ventricular hypertrophy) while telomere attrition occurs only at the last stage (heart dilation/failure).

Telomeres susceptibility to environmental arsenic exposure: Shortening or lengthening?

Maintaining telomere length plays a crucial role in regulating cellular life span. Telomere lengthening or shortening is one of the important biomarkers which could predict the preceding or present diseases. Meanwhile, the impact of environmental arsenic exposure on telomere length has increasingly concerned. Although previous studies demonstrated the effects of arsenic on telomere length, the findings were unclear on whether telomere shortens or lengthens by arsenic exposure. Thus, this manuscript summarized and discussed the telomere length alteration following arsenic exposure and the possible does-response effect of arsenic on telomere length. The present review suggested that different age groups may respond differently to arsenic exposure, and the dose-response effect of arsenic could be a critical factor in its effect on telomere length. Moreover, speciation analysis of arsenic could be more informative in identifying the effect of arsenic on telomere length.

Manipulation of Thymidine Nucleotide Metabolism Controls Human Telomere Length and Promotes Telomere Elongation in Dyskeratosis Congenita Patient Derived Cells

Inherited mutations in telomere maintenance genes are associated with short telomeres and can cause severe diseases including the congenital bone marrow failure syndrome dyskeratosis congenita, liver cirrhosis, and pulmonary fibrosis, collectively referred to as telomere biology disorders (TBDs). Current approaches to treat TBDs rely on bone marrow and organ transplantation, and patients face poor prognoses. New systemic therapies to promote telomere elongation and treat TBDs throughout the body are needed. Here, we performed the first genome-wide CRISPR/Cas9 functional telomere length screen using flow cytometry-FISH (flow-FISH) in human cells to identify novel telomere maintenance pathways that might be manipulated for therapeutic benefit. Validating our approach, we found guide RNAs targeting positive (e.g. TERT) and negative (e.g. POT1 and TRF1) regulators of telomere length enriched in sorted cells with short and long telomeres, respectively. Unbiased pathway analysis of screening hits demonstrated nucleotide metabolism genes to be highly associated with telomere length, consistent with recent genome-wide association studies, and which in follow-up screening we narrowed down to multiple control points specifically along the thymidine (dT) nucleotide metabolism pathway. Targeted genetic disruption using CRISPR/Cas9 revealed that decreasing dT nucleotide salvage by thymidine kinase (TK1) or de novo production by thymidylate synthase (TYMS) reduced telomere length, whereas inactivation of the dNTPase-encoding gene SAMHD1 lengthened telomeres. We next asked whether nucleotide precursor manipulation could alter telomere length dynamics. Remarkably, we found supplementation with dT nucleoside alone drove rapid telomere elongation in human cells (Figure 1). Telomere elongation after dT treatment required conversion to thymidine monophosphate (dTMP) by TK1, was telomerase dependent, and could be achieved at doses that did not inhibit cell cycle progression. In cells with TYMS deletion or after treatment with the TYMS inhibitor 5-fluorouracil, dT supplementation was sufficient to bypass the de novo nucleotide synthesis defect and promoted robust telomere elongation. SAMHD1 overexpression blunted the degree of telomere elongation from dT treatment in a manner requiring its dNTPase activity, suggesting that telomere length control occurs at the level of dTTP in human cells. To assess whether nucleotide manipulation could overcome the genetic causes of telomere insufficiency which drive TBDs, we tested dT on induced pluripotent stem cell (iPSC) lines derived from patients harboring mutations in a spectrum of TBD-associated genes including DKC1, TERC, TERT, TINF2, RTEL1, and PARN. We found dT supplementation or inhibition of SAMHD1 drove robust telomere elongation in patient derived iPSCs spanning genotypes that cause telomere maintenance defects both by telomerase-dependent and telomerase-independent mechanisms. In preliminary experiments using primary human hematopoietic stem and progenitor cells, dT treatment resulted in telomere elongation in vitro, pointing to a potential treatment for TBD-associated bone marrow failure. Collectively, our results demonstrate a critical role of thymidine nucleotide metabolism in regulating human telomere length. Based on our findings, we propose there may be a therapeutic window to modulate telomere length by manipulating dT metabolism in patients with TBDs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TGF-β controls stromal telomere length through epigenetic modifications.

The online version contains supplementary material available at 10.1007/s13205-022-03346-5.

Impact of superovulation and in vitro fertilization on LINE-1 copy number and telomere length in C57BL/6J mice blastocysts.

Millions of babies have been conceived by IVF, yet debate about its safety to offspring continues. We hypothesized that superovulation and in vitro fertilization (IVF) promote genomic changes, including altered telomere length (TL) and activation of the retrotransposon LINE-1 (L1), and tested this hypothesis in a mouse model. Experimental study analyzing TL and L1 copy number in C57BL/6J mouse blastocysts in vivo produced from natural mating cycles (N), in vivo produced following superovulation (S), or in vitro produced following superovulation (IVF). We also examined the effects of prolonged culture on TL and L1 copy number in the IVF group comparing blastocysts cultured 96h versus blastocysts cultured 120h. TL and L1 copy number were measured by Real Time PCR. TL in S (n = 77; Mean: 1.50 ± 1.15; p = 0.0007) and IVF (n = 82; Mean: 1.72 ± 1.44; p < 0.0001) exceeded that in N (n = 16; Mean: 0.61 ± 0.27). TL of blastocysts cultured 120h (n = 15, Mean: 2.14 ± 1.05) was significantly longer than that of embryos cultured for 96h (n = 67, Mean: 1.63 ± 1.50; p = 0.0414). L1 copy number of blastocysts cultured for 120h (n = 15, Mean: 1.71 ± 1.49) exceeded that of embryos cultured for 96h (n = 67, Mean: 0.95 ± 1.03; p = 0.0162). Intriguingly ovarian stimulation, alone or followed by IVF, produced embryos with significantly longer telomeres compared to in vivo, natural cycle-produced embryos. The significance of this enriched telomere endowment for the health and longevity of offspring born from IVF merit future studies.

Acculturative stress, telomere length, and postpartum depression in Latinx mothers

Latinx mothers in the United States are highly vulnerable to psychosocial stressors, including discrimination and acculturative stress, which increase maternal health risks. Previous work in Latinx mothers indicates that prenatal discrimination influences epigenetic immune markers that may increase risk for postpartum depression. Discrimination and acculturative stress have also been linked to cellular aging, including telomere degradation, in Hispanic populations broadly, but not in this particularly vulnerable population. The present work addressed this gap in a sample of 150 Latinx mothers living in the United States (mean age 27.6 years). Psychosocial measures (including discrimination, stress, and mental health) and blood were collected at 24–32 weeks gestation. Psychosocial measures were re-evaluated at 4–6 weeks postpartum. First, we examined the relationship between maternal prenatal cultural stress (i.e., discrimination and acculturative stress) and telomere length (TL). Second, we tested whether TL predicted postpartum depression. Acculturative stress – but not discrimination – predicted shorter TL, especially among participants with high methylation of the FOXP3 promoter region. Further, shorter telomere measures during pregnancy predicted greater postpartum depression symptom severity. TL was not related to any sociodemographic characteristics such as age, income, country of origin, or years in the United States. These results highlight the uniquely impactful role of acculturative stress on Latinx maternal health and the potential interactive role of telomere length and epigenetic immune alterations in risk for maternal mental health concerns.