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BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. RESULTS: Group A (Advanced) included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M (Mild) included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. CONCLUSIONS: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

To study telomere maintenance mechanism (TMM) activation during malignant transformation, we compared neurofibroma (NF) and malignant peripheral nerve sheath tumor (MPNST) in the same patient with type-1 neurofibromatosis (NF1), a total of 20 NF-MPNST pairs in 20 NF1 patients. These comparisons minimized genetic bias and contrasted only changes associated with malignant transformation, while subtracting changes that developed upon the transformation of normal cells to the benign tumor. TGF-β superfamily genes were found to activate the PAX and SOX transcription factors, leading to TMM activation. BMPER activates PAX6 through BMP2 and PAX7 through BMP4; BMP15 activates SOX14; and INHBC activates PAX9 and SOX14. The activated PAX and SOX genes sequentially establish the core architecture of the RAD52-dependent alternative lengthening of telomeres (ALT). Specifically, PAX7 activates the recombinase (RAD52) and a negative regulator (SLX4IP). PAX6 and SOX14 activate positive regulators (BLM and BRCA2, respectively). PAX9 and SOX14 activate RAD9B and FEN1, which are responsible for the stability of homologous recombination intermediates and increase, together with RAD52, the telomere length. Telomere elongation achieved by the activation of PAX7 and PAX9 is associated with a poor prognosis. We demonstrated that TGF-β superfamily-induced transcriptional activation pathways activated the RAD52-dependent ALT during malignant transformation of MPNSTs. [ABSTRACT FROM AUTHOR]

Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown. What is the clinical impact of TL testing on the management of ILD? Patients were evaluated in the Columbia University ILD clinic and underwent Clinical Laboratory Improvement Amendments-certified TL testing by flow cytometry and fluorescence in situ hybridization (FlowFISH) as part of clinical treatment. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared with research quantitative polymerase chain reaction (qPCR) TL measurement. A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR, 2.00; 95% CI, 1.27-3.32). TL testing led to clinical treatment changes for 35 patients (32%), most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n = 34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 patients (29%). Inclusion of TL testing below the 1st percentile helped reclassify eight of nine variants of uncertain significance into actionable findings. The quantitative polymerase chain reaction test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays. Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants. [ABSTRACT FROM AUTHOR]

There is growing interest in telomere length as an indicator of current and future health. Although early childhood is a period of rapid telomere attrition, little is known about the factors that influence telomere biology during this time. Adult research suggests that telomere length is influenced by psychological characteristics. This study's goal was to test associations among repeated measures of temperament and telomere length in a community sample of children (N = 602; 52% male, 73% non-Hispanic White, middle-to-high socioeconomic status) from infancy to age 3 years. Relative telomere length was assessed from DNA in saliva samples collected at infancy (M = 8.4 months), 2 years (M = 24.9 months), and 3 years (M = 37.8 months). Temperament was assessed via maternal report questionnaires administered at infancy (Infant Behavior Report Questionnaire–Revised) and ages 2 and 3 years (Early Childhood Behavior Questionnaire). Temperament was operationalized in two ways: using the established domains of negative affectivity, surgency/extraversion, and regulation/effortful control and using person-centered scores that identified three groups of children with similar profiles across domains (emotionally and behaviorally regulated; emotionally and behaviorally dysregulated; introverted and overcontrolled). Analyses revealed that greater regulation/effortful control was associated with longer telomere length across time points. Additionally, higher surgency/extraversion, beginning in infancy, was associated with decreased rate of telomere attrition. There were no sex differences in the relations between temperament and telomere measures. These findings suggest that, as early as infancy, temperament may influence telomere biology, with a potential protective effect of positive temperament characteristics on telomere erosion. Public Significance Statement: This study suggests that positive temperament characteristics may buffer telomere erosion in early childhood. Telomere erosion is a measure of cellular aging that may contribute to many diseases across the lifespan. Identifying factors in early life that influence telomeres may enhance our understanding of the origins of health and disease and our ability to identify at-risk individuals and to develop targeted, effective interventions that maximize health outcomes across the lifespan. [ABSTRACT FROM AUTHOR]

Objective To investigate the correlation between telomere length of peripheral white blood cells and the levels of advanced glycosylation end products, as well as bone mineral density in patients with type 2 diabetes mellitus, and to assess the impact of advanced glycosylation end product levels on telomere length. Methods From May 1, 2023, to May 1, 2024, 174 patients with T2DM who underwent dual-energy X-ray BMD examination at the Department of Endocrinology, Zhengzhou Central Hospital, were selected. T2DM patients were divided into osteoporosis group, osteopenia group, and normal bone mass group based on the T-value in BMD. qPCR method was used to measure telomere length in peripheral blood leukocytes, and ELISA method was used to determine AGEs levels. General patient data were collected along with measurements for blood glucose, blood lipid levels, 25-hydroxy-vitamin D, and other indicators. Bone mineral density was evaluated using dual-energy X-ray imaging while plasma CTX and PINP levels were measured via ELISA. SPSS 26.0 statistical software was utilized to analyze differences and correlations among all indicators. Results （1）The telomere length of OP group, osteopenia group and normal bone mass group was different, and the telomere length of the three groups increased successively. （2） In individuals with type 2 diabetes mellitus, telomere length exhibited a positive correlation with BMD and a negative correlation with CTX and PINP. Plasma AGEs level showed a negative correlation with BMD and a positive correlation with CTX and PINP, while telomere length demonstrated a negative correlation with AGEs level.（3） Telomere length was an independent factor of BMD, and AGEs level was an independent factor of BMD （P < 0.05）. Conclusion The reduction of telomere length and the increase of AGEs in patients with type 2 diabetes are related to the decrease of bone mineral density, and the reduction of telomere length is related to the increase of AGEs. Telomere length of peripheral leucocytes and plasma AGEs level can jointly evaluate the bone metabolism status of T2DM patients. [ABSTRACT FROM AUTHOR]

Summary Rare germline pathogenic variants (GPVs) in genes essential in telomere length maintenance and function have been implicated in two broad classes of human disease. The telomere biology disorders (TBDs) are a spectrum of life‐threatening conditions, including bone marrow failure, liver and lung disease, cancer and other complications caused by GPVs in telomere maintenance genes that result in short and/or dysfunctional telomeres and reduced cellular replicative capacity. In contrast, cancer predisposition with long telomeres (CPLT) is a disorder associated with elevated risk of a variety of cancers, primarily melanoma, thyroid cancer, sarcoma, glioma and lymphoproliferative neoplasms caused by GPVs in shelterin complex genes that lead to excessive telomere elongation and increased cellular replicative capacity. While telomeres are at the root of both disorders, the term TBD is used to convey the clinical phenotypes driven by critically short or otherwise dysfunctional telomeres and their biological consequences. [ABSTRACT FROM AUTHOR]

Background: Biological aging is a complex process influenced by various factors, including reproductive status and castration. This study aimed to evaluate the impact of castration on biological aging in dogs. Method: Fifteen male crossbred dogs were randomly divided into a sham-operation control group (n = 5) and a castrated group (n = 10). Blood samples were collected at weeks 0, 4, 8, 12, 16, and 18 post-surgery. Malondialdehyde (MDA as indicator of Lipid peroxidation), C-reactive protein (as an indicator of inflammation), telomere length, mitochondrial DNA (mtDNA) copy number, and the expression of age-related (P16, P21, TBX2) and telomerase-related (TERT) genes were assessed in blood samples. Results: Plasma MDA levels were higher in the control group at weeks 16 and 18, while CRP levels were higher only at week 18. Telomere length and mtDNA copy number were lower in the control group at week 18. Gene expression analysis showed that P16 was lower in the control group at weeks 8 and 12, P21 and TERT were lower at weeks 16 and 18, and TBX2 was lower at weeks 16 and 18. The TBX2/P16 ratio was lower in the control group at weeks 16 and 18 but higher at week 12, while the TBX2/P21 ratio did not differ between groups. Conclusion: Castration appears to have a protective effect against biological aging in dogs, as evidenced by lower lipid peroxidation, inflammation, and age-related changes in telomere length, mtDNA copy number, and gene expression. [ABSTRACT FROM AUTHOR]

Telomeres are protective structures at the end of eukaryotic chromosomes that are strongly implicated in ageing and ill health. They attrition upon every cellular reproductive cycle. Evidence suggests that short telomeres trigger DNA damage responses that lead to cellular senescence. Accurate methods for measuring telomeres are required to fully investigate the roles that shortening telomeres play in the biology of disease and human ageing. The last two decades have brought forth several techniques that are used for measuring telomeres. This editorial highlights strengths and limitations of traditional and emerging techniques, guiding researchers to choose the most appropriate methodology for their research needs. These methods include Quantitative Polymerase Chain Reaction (qPCR), Omega qPCR (Ω-qPCR), Terminal Restriction Fragment analysis (TRF), Single Telomere Absolute-length Rapid (STAR) assays, Single TElomere Length Analysis (STELA), TElomere Shortest Length Assays (TESLA), Telomere Combing Assays (TCA), and Long-Read Telomere Sequencing. Challenges include replicating telomere measurement within and across cohorts, measuring the length of telomeres on individual chromosomes, and standardised reporting for publications. Areas of current and future focus have been highlighted, with recent methodical advancements, such as long-read sequencing, providing significant scope to study telomeres at an individual chromosome level. [ABSTRACT FROM AUTHOR]

Cancer cells have the ability to undergo an unlimited number of cell divisions, which gives them immortality. Thus, the cancer cell can extend the length of its telomeres, allowing these cells to divide unlimitedly and avoid entering the state of senescence or cellular apoptosis. One of the main effects of photobiomodulation (PBM) is the increase in the production of adenosine triphosphate (ATP) and free radicals, mainly reactive oxygen species (ROS). Existent data indicates that high levels of ROS can cause shortening and dysfunctional telomeres. Therefore, a better understanding of the effects induced by PBM on cancer cell telomere maintenance is needed. This work aimed to evaluate the effects of low-power red laser (658 nm) and blue LED (470 nm) on the TRF1 and TRF2 mRNA levels and telomere length in human breast cancer cells. MCF-7 and MDA-MB-231 cells were irradiated with a low-power red laser (69 J cm-2, 0.77 W/cm-2) and blue LED (482 J cm-2, 5.35 W/cm-2), alone or in combination, and the relative mRNA levels of the genes and telomere length were assessed by quantitative reverse transcription polymerase chain reaction. The results suggested that exposure to certain red laser and blue LED fluences decreased the TRF1 and TRF2 mRNA levels in both human breast cancer cells. Telomere length was increased in MCF-7 cells after exposure to red laser and blue LED. However, telomere length in MDA-MB-231 was shortened after exposure to red laser and blue LED at fluences evaluated. Our research suggests that photobiomodulation induced by red laser and low-power blue LED could alter telomere maintenance and length. [ABSTRACT FROM AUTHOR]

Background Cognitive decline, a common process of brain ageing, has been associated with telomere length (TL). Delving into the identification of reliable biomarkers of brain ageing is essential to prevent accelerated cognitive impairment. Methods We selected 317 non-smoking 'Prevención con Dieta Mediterránea-Plus' (PREDIMED-Plus) participants (mean age, 65.8 ± 5.0 years) with metabolic syndrome from two trial centres who were following a lifestyle intervention. We measured TL and cognitive function at baseline and after 3 and 4 years of follow-up, respectively. Associations between baseline or 3-year changes in TL and baseline or 4-year changes in cognitive function were analysed using multivariable regression models. Results Baseline TL was not associated with baseline cognitive performance. Nevertheless, longer baseline TL was associated with improved 4-year changes in the Executive Function domain (β: 0.29; 95%CI: 0.12 to 0.44; P < 0.001) and the Global Cognitive Function domain (β: 0.19; 95%CI: 0.05 to 0.34; P = 0.010). Besides, a positive association was found between longer baseline TL and improved 4-year changes in the animal version of the Verbal Fluency Test (β: 0.33; 95%CI: 0.12 to 0.52; P =  0.002). By contrast, 3-year changes in TL were not associated with changes in cognitive function after 4 years. Conclusions Longer baseline TL could protect from cognitive decline and be used as a useful biomarker of brain ageing function in an older Mediterranean population at risk of cardiovascular disease and cognitive impairment. [ABSTRACT FROM AUTHOR]

Telomeres, repetitive sequences located at the extremities of chromosomes, play a pivotal role in sustaining chromosomal stability. Telomerase is a complex enzyme that can elongate telomeres by appending telomeric repeats to chromosome ends and acts as a critical factor in telomere dynamics. The gradual shortening of telomeres over time is a hallmark of cellular senescence and cellular death. Notably, telomere shortening appears to result from the complex interplay of two primary mechanisms: telomere shelterin complexes and telomerase activity. The intricate interplay of genetic, environmental, and lifestyle influences can perturb telomere replication, incite oxidative stress damage, and modulate telomerase activity, collectively resulting in shifts in telomere length. This age-related process of telomere shortening plays a considerable role in various chronic inflammatory and oxidative stress conditions, including cancer, cardiovascular disease, and rheumatic disease. Existing evidence has shown that abnormal telomere shortening or telomerase activity abnormalities are present in the pathophysiological processes of most rheumatic diseases, including different disease stages and cell types. The impact of telomere shortening on rheumatic diseases is multifaceted. This review summarizes the current understanding of the link between telomere length and rheumatic diseases in clinical patients and examines probable telomere shortening in peripheral blood mononuclear cells and histiocytes. Therefore, understanding the intricate interaction between telomere shortening and various rheumatic diseases will help in designing personalized treatment and control measures for rheumatic disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Temperature acclimation enables animals, especially aquatic ones, to safely survive climate fluctuations in the natural environment. The aim of our work was to study how temperature acclimation in aquaculture affects cold-water Baikal whitefish at the embryonic stage and their well-being during a heat shock (24 °C). Selected molecular markers (telomere length, telomerase activity, and expression of target genes) showed that acclimation at the early developmental stages has a positive effect on the Baikal whitefish larvae and allows them to tolerate acute temperature stress without the harmful consequences. The data obtained will improve the survival of fish and increase their plasticity under aquaculture conditions. Acclimation through the hormesis effect increases the plasticity of organisms, which has been shown for many ectothermic animals, including fish. We investigated the effect of temperature acclimation in Baikal whitefish Coregonus baicalensis (Dybowski, 1874). Telomere length, telomerase activity, and the expression of genes, whose products are involved in the regulation of telomere length and defense against reactive oxygen species, were selected to assess the state of the larvae. Acclimation and acute temperature stress (+12 °C) had no effect on telomere length, but altered telomerase activity (acclimation decreased it; stress increased it) and the levels of genes expression. Under stress, the expression of superoxide dismutase genes was increased in acclimated larvae and that of glutathione peroxidases in non-acclimated larvae, which may indicate lower reactive oxygen species formation and slower antioxidant responses in acclimated fish. The expression of some telomere-related genes was reduced under temperature stress, but the expression of the tzap and smg genes, whose products improve the control of telomere length by preventing them from lengthening or shortening, was increased in acclimated individuals. The data obtained indicate a positive effect of acclimation on the state of the Baikal whitefish larvae by remodulation of their telomerase activity and the transcriptional profile. [ABSTRACT FROM AUTHOR]

Telomeres—special DNA–protein structures at the ends of linear eukaryotic chromosomes—define the proliferation potential of cells. Extremely short telomeres promote a DNA damage response and cell death to eliminate cells that may have accumulated mutations after multiple divisions. However, telomere elongation is associated with the increased proliferative potential of specific cell types, such as stem and germ cells. This elongation can be permanent in these cells and is activated temporally during immune response activation and regeneration processes. The activation of telomere lengthening mechanisms is coupled with increased proliferation and the cells' need for energy and building resources. To obtain the necessary nutrients, cells are capable of finely regulating energy production and consumption, switching between catabolic and anabolic processes. In this review, we focused on the interconnection between metabolism programs and telomere lengthening mechanisms during programmed activation of proliferation, such as in germ cell maturation, early embryonic development, neoplastic lesion growth, and immune response activation. It is generally accepted that telomere disturbance influences biological processes and promotes dysfunctionality. Here, we propose that metabolic conditions within proliferating cells should be involved in regulating telomere lengthening mechanisms, and telomere length may serve as a marker of defects in cellular functionality. We propose that it is possible to reprogram metabolism in order to regulate the telomere length and proliferative activity of cells, which may be important for the development of approaches to regeneration, immune response modulation, and cancer therapy. However, further investigations in this area are necessary to improve the understanding and manipulation of the molecular mechanisms involved in the regulation of proliferation, metabolism, and aging. [ABSTRACT FROM AUTHOR]

Objectives To investigate the potential role of shelterin dysfunction in naïve CD4+ T cells in the pathogenesis of Behçet's disease (BD). Methods Naïve CD4+ T cells were isolated from 40 BD patients and 40 sex- and age-matched healthy controls (HC). Senescent profiles, shelterin subunits expression, telomere length, telomerase activity and critical DNA damage response (DDR) were evaluated. Telomere repeat factor-2 (TRF2) silencing was conducted for further validation. Results Compared with HC, BD patients had significantly decreased naïve CD4+ T cells, increased cell apoptosis, senescence, and productions of TNF-α and IFN-γ upon activation. Notably, BD naïve CD4+ T cells had shortened telomere, impaired telomerase activity, and expressed lower levels of shelterin subunits TRF2, TRF1- and TRF2-Interacting Nuclear Protein 2 (TIN2) and Repressor/Activator Protein 1 (RAP1). Furthermore, BD naïve CD4+ T cells exhibited significantly increased DDR, evidenced by elevated phosphorylated ataxia telangiectasia (AT) mutated (pATM), phosphorylated p53 (pp53) and p21. Finally, TRF2 silencing markedly upregulated DDR, apoptosis and proinflammatory cytokines production in HC naïve CD4+ T cells. Conclusion Our study demonstrated that TRF2 deficiency in BD naïve CD4+ T cells promoted cell apoptosis and senescence, leading to proinflammatory cytokines overproduction. Therefore, restoring TRF2 might be a promising therapeutic strategy for BD. [ABSTRACT FROM AUTHOR]

Background: To verify whether shorter telomere length is associated with anorexia of ageing in community‐dwelling older people. Methods: Conducted as a cross‐sectional investigation, the study enrolled 448 participants residing in an urban area of a municipality in Brazil. Relative telomere length in blood samples was measured using quantitative polymerase chain reaction (qPCR), whereas the presence of anorexia of ageing was determined using the Simplified Appetite Nutritional Questionnaire. Data analysis employed multiple logistic regression. Results: Among the 448 older individuals surveyed, 70.69% were female, and the predominant age bracket ranged from 60 to 69 years (45.08%). Approximately 25% exhibited the shortest telomeric length, with a corresponding anorexia of ageing prevalence of 41.16%. Older individuals with diminished telomere lengths displayed an increased likelihood of experiencing anorexia of ageing (odds ratio [OR] = 1.92; 95% confidence interval [CI] = 1.12–3.29), independent of factors such as gender, age group, depressive symptoms, pain and performance in basic daily life activities. Conclusions: The observed association between anorexia of ageing and a telomeric biomarker underscores the imperative to meticulously evaluate the nutritional dimensions of older people, with a view to implementing interventions that may enhance their overall health status. Highlights: Older people with shorter telomere length are more likely to have anorexia of ageing.The association between shorter telomere length and anorexia of ageing is independent of sex, age group, depressive symptoms, pain and performance in basic activities of daily living. [ABSTRACT FROM AUTHOR]

The industrial world exposes living organisms to a variety of metal pollutants. Here we investigated whether such elements affect G-rich sequences susceptible to fold into G-quadruplex (GQ) structures. Thermal stability and conformation of these oligoncleotides was studied at various molar ratios of a variety of heavy metal salts using thermal FRET, transition-FRET (t-FRET) and circular dichroism. Metal ions affected the thermal stability of the GQs to different extents; some metals had no effect on T m while other metals caused small to moderate changes in T m at 1:1 or 1:10 molar ratio. While most of the metals had no major effect, Al3+, Cd2+, Pb2+, Hg2+ and Zn2+ altered the thermal stability and structural features of the GQs. Some metals such as Pb2+ and Hg2+ exhibit differential interactions with telomere, c-myc and c-kit GQs. Overall, toxic heavy metals affect G-quadruplex stability in a sequence and topology dependent manner. This study provides new insight into how heavy metal exposure may affect gene expression and cellular responses. • Heavy metal ions affect the thermal stability of the G-quadruplexes to different extents. • Al3+, Cd2+, Pb2+, Hg2+ and Zn2+ altered the thermal stability and structural features of the GQs. • Pb2+ and Hg2+ exhibit differential interactions with telomere, c-myc and c-kit G-quadruplexes. • Toxic heavy metals affect stability of G-quadruplexes in a sequence and topology dependent manner. • Heavy metal exposure may affect gene expression and cellular responses through direct DNA binding. [ABSTRACT FROM AUTHOR]

Sleep is a fundamental and complex physiological process whose duration decreases and characteristics change with age. Around 50 % of children will experience sleep disturbances at some point in their early life. Sleep disturbances can result in a number of deleterious consequences, including alterations in the levels of cellular senescence (CS) markers. CS is a complex process essential for homeostasis characterized by the irreversible loss of cell proliferation capacity; however, the accumulation of senescent cells can lead to age-related diseases. In this review, our objective was to gather information about the relationship between sleep duration, sleep-disordered breathing (SDB) and cellular senescence markers, namely: oxidative stress, inflammation, insulin-like growth factor 1 (IGF-1), and growth hormone (GH) in newborns, children, and teenagers. To achieve this, we searched six databases: MEDLINE, Scopus, LILACS, Web of Science, Embase, and SciELO, and identified 20 articles that met our inclusion criteria. Our results show that better sleep quality and duration and, both the surgical and non-surgical treatment of sleep disorders are associated with a reduction in oxidative stress, inflammation, and telomeric attrition levels. Furthermore, our results also show that surgical treatment for SDB significantly reduced the levels of cellular senescence markers. Further studies need to be conducted in this area, particularly longitudinal studies, for a greater understanding of the mechanisms involved in the relationship between sleep and senescence. Better sleep quality and duration were associated with less oxidative stress, inflammation, and telomeric attrition and a higher level of IGF-1 in children and teenagers. [Display omitted] • Lower levels of oxidative stress were associated with better sleep. • Sleep problems in childhood can reduce telomere length, impacting health in adulthood. • Sleep-disordered breathing was associated with cellular senescence marker levels. [ABSTRACT FROM AUTHOR]

Zoraptera (also called "angel insects") is one of the most unexplored insect orders. However, it holds promise for understanding the evolution of insect karyotypes and genome organization given its status as an early branching group of Polyneoptera and Pterygota (winged insects) during the Paleozoic. Here, we provide karyotype descriptions of three Zorapteran species: Brazilozoros huxleyi (2n♂; ♀ = 42; 42), B. kukalovae (2n♂; ♀ = 43; 44) and Latinozoros cacaoensis (2n♂; ♀ = 36; 36). These species represent two of the four recently recognized Zorapteran subfamilies. Contrary to an earlier suggestion that Zoraptera has holocentric chromosomes, we found karyotypes that were always monocentric. Interestingly, we detected both X0 (B. kukalovae) and XY (B. huxleyi, L. cacaoensis) sex chromosome systems. In addition to conventional karyotype descriptions, we applied fluorescent in situ hybridization for the first time in Zoraptera to map karyotype distributions of 18S rDNA, histone H3 genes, telomeres and (CAG)n and (GATA)n microsatellites. This study provides a foundation for cytogenetic research in Zoraptera. [ABSTRACT FROM AUTHOR]

A telomere is a repetitive DNA sequence located at the end of human chromosomes, and its length shortens with age. Research has demonstrated that estrogen is associated with the aging of various types of cells, including brain, muscle, and bone cells. This study explored the cross-sectional association between estrogen usage and telomere length, utilizing data from the US National Health and Nutrition Examination Survey (NHANES) 1999-2002. The final number of participants included in this study was 491. This study's bivariate Rao-Scott χ2 test revealed a significant association between telomere length and gender (p < 0.01). Females have longer telomeres than males, indicated by a rate ratio of 1.72. A positive relationship between estrogen usage and telomere length was observed among female participants, yielding a rate ratio of 1.44. The mosaic diagram and Pearson residuals confirmed the statistical significance of this difference (p < 0.001). This suggests that estrogen administration may preserve telomeres and contribute to healthy aging. In conjunction with the findings from the literature, this study supports the need for further investigations into the effects of estrogen administration on telomere length. [ABSTRACT FROM AUTHOR]

Background and Objectives: The association between neurological disability, prognosis, and telomere length (TL) in patients with stroke has been investigated in various ways. However, analysis of the type of stroke and ischemic stroke subgroups is limited. In this study, we aimed to determine the association between TL and neurological disability according to stroke type. Materials and Methods: This prospective study included patients with stroke who visited a single-center emergency department (ED) between January 2022 and December 2023. The association between TL and neurological disabilities, using the Modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS), was evaluated according to the patient's stroke type and subgroup of ischemic stroke. Multivariate analysis was performed to determine the association between neurological disabilities in patients with ischemic stroke and the subgroups. Results: A total of 271 patients with stroke were enrolled. The NIHSS score was found to be higher at the time of ED visit (adjusted odds ratio [OR], 5.23; 95% confidence interval [CI], 1.59–17.2, p < 0.01) and 1 day later (adjusted OR, 7.78; 95% CI, 1.97–30.70, p < 0.01) in the ischemic stroke group with a short TL. In the other determined etiology (OD) or undetermined etiology (UD) group, the NIHSS was higher in the short TL group at the ED visit (adjusted OR, 7.89; 95% CI, 1.32–47.25, p = 0.02) and 1 day after (adjusted OR, 7.02; 95% CI, 1.14–43.47, p = 0.04). Conclusions: TL is associated with neurological disability in early ischemic stroke and is prominent in the UD and OD subgroups. [ABSTRACT FROM AUTHOR]

Background and aims: Healthy weight (lean) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) have a more favorable metabolic and histological profile in cross-sectional studies compared with their non-lean counterparts. Paradoxically, they also have higher overall mortality. The underpinning pathophysiology of this paradox is not understood. Telomere attrition is associated with increased mortality in various diseases. Methods: We investigated the role of telomere length in the pathogenesis of lean MAFLD in cohorts with biopsy‐proven MAFLD (n = 303). We measured serum malondialdehyde (MDA) levels and hepatic 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) expression (reactive oxygen species (ROS) markers), growth/differentiation factor-15 (GDF-15) and tested the effect of H2O2 on telomere length and activity in hepatocyte cell lines. The association between leukocyte telomere length and mortality was examined. Results: Telomere length was significantly lower in patients with lean MAFLD (p < 0.001). They also demonstrated an increase in ROS levels and decreases in GDF-15. H2O2 induced telomere shortening and reducing telomere activity in hepatocyte cell lines. We subsequently confirmed that telomere length shortening at baseline is associated with increased hazards of all-cause mortality; the deleterious effect was more profound in lean people. Conclusion: Differences in telomere length in part explain the increased mortality of lean compared to non-lean patients with MAFLD. The effect is in part mediated through ROS activation and provide opportunities for therapy. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined. Methods: Relevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells. Results: A six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells. Conclusion: Our study identified potential biomarkers for the six-TRLs model related to the prognosis of OC. [ABSTRACT FROM AUTHOR]

Migraine, common in individuals under 50 years, is linked to oxidative stress. The association between telomere length shortening and migraine, along with potential age-related influences, has not been comprehensively studied. This cross-sectional study included data from 6169 participants in the National Health and Nutrition Survey (NHANES) from 1999 to 2002, encompassing information on peripheral blood leukocyte telomere length, severe headache or migraine, and potential confounders. Stratifying by age (20–50 years, > 50 years), we employed multivariable logistic regression, restricted cubic splines and interaction test to investigate age-influenced telomere length in relation to migraine. In participants aged 20–50 years, the odds ratio (OR) for migraine in the shortest telomere length group T1 (0.39–0.89) was 1.35 (95% confidence interval [95% CI] 1.01, 1.79) compared to the longest group T3 (1.10–9.42), whereas in those aged > 50 years, the OR of T1 was 0.93 (95% CI 0.60, 1.43). Additionally, telomere length and age interacted in the development of migraine (p for interaction: 0.010). In individuals aged 20–50, an L-shaped relationship was found between telomere length and migraine, with an inflection point at 1.02T/S ratio. The OR was 9.34 (95% CI 1.56, 55.99) for telomere lengths < 1.02T/S ratio. These findings suggest age influences the association between telomere length and migraine in U.S. adults. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by unexplained irreversible pulmonary fibrosis. Although the etiology of IPF is unclear, studies have shown that it is related to telomere length shortening. However, the prognostic value of telomere-related genes in IPF has not been investigated. Methods: We utilized the GSE10667 and GSE110147 datasets as the training set, employing differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen for disease candidate genes. Then, we used consensus clustering analysis to identify different telomere patterns. Next, we used summary data-based mendelian randomization (SMR) analysis to screen core genes.We further evaluated the relationship between core genes and overall survival and lung function in IPF patients. Finally, we performed immune infiltration analysis to reveal the changes in the immune microenvironment of IPF. Results: Through differential expression analysis and WGCNA, we identified 35 significant telomere regulatory factors. Consensus clustering analysis revealed two distinct telomere patterns, consisting of cluster A (n = 26) and cluster B (n = 19). Immune infiltration analysis revealed that cluster B had a more active immune microenvironment, suggesting its potential association with IPF. Using GTEx eQTL data, our SMR analysis identified two genes with potential causal associations with IPF, including GPA33 (PSMR = 0.0013; PHEIDI = 0.0741) and MICA (PSMR = 0.0112; PHEIDI = 0.9712). We further revealed that the expression of core genes is associated with survival time and lung function in IPF patients. Finally, immune infiltration analysis revealed that NK cells were downregulated and plasma cells and memory B cells were upregulated in IPF. Further correlation analysis showed that GPA33 expression was positively correlated with NK cells and negatively correlated with plasma cells and memory B cells. Conclusion: Our study provides a new perspective for the role of telomere dysfunction and immune infiltration in IPF and identifies potential therapeutic targets. Further research may reveal how core genes affect cell function and disease progression, providing new insights into the complex mechanisms of IPF. [ABSTRACT FROM AUTHOR]

ABSTRACT Dyskeratosis congenita (DC) is a rare inherited bone marrow disease that classically presents with the triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. It is most commonly caused by a defect in the DKC1 gene involved in telomere stability. Malignant progression of oral leukoplakia to squamous cell carcinoma (SCC) is rare in DC, especially in younger patients, and cutaneous SCC is only reported in 1.5% of cases of DC. Here we report a case of a 12‐year‐old female with a familial heterozygous RTEL1 (regulator of telomere elongation helicase 1) gene mutation associated with a severe phenotype of DC characterized by multiple cutaneous SCCs. [ABSTRACT FROM AUTHOR]

Women typically outlive men, yet they often experience greater frailty and a higher incidence of chronic diseases as they age. By exploring the biological foundations of aging, with a particular focus on telomere dynamics, this manuscript aims to describe how dietary and lifestyle choices can significantly influence the aging process. The review comprehensively examines current research, underscoring the power of nutrition to counteract age-related changes, support healthy aging, and maintain vitality and beauty in women. The exploration of telomeres—the protective caps at the ends of chromosomes—reveals how they serve as markers of cellular aging and are potential targets for interventions aimed at enhancing women's longevity and quality of life. This study also emphasizes the importance of sex-specific approaches and precision medicine in understanding the unique health challenges women face as they age. By proposing targeted strategies, the review seeks to address these challenges, offering insights into preventive measures that can foster resilience, promote well-being, and extend healthy life expectancy in women. Ultimately, this work provides a sophisticated understanding of the aging process in women, highlighting the pivotal role of tailored interventions in preserving both health and beauty. [ABSTRACT FROM AUTHOR]

Introduction: Alternative lengthening of telomeres (ALT) occurs in sarcomas and ALT cancers share common mechanisms of therapy resistance or sensitivity. Telomeric DNA C-circles are self-primed circular telomeric repeats detected with a PCR assay that provide a sensitive and specific biomarker exclusive to ALT cancers. We have previously shown that 23% of high-risk neuroblastomas are of the ALT phenotype. Here, we investigate the frequency of ALT in Ewing's family sarcoma (EFS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) by analyzing DNA from fresh frozen primary tumor samples utilizing the real-time PCR C-circle Assay (CCA). Methods: We reviewed prior publications on ALT detection in pediatric sarcomas. DNA was extracted from fresh frozen primary tumors, fluorometrically quantified, C-circles were selectively enriched by isothermal rolling cycle amplification and detected by real-time PCR. Results: The sample cohort consisted of DNA from 95 EFS, 191 RMS, and 87 OS primary tumors. One EFS and 4 RMS samples were inevaluable. Using C-circle positive (CC+) cutoffs previously defined for high-risk neuroblastoma, we observed 0 of 94 EFS, 5 of 187 RMS, and 62 of 87 OS CC+ tumors. Conclusions: Utilizing the ALT-specific CCA we observed ALT in 0% of EFS, 2.7% of RMS, and 71% of OS. These data are comparable to prior studies in EFS and OS using less specific ALT markers. The CCA can provide a robust and sensitive means of identifying ALT in sarcomas and has potential as a companion diagnostic for ALT targeted therapeutics. [ABSTRACT FROM AUTHOR]

The oocytes of aging women are more prone to aneuploidy. Oocyte aneuploidy is a significant factor contributing to the reduced fertility in aging women and the unfavorable pregnancy outcomes, including miscarriage, chromosomal abnormalities and birth defects. With the increase of age, the accumulation of reactive oxygen species (ROS) in oocytes causes the oxidative stress damage that interferes with the signal transduction of spindle assembly and spindle assembly checkpoints, shortens telomeres and reduces chromosome cohesion. The oxidative stress is therefore an important reason for the increase of aneuploidy of oocytes. We review the relationship between oxidative stress and aneuploidy in oocytes of aging women, in order to provide a reference for saving the fertility of aging women. [ABSTRACT FROM AUTHOR]

MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments. Mechanisms of action of miRNAs in regulating the hTERT complex and their impact on the tumor cells phenotypes. [ABSTRACT FROM AUTHOR]

Shortening telomere length (TL) is an important ageing marker associated with substance use disorder (SUD). However, the influence of psychiatric and clinical comorbidities and alcohol-related outcomes has not been much explored in the context of TL in individuals with alcohol use disorder (AUD) and may be a source of heterogeneity in AUD studies. Therefore, our aim was to investigate the influence of AUD, alcohol-related outcomes, and common psychiatric comorbidities on TL in men with AUD and healthy controls (HC). Men with AUD (n = 108, mean age = 52.4, SD = 8.6) were recruited in a detoxification unit, and HC (n = 80, mean age = 50.04, SD = 9.1) from the blood bank, both located in Brazil. HC had no current or lifetime diagnosis of any substance use disorder. Psychiatric comorbidities were assessed using SCID-I. TL ratio was measured in triplicates using quantitative multiplex PCR. Telomere length did not differ between individuals with AUD and HC (p = 0.073) or was associated with AUD-related outcomes, trauma, or clinical comorbidities. Individuals with externalizing disorders had longer TL when comparing with those with internalizing disorders (p = 0.018) or without comorbidity (p = 0.018). Our findings indicate that TL was influenced by the presence of psychiatric comorbidity rather than case or control status. These results were adjusted for potential confounders, such as age. • Telomere length is a marker of ageing. • Telomere length did not differ between individuals with AUD and controls. • Individuals with externalizing disorders have longer telomere length. [ABSTRACT FROM AUTHOR]

Viruses are the most abundant biological entities in the world's oceans, where they play important ecological and biogeochemical roles. Metagenomics is revealing new groups of eukaryotic viruses, although disconnected from known hosts. Among these are the recently described mirusviruses, which share some similarities with herpesviruses.1 50 years ago, "herpes-type" viral particles2 were found in a thraustochytrid member of the labyrinthulomycetes, a diverse group of abundant and ecologically important marine eukaryotes,3,4 but could not be further characterized by methods then available. Long-read sequencing has allowed us to connect the biology of mirusviruses and thraustochytrids. We sequenced the genome of the genetically tractable model thraustochytrid Aurantiochytrium limacinum ATCC MYA-1381 and found that its 26 linear chromosomes have an extraordinary configuration. Subtelomeric ribosomal DNAs (rDNAs) found at all chromosome ends are interspersed with long repeated sequence elements denoted as long repeated-telomere and rDNA spacers (LORE-TEARS). We identified two genomic elements that are related to mirusvirus genomes. The first is a ∼300-kbp episome (circular element 1 [CE1]) present at a high copy number. Strikingly, the second, distinct, mirusvirus-like element is integrated between two sets of rDNAs and LORE-TEARS at the left end of chromosome 15 (LE-Chr15). Similar to metagenomically derived mirusviruses, these putative A. limacinum mirusviruses have a virion module related to that of herpesviruses along with an informational module related to nucleocytoplasmic large DNA viruses (NCLDVs). CE1 and LE-Chr15 bear striking similarities to episomal and endogenous latent forms of herpesviruses, respectively, and open new avenues of research into marine virus-host interactions.

Abstract To study telomere maintenance mechanism (TMM) activation during malignant transformation, we compared neurofibroma (NF) and malignant peripheral nerve sheath tumor (MPNST) in the same patient with type-1 neurofibromatosis (NF1), a total of 20 NF-MPNST pairs in 20 NF1 patients. These comparisons minimized genetic bias and contrasted only changes associated with malignant transformation, while subtracting changes that developed upon the transformation of normal cells to the benign tumor. TGF-β superfamily genes were found to activate the PAX and SOX transcription factors, leading to TMM activation. BMPER activates PAX6 through BMP2 and PAX7 through BMP4; BMP15 activates SOX14; and INHBC activates PAX9 and SOX14. The activated PAX and SOX genes sequentially establish the core architecture of the RAD52-dependent alternative lengthening of telomeres (ALT). Specifically, PAX7 activates the recombinase (RAD52) and a negative regulator (SLX4IP). PAX6 and SOX14 activate positive regulators (BLM and BRCA2, respectively). PAX9 and SOX14 activate RAD9B and FEN1, which are responsible for the stability of homologous recombination intermediates and increase, together with RAD52, the telomere length. Telomere elongation achieved by the activation of PAX7 and PAX9 is associated with a poor prognosis. We demonstrated that TGF-β superfamily-induced transcriptional activation pathways activated the RAD52-dependent ALT during malignant transformation of MPNSTs.

Abstract Background Biological aging is a complex process influenced by various factors, including reproductive status and castration. This study aimed to evaluate the impact of castration on biological aging in dogs. Method Fifteen male crossbred dogs were randomly divided into a sham-operation control group (n = 5) and a castrated group (n = 10). Blood samples were collected at weeks 0, 4, 8, 12, 16, and 18 post-surgery. Malondialdehyde (MDA as indicator of Lipid peroxidation), C-reactive protein (as an indicator of inflammation), telomere length, mitochondrial DNA (mtDNA) copy number, and the expression of age-related (P16, P21, TBX2) and telomerase-related (TERT) genes were assessed in blood samples. Results Plasma MDA levels were higher in the control group at weeks 16 and 18, while CRP levels were higher only at week 18. Telomere length and mtDNA copy number were lower in the control group at week 18. Gene expression analysis showed that P16 was lower in the control group at weeks 8 and 12, P21 and TERT were lower at weeks 16 and 18, and TBX2 was lower at weeks 16 and 18. The TBX2/P16 ratio was lower in the control group at weeks 16 and 18 but higher at week 12, while the TBX2/P21 ratio did not differ between groups. Conclusion Castration appears to have a protective effect against biological aging in dogs, as evidenced by lower lipid peroxidation, inflammation, and age-related changes in telomere length, mtDNA copy number, and gene expression.

Abstract Background Telomeric repeat arrays at the ends of chromosomes are highly dynamic in composition, but their repetitive nature and technological limitations have made it difficult to assess their true variation in genome diversity surveys. Results We have comprehensively characterized the sequence variation immediately adjacent to the canonical telomeric repeat arrays at the very ends of chromosomes in 74 genetically diverse Arabidopsis thaliana accessions. We first describe several types of distinct telomeric repeat units and then identify evolutionary processes such as local homogenization and higher-order repeat formation that shape diversity of chromosome ends. By comparing largely isogenic samples, we also determine repeat number variation of the degenerate and variant telomeric repeat array at both the germline and somatic levels. Finally, our analysis of haplotype structure uncovers chromosome end-specific patterns in the distribution of variant telomeric repeats, and their linkage to the more proximal non-coding region. Conclusions Our findings illustrate the spectrum of telomeric repeat variation at multiple levels in A. thaliana—in germline and soma, across all chromosome ends, and across genetic groups—thereby expanding our knowledge of the evolution of chromosome ends.

Abstract Migraine, common in individuals under 50 years, is linked to oxidative stress. The association between telomere length shortening and migraine, along with potential age-related influences, has not been comprehensively studied. This cross-sectional study included data from 6169 participants in the National Health and Nutrition Survey (NHANES) from 1999 to 2002, encompassing information on peripheral blood leukocyte telomere length, severe headache or migraine, and potential confounders. Stratifying by age (20–50 years, > 50 years), we employed multivariable logistic regression, restricted cubic splines and interaction test to investigate age-influenced telomere length in relation to migraine. In participants aged 20–50 years, the odds ratio (OR) for migraine in the shortest telomere length group T1 (0.39–0.89) was 1.35 (95% confidence interval [95% CI] 1.01, 1.79) compared to the longest group T3 (1.10–9.42), whereas in those aged > 50 years, the OR of T1 was 0.93 (95% CI 0.60, 1.43). Additionally, telomere length and age interacted in the development of migraine (p for interaction: 0.010). In individuals aged 20–50, an L-shaped relationship was found between telomere length and migraine, with an inflection point at 1.02T/S ratio. The OR was 9.34 (95% CI 1.56, 55.99) for telomere lengths

Abstract Background Telomeres are a critical component of chromosome integrity and are essential to the development of cancer and cellular senescence. The regulation of breast cancer by telomere-associated lncRNAs is not fully known, though. The goals of this study were to describe predictive telomere-related LncRNAs (TRL) in breast cancer and look into any possible biological roles for these RNAs. Methods We obtained RNA-seq data, pertinent clinical data, and a list of telomere-associated genes from the cancer genome atlas and telomere gene database, respectively. We subjected differentially expressed TRLs to co-expression analysis and univariate Cox analysis to identify a prognostic TRL. Using LASSO regression analysis, we built a prognostic model with 14 TRLs. The accuracy of the model’s prognostic predictions was evaluated through the utilization of Kaplan-Meier (K-M) analysis as well as receiver operating characteristic (ROC) curve analysis. Additionally, immunological infiltration and immune drug prediction were done using this model. Patients with breast cancer were divided into two subgroups using cluster analysis, with the latter analyzed further for variations in response to immunotherapy, immune infiltration, and overall survival, and finally, the expression of 14-LncRNAs was validated by RT-PCR. Results We developed a risk model for the 14-TRL, and we used ROC curves to demonstrate how accurate the model is. The model may be a standalone prognostic predictor for patients with breast cancer, according to COX regression analysis. The immune infiltration and immunotherapy results indicated that the high-risk group had a low level of PD-1 sensitivity and a high number of macrophages infiltrating. In addition, we’ve discovered a number of small-molecule medicines with considerable for use in treating high-risk groups. The cluster 2 subtype showed the highest immune infiltration, the highest immune checkpoint expression, and the worst prognosis among the two subtypes defined by cluster analysis, which requires more attention and treatment. Conclusion As a possible biomarker, the proposed 14-TRL signature could be utilized to evaluate clinical outcomes and treatment efficacy in breast cancer patients.

Advances in long-read sequencing and assembly now mean that individual labs can generate phased genomes that are more accurate and more contiguous than the original human reference genome. With declining costs and increasing democratization of technology, we suggest that complete genome assemblies, where both parental haplotypes are phased telomere to telomere, will become standard in human genetics. Soon, even in clinical settings where rigorous sample-handling standards must be met, affected individuals could have reference-grade genomes fully sequenced and assembled in just a few hours given advances in technology, computational processing, and annotation. Complete genetic variant discovery will transform how we map, catalog, and associate variation with human disease and fundamentally change our understanding of the genetic diversity of all humans.

BackgroundStudies suggest a harmful pharmacogenomic interaction exists between short leukocyte telomere length (LTL) and immunosuppressants in idiopathic pulmonary fibrosis (IPF). It remains unknown if a similar interaction exists in non-IPF interstitial lung disease (ILD).MethodsA retrospective, multicentre cohort analysis was performed in fibrotic hypersensitivity pneumonitis (fHP), unclassifiable ILD (uILD) and connective tissue disease (CTD)-ILD patients from five centres. LTL was measured by quantitative PCR for discovery and replication cohorts and expressed as age-adjusted percentiles of normal. Inverse probability of treatment weights based on propensity scores were used to assess the association between mycophenolate or azathioprine exposure and age-adjusted LTL on 2-year transplant-free survival using weighted Cox proportional hazards regression incorporating time-dependent immunosuppressant exposure.ResultsThe discovery and replication cohorts included 613 and 325 patients, respectively. In total, 40% of patients were exposed to immunosuppression and 22% had LTL

BACKGROUND: Womens reproduction requires increased energy demands, which consequently may lead to cellular damage and aging. Hence, Telomere Length (TL), a biomarker of biological aging and health status may possibly serve as a biomarker of reproductive effort. The aim of this systematic review is to evaluate telomere dynamics throughout pregnancy and the association between parity and TL. METHODS: A systematic search was conducted across seven databases including CINAHL, Cochrane, PsycINFO, Proquest, PubMed; Scopus; and Web of Science, using keywords and MeSH descriptors of parity and TL. Predefined inclusion and exclusion criteria were used to screen abstracts and titles. After the removal of duplicates, 3431 articles were included in the primary screening, narrowed to 194 articles included in the full-text screening. Consensus was reached for the 14 studies that were included in the final review, and the Newcastle-Ottawa scale (NOS) was utilized to assess the quality of the selected studies. A mini meta-analysis utilized JASP 0.17.3 software and included 4 applicable studies, comprising a total of 2564 participants to quantitatively assess the estimated effect size of parity on TL. RESULTS: Of the 11 studies reviewed on parity and TL, four demonstrated a negative correlation; one - a positive correlation and six -found no correlation. Studies demonstrating a negative correlation encompassed rigorous methodological practices possibly suggesting having more children is associated with enhanced telomere attrition. Of the four longitudinal studies assessing telomere dynamics throughout pregnancy, most found no change in TL from early pregnancy to postpartum suggesting pregnancy does not affect TL from early pregnancy to early postpartum. The meta-analysis revealed a negative, yet, non-significant effect, of the estimated effect size of parity on TL(ES = -0.009, p = 0.126, CI -0.021, 0.03). CONCLUSIONS: Studies assessing pregnancy, parity and TL yielded mixed results, most likely due to the different research methods utilized in each study. Improvements in study design to better understand the short-term effects of pregnancy on TL and the effect of parity on TL over time, include precise definitions of parity, comparisons of different age groups, inclusion of reproductive lifespan and statistically adjusting for potential confounders in the parity and TL relationship.

BackgroundAlthough maternal stressor exposure has been associated with shorter telomere length (TL) in offspring, this literature is based largely on White samples. Furthermore, timing of maternal stressors has rarely been examined. Here, we examined how maternal stressors occurring during adolescence, pregnancy, and across the lifespan related to child TL in Black and White mothers.MethodMothers (112 Black; 110 White; Mage = 39) and their youngest offspring (n = 222; Mage = 8) were part of a larger prospective cohort study, wherein mothers reported their stressors during adolescence (assessed twice during adolescence for the past year), pregnancy (assessed in midlife for most recent pregnancy), and across their lifespan (assessed in midlife). Mother and child provided saliva for TL measurement. Multiple linear regression models examined the interaction of maternal stressor exposure and race in relation to child TL, controlling for maternal TL and child gender and age. Race-stratified analyses were also conducted.ResultsNeither maternal adolescence nor lifespan stressors interacted with race in relation to child TL. In contrast, greater maternal pregnancy stressors were associated with shorter child TL, but this effect was present for children of White but not Black mothers. Moreover, this effect was significant for financial but not social pregnancy stressors. Race-stratified models revealed that greater financial pregnancy stressors predicted shorter telomeres in offspring of White, but not Black mothers.ConclusionsRace and maternal stressors interact and are related to biological aging across generations, but these effects are specific to certain races, stressors, and exposure time periods.

Genomic stability in proliferating cells critically depends on telomere maintenance by telomerase reverse transcriptase. Here we report the development and proof-of-concept results of a single-molecule approach to monitor the catalytic activity of human telomerase in real time and with single-nucleotide resolution. Using zero-mode waveguides and multicolor FRET, we recorded the processive addition of multiple telomeric repeats to individual DNA primers. Unlike existing biophysical and biochemical tools, the novel approach enables the quantification of nucleotide-binding kinetics before nucleotide incorporation. Moreover, it provides a means to dissect the unique translocation dynamics that telomerase must undergo after synthesis of each hexameric DNA repeat. We observed an unexpectedly prolonged binding dwell time of dGTP in the enzyme active site at the start of each repeat synthesis cycle, suggesting that telomerase translocation is composed of multiple rate-contributing sub-steps that evade classical biochemical analysis.

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

Lithium is an established first-line treatment for bipolar disorder. Beyond its therapeutic effect as a mood stabiliser, lithium exhibits potential anti-ageing effects. This study aimed to examine the relationship between the duration of lithium use, biological ageing and mortality. The UK Biobank is an observational study of middle-aged and older adults. We tested associations between the duration of lithium use (number of prescriptions, total duration of use and duration of the first prescription period) and telomere length, frailty, metabolomic age (MileAge) delta, pulse rate and all-cause mortality. Five hundred ninety-one individuals (mean age = 57.49 years; 55% females) had been prescribed lithium. There was no evidence that the number of prescriptions (β = − 0.022, 95% CI − 0.081 to 0.037, p = 0.47), the total duration of use (β = − 0.005, 95% CI − 0.023 to 0.013, p = 0.57) or the duration of the first prescription period (β = − 0.018, 95% CI − 0.051 to 0.015, p = 0.29) correlated with telomere length. There was also no evidence that the duration of lithium use correlated with frailty or MileAge delta. However, a higher prescription count and a longer duration of use was associated with a lower pulse rate. The duration of lithium use did not predict all-cause mortality. We observed no evidence of associations between the duration of lithium use and biological ageing markers, including telomere length. Our findings suggest that the potential anti-ageing effects of lithium do not differ by the duration of use. [ABSTRACT FROM AUTHOR]

The present study examined whether male resveratrol intake affected mitochondrial DNA copy number (mt-cn) and telomere length (TL) in blastocysts fathered by young and aged male mice. C57BL/6N male mice supplied with water or water containing 0.1 mM resveratrol were used for embryo production at 14–23 and 48–58 weeks of age. Two-cell-stage embryos were collected from the oviducts of superovulated female mice (8–15 weeks old) and cultured for 3 days until the blastocyst stage. Mt-cn and TL levels were measured by real-time polymerase chain reaction. Resveratrol intake did not affect body weight or water consumption. Resveratrol intake increased the expression levels of SIRT1 in the liver, the antioxidative ability of serum, and extended TL in the heart, whereas there was no significant difference in mt-cn in the heart or TL in sperm. The rate of blastocyst development was significantly lower in aged male mice than in younger mice, and resveratrol intake increased the total number of blastocysts derived from both young and aged males. Resveratrol intake did not affect mt-cn or TL in blastomeres of blastocyst-stage embryos derived from young mice, but significantly increased both mt-cn and TL in blastomeres of blastocysts derived from aged fathers. In conclusion, resveratrol intake increased mt-cn and TL levels in blastocysts derived from aged male mice.

Emmanuel Ifeanyi Obeagu,1 Getrude Uzoma Obeagu2 1Department of Medical Laboratory Science, Kampala International University, Ishaka, Uganda; 2School of Nursing Science, Kampala International University, Ishaka, UgandaCorrespondence: Emmanuel Ifeanyi Obeagu, Department of Medical Laboratory Science, Kampala International University, Uganda, Email emmanuelobeagu@yahoo.comAbstract: Sickle Cell Anemia (SCA) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. While extensive research has unraveled many aspects of the genetic and molecular basis of SCA, the role of telomere dynamics in disease progression remains a relatively unexplored frontier. This review seeks to provide a comprehensive examination of telomere biology within the context of SCA, aiming to elucidate its potential impact on molecular aging and the progression of the disease. The impact of oxidative stress on telomere dynamics in SCA is explored, with a particular focus on how increased reactive oxygen species (ROS) may contribute to accelerated telomere shortening and genomic instability. Furthermore, the potential relationship between telomere dysfunction and cellular senescence in SCA is investigated, shedding light on how telomere dynamics may contribute to the premature aging of cells in this population. The review concludes by summarizing key findings and proposing potential therapeutic strategies targeting telomere dynamics to mitigate disease progression in SCA. It also identifies gaps in current understanding and suggests avenues for future research, emphasizing the importance of further investigating telomere biology to advance our understanding of molecular aging and disease progression in Sickle Cell Anemia. This comprehensive exploration of telomere dynamics in SCA offers insights into potential mechanisms of molecular aging and disease progression, paving the way for targeted therapeutic interventions and improved disease management.Keywords: sickle cell anemia, telomere, molecular aging, hemoglobinopathy, telomere shortening, oxidative stress

Here, a comprehensive cytogenetic analysis of three species of tenebrionid beetles: Alphitobius diaperinus, Tenebrio molitor and Zophobas morio, is presented. This paper also contains a review of the cytogenetic information for each species and adds new data. The male karyotype of both T. molitor and Z. morio is 2n = 18 + Xyp, with large heterochromatic blocks in the pericentromeric regions of all chromosomes. The male A. diaperinus karyotype is 2n = 18 + X0, also with heterochromatic pericentromeric regions in all chromosomes. The location of the nucleolar organizer regions (NORs) differs in each species: in A. diaperinus, it is located on the smallest pair of autosomes, while in T. molitor, it is on two pairs of autosomes and both sex chromosomes. In contrast, it is exclusively located on the X chromosome in Z. morio. Telomere analysis revealed that all species have TCAGG repeats in their telomeres, but lack the canonical TTAGG insect telomeric motif. In addition, a study of the distribution of satellite DNA and composition revealed that each species has a main satellite DNA family forming the pericentromeric heterochromatin. Fluorescence in situ hybridization of each of these satellites did not produce hybridization signal in the other two species, indicating a divergence in repetitive DNA composition among them. This study adds to the understanding of chromosomal organization, heterochromatin distribution and repetitive DNA dynamics in tenebrionid beetles and sheds light on their cytogenetic diversity and evolutionary significance.

Abstract Background Telomeres consist of repetitive DNA sequences at the chromosome ends to protect chromosomal stability, and primarily maintained by telomerase or occasionally by alternative telomere lengthening of telomeres (ALT) through recombination-based mechanisms. Additional mechanisms that may regulate telomere maintenance remain to be explored. Simultaneous measurement of telomere length and transcriptome in the same human embryonic stem cell (hESC) revealed that mRNA expression levels of UBQLN1 exhibit linear relationship with telomere length. Methods In this study, we first generated UBQLN1-deficient hESCs and compared with the wild-type (WT) hESCs the telomere length and molecular change at RNA and protein level by RNA-seq and proteomics. Then we identified the potential interacting proteins with UBQLN1 using immunoprecipitation-mass spectrometry (IP-MS). Furthermore, the potential mechanisms underlying the shortened telomeres in UBQLN1-deficient hESCs were analyzed. Results We show that Ubiquilin1 (UBQLN1) is critical for telomere maintenance in human embryonic stem cells (hESCs) via promoting mitochondrial function. UBQLN1 deficiency leads to oxidative stress, loss of proteostasis, mitochondria dysfunction, DNA damage, and telomere attrition. Reducing oxidative damage and promoting mitochondria function by culture under hypoxia condition or supplementation with N-acetylcysteine partly attenuate the telomere attrition induced by UBQLN1 deficiency. Moreover, UBQLN1 deficiency/telomere shortening downregulates genes for neuro-ectoderm lineage differentiation. Conclusions Altogether, UBQLN1 functions to scavenge ubiquitinated proteins, preventing their overloading mitochondria and elevated mitophagy. UBQLN1 maintains mitochondria and telomeres by regulating proteostasis and plays critical role in neuro-ectoderm differentiation.

Abstract Alterations in telomeres constitute some of the earliest occurrences in the tumourigenesis of prostate adenocarcinoma (PRAD) and persist throughout the progression of the tumour. While the activity of telomerase and the length of telomeres have been demonstrated to correlate with the prognosis of PRAD, the prognostic potential of telomere-related genes (TRGs) in this disease remains unexplored. Utilising mRNA expression data from the Cancer Genome Atlas (TCGA), we devised a risk model and a nomogram to predict the survival outcomes of patients with PRAD. Subsequently, our investigations extended to the relationship between the risk model and immune cell infiltration, sensitivity to chemotherapeutic drugs, and specific signalling pathways. The risk model we developed is predicated on seven key TRGs, and immunohistochemistry results revealed significant differential expression of three TRGs in tumours and paracancerous tissues. Based on the risk scores, PRAD patients were stratified into high-risk and low-risk cohorts. The Receiver operating characteristics (ROC) and Kaplan–Meier survival analyses corroborated the exceptional predictive performance of our novel risk model. Multivariate Cox regression analysis indicated that the risk score was an independent risk factor associated with Overall Survival (OS) and was significantly associated with T and N stages of PRAD patients. Notably, the high-risk group exhibited a greater response to chemotherapy and immunosuppression compared to the low-risk group, offering potential guidance for treatment strategies for high-risk patients. In conclusion, our new risk model, based on TRGs, serves as a reliable prognostic indicator for PRAD. The model holds significant value in guiding the selection of immunotherapy and chemotherapy in the clinical management of PRAD patients.