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Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Schizosaccharomyces pombe. Using quantitative measures, iterative genetic screening and domain-specific heterochromatin reporters, we identified 369 mutants with different degrees of reduced or enhanced silencing. As expected, mutations in the core heterochromatin machinery globally decreased silencing. However, most other mutants exhibited distinct qualitative and quantitative profiles that indicate heterochromatin domain-specific functions, as seen for example for metabolic pathways affecting primarily subtelomere silencing. Moreover, similar phenotypic profiles revealed shared functions for subunits within complexes. We further discovered that the uncharacterized protein Dhm2 plays a crucial role in heterochromatin maintenance, affecting the inheritance of H3K9 methylation and the clonal propagation of the repressed state. Additionally, Dhm2 loss resulted in delayed S-phase progression and replication stress. Collectively, our systematic approach unveiled a landscape of domain-specific heterochromatin regulators controlling distinct states and identified Dhm2 as a previously unknown factor linked to heterochromatin inheritance and replication fidelity.

Weight-inducing psychotropic treatments are risk factors for age-related diseases such as cardiovascular disorders, which are associated with both inflammation and telomere length shortening. With a longitudinal design, the present study evaluates telomere length trajectories after 1 year of weight-inducing psychotropic medication, accounting for weight changes and the inflammatory biomarker high-sensitivity C-Reactive Protein (CRP). Among 200 patients, an overall median telomere shortening of -41.2 bp was observed (p = 0.014), which is comparable with the general populations yearly telomere attrition. Linear regression showed on average -93.1 and -58.9 bp of further telomere shortening per five units of BMI for BMI values < or ≥30 kg/m2, respectively (p = 0.003 and p = 0.009, respectively). Importantly, the overall telomere shortening was predicted to be increased four-fold among patients with low baseline weight (i.e., 50 kg) and with clinically relevant weight gain (≥ 7%) after 1 year of treatment (interaction term between relevant weight gain and baseline weight: +6.3 bp, p = 0.016). Patients with relevant weight gain showed greater CRP levels (+ 49%; p = 0.016), and a telomere shortening of -36.2 bp (p = 0.010) was estimated whenever CRP level doubled. Mendelian randomization using UKBiobank data showed a causal effect of BMI on telomere shortening, notably stronger among patients receiving weight-inducing psychotropic treatments (n = 9798) than among psychiatric patients without such drugs (n = 16228) and non-psychiatric controls (n = 252932) (beta: -0.37, -0.12, -0.06, respectively; p = 0.004, p

The human telomere system is highly dynamic. Both short and long leucocyte average telomere lengths (aTL) are associated with an increased risk of cancer and early death, illustrating the complex relationship between TL and human health and the importance of assessing TL distributions with single TL analysis. A DNA microarray and telomere fluorescent in situ hybridization (DNA-array-FISH) approach was developed to measure the base-pair (bp) lengths of single telomeres. On average 32000 telomeres were measured per DNA sample with one microarray chip assaying 96 test DNA samples. Various telomere parameters, i.e. aTL and the frequency of short/long telomeres, were computed to delineate TL distribution. The intra-assay and inter-assay coefficient of variations of aTL ranged from 1.37% to 3.98%. The correlation coefficient (r) of aTL in repeated measurements ranged from 0.91 to 1.00, demonstrating high measurement precision. aTLs measured by DNA-array-FISH predicted aTLs measured by terminal restriction fragment (TRF) analysis with r ranging 0.87-0.99. A new accurate and high-throughput method has been developed to measure the bp lengths of single telomeres. The large number of single TL data provides an opportunity for an in-depth analysis of telomere dynamics and the complex relationship between telomere and age-related diseases.

The Human Genome Project was an enormous accomplishment, providing a foundation for countless explorations into the genetics and genomics of the human species. Yet for many years, the human genome reference sequence remained incomplete and lacked representation of human genetic diversity. Recently, two major advances have emerged to address these shortcomings: complete gap-free human genome sequences, such as the one developed by the Telomere-to-Telomere Consortium, and high-quality pangenomes, such as the one developed by the Human Pangenome Reference Consortium. Facilitated by advances in long-read DNA sequencing and genome assembly algorithms, complete human genome sequences resolve regions that have been historically difficult to sequence, including centromeres, telomeres, and segmental duplications. In parallel, pangenomes capture the extensive genetic diversity across populations worldwide. Together, these advances usher in a new era of genomics research, enhancing the accuracy of genomic analysis, paving the path for precision medicine, and contributing to deeper insights into human biology.

Structural variants (SVs) account for the majority of base pair differences both within and between primate species. However, our understanding of inter- and intra-species SV has been historically hampered by the quality of draft primate genomes and the absence of genome resources for key taxa. Recently, advances in long-read sequencing and genome assembly have begun to radically reshape our understanding of SVs. Two landmark achievements include the publication of a human telomere-to-telomere (T2T) genome as well as the development of the first human pangenome reference. In this review, we first look back to the major works laying the foundation for these projects. We then examine the ways in which T2T genome assemblies and pangenomes are transforming our understanding of and approach to primate SV. Finally, we discuss what the future of primate SV research may look like in the era of T2T genomes and pangenomics.

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.

Aim: Bioinformatics analyses were performed to identify telomere biomarkers to develop a diagnostic model for lung adenocarcinoma (LUAD) and to predict potential target drugs for patients with LUAD. Background: Telomeres function crucially in maintaining genome stability and chromosome integrity, and telomere-related genes (TRGs) serve as potential prognostic markers in a variety of cancers. However, studies focusing on TRGs in LUAD are limited. Objective: To screen key telomere-related markers for LUAD and to evaluate their potential impact on the occurrence and development of LUAD. Methods: LUAD samples were collected from University of California Santa Cruz (UCSC) Xena and 2093 telomere-related genes (TRGs) were obtained from TelNet database. Hub genes were screened using "WGCNA" package. Differentially expressed genes (DEGs) between tumor and control samples were filtered using "DESeq" package. Protein–protein interaction (PPI) network analysis was performed to select candidate genes, from which telomere-related biomarkers were identified by machine learning and used to develop a nomogram. Functional enrichment pathways of the biomarkers were analyzed using "clusterProfiler" package. Correlation between immune cell infiltration and the biomarkers was examined by Spearman method. Targeted drugs were predicted and molecular docking models were developed using AutoDockTools. Finally, the screened biomarkers were validated by performing in vitro cellular assays. Results: A total of 259 hub genes, 2848 DEGs, and 48 differentially expressed TRGs in LUAD were screened. Subsequently, 13 candidate genes were obtained by PPI network analysis. LASSO and support vector machine-recursive feature elimination (SVM-RFE) algorithms further reduced the number of telomere-related biomarkers to four (CCNB1, CDC20, PLK1, and TOP2A). A nomogram with a strong predictive performance was created. These four biomarkers were mainly enriched in the mitogenic pathways and exhibited a strong correlation with immune cell infiltration. Three drugs (Lucanthone, Fulvestrant, and Myricetin) targeting the four biomarkers were predicted to be able to treat LUAD. Finally, in vitro cellular experiments demonstrated that CCNB1 and PLK1 have potential effects on proliferation, migration, invasion and AKT/mTOR signaling pathway in LUAD cells. Conclusion: This study provided novel diagnostic biomarkers, therapeutic targets, and potential drugs for LUAD. [ABSTRACT FROM AUTHOR]

Telomeres protect chromosome ends from damage, but they shorten with each cell division due to the limitations of DNA replication and are further affected by oxidative stress. This shortening is a key feature of aging, and telomerase, an enzyme that extends telomeres, helps mitigate this process. Aging is also associated with mitochondrial dysfunction, leading to increased reactive oxygen species (ROS) that exacerbate cellular damage and promote apoptosis. Elevated ROS levels can damage telomeres by oxidizing guanine and disrupting their regulation. Conversely, telomere damage impacts mitochondrial function, and activation of telomerase has been shown to reverse this decline. A critical link between telomere shortening and mitochondrial dysfunction is the DNA damage response, which activates the tumor suppressor protein p53, resulting in reduced mitochondrial biogenesis and metabolic disruptions. This highlights the bidirectional relationship between telomere maintenance and mitochondrial function. This review explores the complex interactions between telomeres and mitochondria across various cell types, from fibroblasts to sperm cells, shedding light on the interconnected mechanisms underlying aging and cellular function. [ABSTRACT FROM AUTHOR]

Biomarkers of ageing (BA) can predict health risks beyond chronological age, but little is known about how marital/living status affects longitudinal changes in BA. We examined the association between marital/living status and BA over time using the-Swedish-Adoption/Twin-Study-of-Aging (SATSA) cohort. Four BAs were analyzed: telomere length (TL) (638 individuals; 1603 measurements), DNAmAge (535 individuals; 1392 measurements), cognition (823 individuals; 3218 measurements), and frailty index (FI) (1828 individuals; 9502 measurements). Individuals were born between 1900 and 1948, and data on marital/living status, BAs, and covariates were collected through nine waves of questionnaires and in-person testing from 1986 to 2014. Mixed linear regression with random effects at twin-pair and individual levels were used to assess BA changes for constant marital/living status. Conditional generalized estimating equation assessed within-individual BA changes for varying marital/living status. Results showed that individuals who were consistently unmarried/non-cohabiting (β = 0.291, 95%CI = 0.189–0.393) or living alone (β = 0.203, 95%CI = 0.090–0.316) were more frail, and experienced accelerated frailty (p-for-interaction with age < 0.001 for marital status; p-for-interaction = 0.002 for living status) and cognitive decline (p-for-interaction < 0.001), compared to those married/cohabiting or living with someone Among individuals whose marital/living status changed, frailty was higher when living alone (β = 0.089, 95%CI = 0.017–0.162) and frailty accelerated when they became unmarried/non-cohabiting or were living alone (p-for-interaction < 0.001). Cognitive decline also accelerated when living alone (p-for-interaction = 0.020). No associations were observed for TL and DNAmAge. In conclusion, being unmarried/non-cohabiting or living alone from mid-to-old age is linked to accelerated cognitive decline and frailty. These findings highlight the potential importance of social support networks and living arrangements for healthy ageing. [ABSTRACT FROM AUTHOR]

Rare germline variation in regulator of telomere elongation helicase 1 (RTEL1) is associated with telomere biology disorders (TBDs). Biallelic RTEL1 variants result in childhood onset dyskeratosis congenita and Hoyeraal‐Hreidarsson syndrome whereas heterozygous individuals usually present later in life with pulmonary fibrosis or bone marrow failure. We compiled all TBD‐associated RTEL1 variants in the literature and assessed phenotypes and outcomes of 44 individuals from 14 families with mono‐ or biallelic RTEL1 variants enrolled in clinical trial NCT00027274. Variants were classified by adapting ACMG‐AMP guidelines using clinical information, telomere length, and variant allele frequency data. Compared with heterozygotes, individuals with biallelic RTEL1 variants had an earlier age at diagnosis (median age 35.5 vs. 5.1 years, p < 0.01) and worse overall survival (median age 66.5 vs. 22.9 years, p < 0.001). There were 257 unique RTEL1 variants reported in 47 publications, and 209 had a gnomAD minor allele frequency <1%. Only 38.3% (80/209) met pathogenic/likely pathogenic criteria. Notably, 8 of 209 reported disease‐associated variants were benign or likely benign and the rest were variants of uncertain significance. Given the considerable differences in outcomes of TBDs associated with RTEL1 germline variants and the extent of variation in the gene, systematic functional studies and standardization of variant curation are urgently needed to inform clinical management. [ABSTRACT FROM AUTHOR]

• Different degrees of MS have varying effects on the susceptibility of adult rats to PTSD. • Rats subjected to short-term MS demonstrate adaptability when confronted with 'secondary stress'. • This process involves telomere shortening in the hippocampus, with notable gender differences. • The relative gene and protein expressions levels of TRF1 and TRF2 were upregulated. Early life stress (ELS) is thought to be a leading cause of mental disorders in adulthood, including PTSD. Recent studies have found that such stress has a gender and resilient specific effect on adult PTSD. This study aimed to assess emotion, and cognitive behavior, and to examine the sex differences and resilience of ELS on adult PTSD. At the same time, the expression of hippocampal telomere length and telomere repeat binding factors (TRF1 and TRF2) were detected to explore the mechanism of telomere length change. Rat offspring were separated from their dams (3 h/day or 6 h/day from PND2 ∼ PND14). Then, pups were treated with a single prolonged stress (SPS) procedure when they reached adulthood (PND80). Rats exposed early to MS and SPS showed anxiety-like and depression-like behaviors as well as impaired learning and memory. The rats exposed to MS3h showed reduced anxiety-like and depression-like behavior upon re-experiencing "secondary stress" compared to the SPS and MS6h groups. Behavioral results showed no significant gender difference. However, gender and SPS factors significantly affected telomere length and TRF1 and TRF2 gene expression in hippocampus. The SPS effect and MS*SPS interaction significantly impacted TRF1 and TRF2 protein expression. In conclusion, this study shows that MS has different effects on anxiety, depression, and cognitive memory deficits in rats experiencing "secondary stress" in adulthood and is accompanied by telomere shortening in the hippocampus. This reveals the potential impact of early MS on PTSD and provides a new perspective for further research in the field of psychological stress. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC), half of which are lung adenocarcinoma (LUAD), is one of the most widely spread cancers in the world. Telomerase, which maintains telomere length and chromosomal integrity, enables cancer cells to avoid replicative senescence. When telomerase is inhibited, cancer cells' senescence began, preventing them from growing indefinitely. Cellular senescence and telomeres are intrinsically linked. As of yet, still laking a systematic study of the involvement of telomere-senescence related genes in lung adenocarcinoma development. In this study, myeloid cells were identified as the cell type which are most correlated with cellular senescence based on its highest telomere-related gene activity. GO, KEGG, GSEA and GSVA analyses were used to explore the biological function of telomere-senescence related genes in LUAD. The combined analysis of single-cell RNA-sequencing and bulk-RNA sequencing identified a gene signature composed of 14 genes which can accurately predict the prognosis of patients with LUAD. In one training and four validation sets, patients with higher Telomere Related Gene Signature (TRGS) had a worse prognosis than those with lower TRGS. Different TRGS patient groups showed varying degrees of immune cell infiltration, frequency of gene missense mutation, sensitivity to different drugs, and tumor mutation burden (TMB). Collectively, we developed a brand new signature composed of telomere-senescence related genes that can accurately predicts patients' prognosis in LUAD, which provides new insights for future research into the role of cellular senescence in LUAD. [ABSTRACT FROM AUTHOR]

Background: Lung adenocarcinoma (LUAD) is a high-risk malignancy. Telomeres- (TRGs) and aging-related genes (ARGs) play an important role in cancer progression and prognosis. This study aimed to develop a novel prognostic model combined TRGs and ARGs signatures to predict the prognosis of patients with LUAD. Methods: LUAD patient's sample data and clinical data were obtained from public databases. The prognostic model was constructed and evaluated using the least absolute shrinkage and selection operator (LASSO), multivariate Cox analysis, time-dependent receiver operating characteristic (ROC), and Kaplan-Meier (K-M) analysis. Immune cell infiltration levels were assessed using single-sample gene set enrichment analysis (ssGSEA). Antitumor drugs with significant correlations between drug sensitivity and the expression of prognostic genes were identified using the CellMiner database. The distribution and expression levels of prognostic genes in immune cells were subsequently analyzed based on the TISCH database. Results: This study identified eight characteristic genes that are significantly associated with LUAD prognosis and could serve as independent prognostic factors, with the low-risk group demonstrating a more favorable outcome. Additionally, a comprehensive nomogram was developed, showing a high degree of prognostic predictive value. The results from ssGSEA indicated that the low-risk group had higher immune cell infiltration. Ultimately, our findings revealed that the high-risk group exhibited heightened sensitivity to the Linsitinib, whereas the low-risk group demonstrated enhanced sensitivity to the OSI-027 drug. Conclusion: The risk score exhibited robust prognostic capabilities, offering novel insights for assessing immunotherapy. This will provide a new direction to achieve personalized and precise treatment of LUAD in the future. [ABSTRACT FROM AUTHOR]

ABSTRACT Genomic projections of (mal)adaptation under future climate change, known as genomic offset, faces limited application due to challenges in validating model predictions. Individuals inhabiting regions with high genomic offset are expected to experience increased levels of physiological stress as a result of climate change, but documenting such stress can be challenging in systems where experimental manipulations are not possible. One increasingly common method for documenting physiological costs associated with stress in individuals is to measure the relative length of telomeres—the repetitive regions on the caps of chromosomes that are known to shorten at faster rates in more adverse conditions. Here we combine models of genomic offsets with measures of telomere shortening in a migratory bird, the yellow warbler (Setophaga petechia), and find a strong correlation between genomic offset, telomere length and population decline. While further research is needed to fully understand these links, our results support the idea that birds in regions where climate change is happening faster are experiencing more stress and that such negative effects may help explain the observed population declines. [ABSTRACT FROM AUTHOR]

Genome maintenance is essential for the integrity of the genetic blueprint, of which only a small fraction is transcribed in higher eukaryotes. DNA lesions occurring in the transcribed genome trigger transcription pausing and transcription‐coupled DNA repair. There are two major transcription‐coupled DNA repair pathways. The transcription‐coupled nucleotide excision repair (TC‐NER) pathway has been well studied for decades, while the transcription‐coupled homologous recombination repair (TC‐HR) pathway has recently gained attention. Importantly, recent studies have uncovered crucial roles of RNA transcripts in TC‐HR, opening exciting directions for future research. Transcription also plays pivotal roles in regulating the stability of highly specialized genomic structures such as telomeres, centromeres, and fragile sites. Despite their positive function in genome maintenance, transcription and RNA transcripts can also be the sources of genomic instability, especially when colliding with DNA replication and forming unscheduled pathological RNA:DNA hybrids (R‐loops), respectively. Pathological R‐loops can result from transcriptional stress, which may be induced by transcription dysregulation. Future investigation into the interplay between transcription and DNA repair will reveal novel molecular bases for genome maintenance and transcriptional stress‐associated genomic instability, providing therapeutic targets for human disease intervention. [ABSTRACT FROM AUTHOR]

Introduction: The changes in histone modifications are linked to the progression of benign and normal tissue to malignancy. Thus, numerous findings suggest that targeting epigenetic factors might be a focus for anti-cancer treatment. In this study, we tested the hypothesis that telomerase activator might be a potential epigenetic regulator in combatting skin cancer cell proliferation. Methods: Melanoma cell line A375 cells were treated with telomerase activator TA-65. Cell senescence assay was done to evaluate the senescence induction. Morphological changes and differences in expression of HDACs and hTERT genes were studied. Further, hyaluronidase and anti-oxidant assays were also performed. Additionally, telomerase enzyme and 20S proteasome activity was also studied. Results: Morphological changes were observed in treated cells and it is evident that telomerase activator induced cellular senescence in high concentrations. From our results, it is evident that HDAC8 and HDAC10 expression was upregulated, whereas hTERT gene expression was downregulated in treated groups. This suggests that the telomerase activator has a regulatory role in skin cancer cells proliferation by targeting the epigenetic factors. Conclusion: Targeting HDACs and hTERT in the treatment of melanoma is a prominent concern. In our current study, we highlight the most recent research, although in its initial stage, involving various epigenetic factors involved in melanoma cells proliferation. [ABSTRACT FROM AUTHOR]

Telomerase (TERT) is a ribonucleoprotein that regulates telomere length and maintains chromosomal integrity. TERT is a widely expressed protein for replicative immortality in most malignant tumours. TERT is a protein produced by cancer cells that prevents telomere shortening by adding telomere sequences beyond the Hayflick limit, allowing them to divide in an uncontrolled manner. Inhibition of the TERT enzyme is a recognised therapy for treating cancer. The basic objective of the review is to collectively represent the current scenario of treating cancer by inhibiting TERT. With a focus on the recently patented TERT inhibitors and clinical trial data released between 2015 and 2023, this review highlights the work relevant to the development of TERT inhibitors. Furthermore, recent advancements in the clinical development of TERT inhibitors, along with prospective new combinations, are also discussed. The use of TERT inhibitors in cancer therapy has been granted with great interest and significant attention by researchers along with a promising outcome in terms of therapeutic value. Several clinical trial applications and their data gave strong evidence of the use of TERT inhibitors for cancer therapy which provided target therapies, vaccine therapies, nucleoside, non‐nucleoside therapies, and so forth with reduced side effects and enhanced potency. [ABSTRACT FROM AUTHOR]

Previous studies have reported an association between telomere length and non-alcoholic fatty liver disease (NAFLD). This study aimed to explore the involvement of alternative lengthening of telomere-related genes (ALTRGs) in the pathology of NAFLD, construct a risk signature, and evaluate both treatment and prognosis. Three NAFLD datasets (GSE48452, GSE89632, and GSE63067) were collected from the GEO database and merged into combined GEO datasets. ALTRGs were collected from GeneCards and PubMed databases. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. This study employed a support vector machine algorithm and least absolute shrinkage and selection operator regression analysis to identify key genes for constructing a diagnostic model. High- and low-risk groups were identified from the combined GEO datasets using the diagnostic model. Gene set enrichment analysis, regulatory network analysis, and intergroup immune infiltration analysis were performed. This study identified the key genes using receiver operating characteristic and Friends analysis. Expression of these genes was validated in a mouse model of NAFLD. Twenty-five genes were differentially expressed, with a positive correlation between FOS and EGR1 and a negative correlation between MYC and CEBPA. A diagnostic model was constructed using 12 genes, and high- and low-risk groups were identified. CAMK2G, ERBB2, FOSB, WT1, and CEBPA showed certain accuracy, and their expression levels were significantly different in the model. Immune infiltration analysis between the risk groups revealed that six immune cells were statistically significant. This includes a strong negative interaction between type 2 T helper cells and SPHK2 in the high-risk group. These findings suggest that ALTRDEGs are potential therapeutic targets and prognostic indicators for NAFLD. However, further investigations are required to elucidate the specific underlying mechanisms. [ABSTRACT FROM AUTHOR]

Telomeres, which are situated at the terminal ends of chromosomes, undergo a reduction in length with each cellular division, ultimately reaching a critical threshold that triggers cellular senescence. Cancer cells circumvent this senescence by utilizing telomere maintenance mechanisms (TMMs) that grant them a form of immortality. These mechanisms can be categorized into two primary processes: the reactivation of telomerase reverse transcriptase and the alternative lengthening of telomeres (ALT) pathway, which is dependent on homologous recombination (HR). Various strategies have been developed to inhibit telomerase activation in 85–95% of cancers, including the use of antisense oligonucleotides such as small interfering RNAs and endogenous microRNAs, agents that simulate telomere uncapping, expression modulators, immunotherapeutic vaccines targeting telomerase, reverse transcriptase inhibitors, stabilization of G-quadruplex structures, and gene therapy approaches. Conversely, in the remaining 5–15% of human cancers that rely on ALT, mechanisms involve modifications in the chromatin environment surrounding telomeres, upregulation of TERRA long non-coding RNA, enhanced activation of the ataxia telangiectasia and Rad-3-related protein kinase signaling pathway, increased interactions with nuclear receptors, telomere repositioning driven by HR, and recombination events between non-sister chromatids, all of which present potential targets for therapeutic intervention. Additionally, combinatorial therapy has emerged as a strategy that employs selective agents to simultaneously target both telomerase and ALT, aiming for optimal clinical outcomes. Given the critical role of anti-TMM strategies in cancer treatment, this review provides an overview of the latest insights into the structure and function of telomeres, their involvement in tumorigenesis, and the advancements in TMM-based cancer therapies. [ABSTRACT FROM AUTHOR]

Introduction:Gloriosa superba L. is a horticulturally and medicinally important plant native to Africa. However, the few cytogenetic studies of the species are mainly focused on chromosome counting and chromosome morphology-based karyotyping. Fluorescence in situ hybridization (FISH) is a powerful tool for the detection of DNA repetitive elements in a specific region of a chromosome. Methods: Here, detailed karyotypes of G. superba were constructed by FISH using 5S and 45S rDNAs, and telomeric repeat (TTTAGGG)3 oligonucleotides. Results and Conclusion: Twenty-two chromosomes were observed. Two 5S rDNA hybridization signals were detected in the proximal regions of the short arms of one pair of chromosomes, which were adjacent to the (TTTAGGG)3 terminal signals. Four 45S rDNA signals were detected near the centromere region of the short arm of the four chromosomes, but one of these was very weak and almost undetectable compared to the others. Telomeric repeat hybridization signals were distributed at the terminal region of each chromosome. The chromosomes displayed were intact, and the chromosome counts were accurate. Chromosome length ranged from 3.46 to 9.31 μm. These results will facilitate the cytogenetic mapping of other major repeats, thus contributing to an improved understanding of the G. superba genome structure and evolutionary history. Introduction:Gloriosa superba L. is a horticulturally and medicinally important plant native to Africa. However, the few cytogenetic studies of the species are mainly focused on chromosome counting and chromosome morphology-based karyotyping. Fluorescence in situ hybridization (FISH) is a powerful tool for the detection of DNA repetitive elements in a specific region of a chromosome. Methods: Here, detailed karyotypes of G. superba were constructed by FISH using 5S and 45S rDNAs, and telomeric repeat (TTTAGGG)3 oligonucleotides. Results and Conclusion: Twenty-two chromosomes were observed. Two 5S rDNA hybridization signals were detected in the proximal regions of the short arms of one pair of chromosomes, which were adjacent to the (TTTAGGG)3 terminal signals. Four 45S rDNA signals were detected near the centromere region of the short arm of the four chromosomes, but one of these was very weak and almost undetectable compared to the others. Telomeric repeat hybridization signals were distributed at the terminal region of each chromosome. The chromosomes displayed were intact, and the chromosome counts were accurate. Chromosome length ranged from 3.46 to 9.31 μm. These results will facilitate the cytogenetic mapping of other major repeats, thus contributing to an improved understanding of the G. superba genome structure and evolutionary history. [ABSTRACT FROM AUTHOR]

Objective: Knowing the important repercussions of menopause for women's health and that female longevity can be better understood through studies based on aging biomarkers, studies on the relationship between menopause and telomere shortening may help to better understand this stage of life. This study aimed to analyze what research has been produced regarding the relationship between menopause and telomere length. Methods: This integrative literature review included searches in PubMed, CINAHL, LILACS, Web of Science and Scopus databases. Four studies were selected for the final sample. Results: The findings of these studies indicate that older age for menopause and longer reproductive life (difference between age at menopause and menarche) are associated with longer telomeres, that is, with longevity. Conclusion: The relationship between menopause and telomere length is uncertain. The small number of studies included in this review, and the fact that the results indicate that the relationship between menopause and telomere length may be dependent on the stage of the menopause and race/ethnicity, suggest that additional research focusing on these variables should be carried out. [ABSTRACT FROM AUTHOR]

The interest in aging and anti-aging research has increased significantly in recent years, leading to rapid expansion in the anti-aging market. Aging is associated with gradual physiological changes and an elevated risk of age-related ailments, and is divided into three categories: usual aging, successful aging, and pathological aging. Each category is associated with distinct implications for health and well-being. Middle-aged women who experience accelerated physiological changes that are intensified by hormonal changes during menopause are particularly vulnerable to chronic diseases. The importance of anti-aging tests is increasing since they enable early identification and intervention. Telomere length, oxidative stress markers, DNA repair markers, RNA profiles, inflammatory markers, hormone levels, and epigenetic changes are some molecular parameters studied to test for aging. In addition, a thorough review of middle-aged women's anti-aging profiles also includes monitoring the vitamin D levels and assessing the effects of endocrinedisrupting substances on ovarian aging. The application of personalized medicine paradigms, utilizing various diagnostic methods, will enable accurate risk prediction and the implementation of focused therapies, ultimately promoting the extension of health span and the improvement of quality of life in middle-aged women. [ABSTRACT FROM AUTHOR]

A 14-year boy is given a microscope by his parents. It is not a toy – but a real microscope. He deploys it to rediscover the biology he had known before, but now in a magnified world. With extraordinary intellectual gifts he then, and manifestly later becomes absorbed by the idea that all this, however mysterious at first glance, might be subject to rational understanding, with painstaking study. Thus, was the genesis of one of the greatest cell biologists of the 20th century, Joseph Grafton Gall, who died 12 September 2024, at 96. He had been professionally active up until only a few years ago. There was no one like him in the modern era of cell biology and there will not be another figure like him anytime soon. [ABSTRACT FROM AUTHOR]

Heterochromatin is an organizational property of eukaryotic chromosomes, characterized by extensive DNA and histone modifications, that is associated with the silencing of transposable elements and repetitive sequences. Maintaining heterochromatin is crucial for ensuring genomic integrity and stability during the cell cycle. During meiosis, heterochromatin is important for homologous chromosome synapsis, recombination, and segregation, but our understanding of meiotic heterochromatin formation and condensation is limited. In this review, we focus on the dynamics and features of heterochromatin and how it condenses during meiosis in plants. We also discuss how meiotic heterochromatin influences the interaction and recombination of homologous chromosomes during prophase I. [ABSTRACT FROM AUTHOR]

Background: Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere length (LTL) decreasing with age. Reduced telomerase activity has been linked to reproductive issues in females, such as low pregnancy rates and premature ovarian failure, with recent studies indicating correlations between telomere length in granulosa cells and IVF outcomes. Objectives: The study aims to explore the relationship between telomere length, telomerase activity, and euploid blastocyst rate in infertile women undergoing IVF/ICSI PGT-A cycles. Methods: This prospective study involves 108 patients undergoing controlled ovarian stimulation and PGT-A. Telomere length and telomerase activity were measured in peripheral mononuclear cells and granulosa cells (GC), respectively. Results: The telomere repeat copy number to single gene copy number ratio (T/S) results respectively 0.6 ± 0.8 in leukocytes and 0.7 ± 0.9 in GC. An inverse relationship was found between LTL and the patient's age (p <.01). A higher aneuploid rate was noticed in patients with short LTL, with no differences in ovarian reserve markers (p =.15), number of oocytes retrieved (p =.33), and number of MII (p = 0.42). No significant association was noticed between telomere length in GC and patients' age (p = 0.95), in ovarian reserve markers (p = 0.32), number of oocytes retrieved (p =.58), number of MII (p =.74) and aneuploidy rate (p =.65). Conclusion: LTL shows a significant inverse correlation with patient age and higher aneuploidy rates. Telomere length in GCs does not correlate with patient age or reproductive outcomes, indicating differential telomere dynamics between leukocytes and granulosa cells. [ABSTRACT FROM AUTHOR]

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]

Telomere length (TL) predicts the onset of replicative senescence, and its shortening is a limiter on the number of divisions individual somatic cells can perform. Metal-induced genotoxic events are discussed in Agency for Toxic Substances and Disease Registry's (ATSDR) toxicological profiles. In vivo and in vitro toxicological studies suggest the correlation between toxic metals and TL. However, the correlation between TL and exposure to toxic metals in human populations is unclear despite decades of observational research. We conducted a literature search within the ATSDR toxicological profiles and PubMed database for peer-reviewed articles as of 04/2023 discussing TL and metal exposure in human populations. Through review of the 272 publications meeting these criteria, we identified 25 observational studies that considered the correlation between TL and exposure to some or all of six metals: cadmium (Cd), arsenic (As), nickel (Ni), selenium (Se), lead (Pb), and cesium (Cs). Because reported effect sizes were often not comparable across studies, we performed a sign test based on the reported significance for each metal–TL correlation. We found that Cd was consistently significantly correlated with shorter telomeres (p = 0.016). However, no consistent linear relationship was observed between TL and any of the other metals considered. Exploring this association can enhance our understanding of how metal exposure may influence TL dysfunction. Our findings suggest that Cd exposure contributes to shorter TL, which may affect the DNA damage response (DDR) resulting in numerous chronic health conditions. Further, we highlight inconsistencies in findings on the correlation between metal exposure and TL across different populations and exposure levels. This suggests that correlations between some metals and TL may vary across populations, and that correlations may change at different exposure levels. Also, our findings suggest the need for further research on the potential for nonlinear relationships and non-additive effects of co-exposure to multiple hazardous metals, which could explain the inconsistencies observed across studies. The inconsistent incidences of metal–TL correlations justify additional exploration into the complex interaction between metals and TL. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]