Telomere Shortening Research Articles

X-chromosome inactivation pattern and telomere length in recurrent pregnancy loss

Recurrent pregnancy loss is a reproductive disorder affecting about 1 to 5 % of pregnant women worldwide that requires our attention, especially considering that about 50 % of cases are idiopathic. The present study is focused on testing a possible association between extreme skewed X-chromosome inactivation patterns and/or shortened telomeres with idiopathic cases since both are considered non-consensual potential causes underlying recurrent pregnancy loss in the scientific community. For this purpose, two groups of women were analyzed and compared: a group of women with idiopathic recurrent pregnancy loss and a second group of age-matched women with proven fertility, and both X-chromosome inactivation patterns and telomere length were measured and compared from maternal DNA extracted from peripheral blood. Our data showed no statistically significant differences between groups, suggesting no association between extreme skewed X-chromosome inactivation or shortened telomeres with recurrent pregnancy losses. Additionally, the effect of maternal age on both X-chromosome inactivation pattern and telomere length was tested, but no significant correlation was observed between advanced maternal age and extreme skewed X-chromosome inactivation or telomere shortening. This study represents one more valid contribution to the investigation of causes underlying recurrent pregnancy loss suggesting that, new variables may be considered since the pattern of X-chromosome inactivation and telomere length do not seem to be related to this reproductive disorder. Briefly, considering its clinical relevance, it is mandatory a continuous effort in the scientific community to cover new potential recurrent pregnancy loss-related causes.

RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening

Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Shortening of telomere length may be associated with inflammatory cytokine levels in patients with bipolar disorder

BackgroundBipolar disorder (BD) is hypothesized to be associated with accelerated biological aging. Telomere length (TL) is a biomarker of aging, and although TL decreases with each cell division, the rate of telomere shortening may be affected by inflammation. We aimed to investigate whether TL is decreased in BD patients and to determine the association between TL and inflammatory markers in such patients. Methods137 BD patients and 118 healthy controls (HCs) were recruited. Leukocyte TL and plasma levels of cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-6, IL-10, transforming growth factor (TGF)-β1], C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were assessed. ResultsTL did not differ significantly between the BD patients and HCs after adjustment for potential confounding factors (P = 0.79). TL was significantly negatively associated with age (β = −0.007, P < 0.001). In addition, log TNF-α levels were significantly negatively associated with TL (P = 0.009), in both the BD patients (P = 0.02) and HCs (P = 0.05). ConclusionWe found a significant association between TNF-α levels and TL shortening in both BD patients and HCs. However, BD patients did not display increased TL shortening relative to HCs. Studies that involve larger sample sizes and control for the heterogeneity of BD participants will be needed.

Maternal peripheral blood telomere length and preterm birth in African American women: a pilot study.

This study aimed to explore the association between preterm birth and telomere length of maternal peripheral blood in African American women. 78 African American women were recruited for this study between 2018 and 2023 from 2 prenatal clinics in central and east Texas. Participants provided blood samples and completed clinic questionnaires, with clinical data collected from their post-delivery medical records. Telomere length was measured using monochrome multiplex quantitative real-time polymerase chain reaction. Linear regression and multinomial logistic regression were used to analyze the association between telomere length and gestational length. Kruskal-Wallis's test and Fisher's exact test were used to compare preterm birth, early-term birth and full-term birth by telomere length, social-demographic characteristics, stress and discrimination. The rates of preterm birth was higher in pregnant women with shorter telomeres. After adjusting for confounders, for every 10-units increase in the relative telomere-to-single-copy gene (T/S) ratio, gestational days increased by 1.090 days (90% CI 0.182, 1.997), and for every 10-units decrease in the T/S ratio, the odds of preterm birth was 2.664 (90% CI 1.064, 6.673) times greater than the odds of full-term birth. No statistically significant associations were observed between stress, discrimination, and either preterm birth or telomere length. Maternal peripheral blood telomere shortening is associated with preterm birth, providing support to further explore the clinical utility of maternal telomere testing for prediction and early intervention of preterm birth and the study of biological mechanisms of spontaneous preterm birth.

Association of hTERT expression, Her2Neu, estrogen receptors, progesterone receptors, with telomere length before and at the end of treatment in breast cancer patients.

Breast cancer shows significant clinical, morphologic, and molecular variation. Telomeres are nucleoprotein complexes composed of hexanucleotide repeat DNA sequence, TTAGGG, and numerous telomere-associated proteins. The maintenance of telomere length is carried out by a ribonucleoprotein called telomerase, which consists of two main components: a catalytic subunit called hTERT (human telomerase reverse transcriptase) and an RNA template called hTR (human telomerase RNA). The importance of evaluating hTERT expression lies in its potential therapeutic application, being an attractive target due to its almost non-existent expression in normal somatic cells. It is also expected that the anti-neoplastic effect would appear earlier in neoplastic cells with shorter telomeres. Additionally, a significant relationship has been observed between Her2-Neu overexpression and Her2-Neu positivity, which could suggest new combined therapies.The aim of this study was to detect the expression of hTERT, estrogen receptor (ER), progesterone receptor (PR), and HER2-Neu in neoplastic breast tissue embedded in paraffin before treatment and to investigate the relationship between them and with baseline and post-treatment telomere length, as well as with various clinicopathological parameters. A cross-sectional-correlational, 21 women diagnosed with breast cancer at the Oncology Service of the High Specialty Medical Unit No. 1 of Bajio of the Mexican Institute of Social Security. The study complies with the Helsinki Declaration and was approved by the Institutional Ethical Committee of the Mexican Institute of Social Security (R-2019-1001-127). A peripheral blood sample was obtained before oncological treatment and at the end of oncological treatment for the measurement of telomere length by extracting DNA from leukocytes, was performed by the quantitative polymerase chain reaction (PCR) method described by Cawthon. Tumor samples were collected from each patient at the oncology department for immunohistochemical determination of biomarker expression (ER, PR, Her2/neu) and hTERT. Of the 21 cases included in the study, the median age was 57.57 years. Eighteen cases were classified as invasive ductal carcinoma NOS (85.71%), 10 were histologic grade 2 (47.61%), 16 cases were hormone receptor positive (76.19%), 7 were Her2Neu positive (33.33%), and only 2 cases were triple negative (9.52%). Positive hTERT expression was detected in 11 cases (52.38%) and was negative in the remaining cases. A significant association was identified between hTERT-positive cases and Her2-Neu positive cases (p = 0.04). Baseline and post-treatment telomere lengths showed a significant difference using the non-parametric Wilcoxon t-test (p = 0.002). In hTERT-positive cases, there was significant telomere shortening at the end of oncological treatment (6.14 ± 1.54 vs. 4.75 ± 1.96 Kb, p = 0.007). Positive hTERT immunostaining cases were associated with poor prognostic factors, such as Her2-Neu overexpression and post-treatment telomere shortening. In the future, hTERT immunostaining could be used to select patients for therapies with antagonistic effects on hTERT, as well as in the selection of more appropriate chemotherapy regimens for patients who express it.

Analysis by TeloView® Technology Predicts the Response of Hodgkin's Lymphoma to First-Line ABVD Therapy.

Classic Hodgkin's lymphoma (cHL) is a curable cancer with a disease-free survival rate of over 10 years. Over 80% of diagnosed patients respond favorably to first-line chemotherapy, but few biomarkers exist that can predict the 15-20% of patients who experience refractory or early relapsed disease. To date, the identification of patients who will not respond to first-line therapy based on disease staging and traditional clinical risk factor analysis is still not possible. Three-dimensional (3D) telomere analysis using the TeloView® software platform has been shown to be a reliable tool to quantify genomic instability and to inform on disease progression and patients' response to therapy in several cancers. It also demonstrated telomere dysfunction in cHL elucidating biological mechanisms related to disease progression. Here, we report 3D telomere analysis on a multicenter cohort of 156 cHL patients. We used the cohort data as a training data set and identified significant 3D telomere parameters suitable to predict individual patient outcomes at the point of diagnosis. Multivariate analysis using logistic regression procedures allowed for developing a predictive scoring model using four 3D telomere parameters as predictors, including the proportion of t-stumps (very short telomeres), which has been a prominent predictor for cHL patient outcome in a previously published study using TeloView® analysis. The percentage of t-stumps was by far the most prominent predictor to identify refractory/relapsing (RR) cHL prior to initiation of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy. The model characteristics include an AUC of 0.83 in ROC analysis and a sensitivity and specificity of 0.82 and 0.78 respectively.

Advancements in Telomerase-Targeted Therapies for Glioblastoma: A Systematic Review.

Glioblastoma (GBM) is a primary CNS tumor that is highly lethal in adults and has limited treatment options. Despite advancements in understanding the GBM biology, the standard treatment for GBM has remained unchanged for more than a decade. Only 6.8% of patients survive beyond five years. Telomerase, particularly the hTERT promoter mutations present in up to 80% of GBM cases, represents a promising therapeutic target due to its role in sustaining telomere length and cancer cell proliferation. This review examines the biology of telomerase in GBM and explores potential telomerase-targeted therapies. We conducted a systematic review following the PRISMA-P guidelines in the MEDLINE/PubMed and Scopus databases, from January 1995 to April 2024. We searched for suitable articles by utilizing the terms "GBM", "high-grade gliomas", "hTERT" and "telomerase". We incorporated studies addressing telomerase-targeted therapies into GBM studies, excluding non-English articles, reviews, and meta-analyses. We evaluated a total of 777 records and 46 full texts, including 36 studies in the final review. Several compounds aimed at inhibiting hTERT transcription demonstrated promising preclinical outcomes; however, they were unsuccessful in clinical trials owing to intricate regulatory pathways and inadequate pharmacokinetics. Direct hTERT inhibitors encountered numerous obstacles, including a prolonged latency for telomere shortening and the activation of the alternative lengthening of telomeres (ALT). The G-quadruplex DNA stabilizers appeared to be potential indirect inhibitors, but further clinical studies are required. Imetelstat, the only telomerase inhibitor that has undergone clinical trials, has demonstrated efficacy in various cancers, but its efficacy in GBM has been limited. Telomerase-targeted therapies in GBM is challenging due to complex hTERT regulation and inadequate inhibitor pharmacokinetics. Our study demonstrates that, despite promising preclinical results, no Telomerase inhibitors have been approved for GBM, and clinical trials have been largely unsuccessful. Future strategies may include Telomerase-based vaccines and multi-target inhibitors, which may provide more effective treatments when combined with a better understanding of telomere dynamics and tumor biology. These treatments have the potential to be integrated with existing ones and to improve the outcomes for patients with GBM.

Dietary Zinc Intake and the Association of Insulin Level and HOMA-IR with Telomere Shortening in Mexican Children.

The relationship between dietary zinc (Zn) intake, metabolic diseases, and telomere length has been little explored in the children population. This observational cross-sectional study assesses the association between obesity (OB), cardiometabolic traits, telomere length, and dietary Zn intake in children with normal weight (NW) and OB from Mexico City. Anthropometric data, blood pressure, biochemical measurements, the homeostatic model assessment of insulin resistance (HOMA-IR) and leucocyte telomere length (determined by quantitative-PCR) were analyzed in 171 children with NW and 172 with OB. Furthermore, dietary Zn intake was evaluated in 117 children NW and 120 with OB. Telomere shortening was associated with fasting plasma insulin (FPI) and HOMA-IR in NW (beta coefficient [β]FPI = -0.022 ± 0.008, p = 0.009; βHOMA-IR = -0.096 ± 0.040, p = 0.020) and OB (βFPI = -0.007 ± 0.002,p = 0.003; βHOMA-IR = -0.034 ± 0.012,p = 0.005) children. Dietary Zn intake resulted negatively associated with FPI (β = -2.418 ± 0.764, p = 0.002) and HOMA-IR (β = -0.399 ± 0.014, p = 0.009) in children with OB. Then, in children with OB, the association between FPI, HOMA-IR, and telomere shortening was evaluated separately in groups of low, medium, and high dietary Zn intake (according to tertiles). The association between FPI, HOMA-IR, and telomere shortening was not significant in the high Zn intake group (PFPI = 0.633; PHOMA-IR = 0.567). Our results suggest that a high Zn intake may ameliorate the telomere shortening related to high FPI and HOMA-IR.

Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes virus-induced-senescence. There is an association between shorter telomere length (TL) in coronavirus disease 2019 (COVID-19) patients and hospitalization, severity, or even death. However, it remains unknown whether virus-induced-senescence is reversible. We aim to evaluate the dynamics of TL in COVID-19 patients 1 year after recovery from intensive care units (ICU). Longitudinal study enrolling 49 patients admitted to ICU due to COVID-19 (August 2020 to April 2021). Relative telomere length (RTL) quantification was carried out in whole blood by monochromatic multiplex real-time quantitative PCR (MMqPCR) assay at hospitalization (baseline) and 1 year after discharge (1-year visit). The association between RTL and ICU length of stay (LOS), invasive mechanical ventilation (IMV), prone position, and pulmonary fibrosis development at 1-year visit was evaluated. The median age was 60 years, 71.4% were males, median ICU-LOS was 12 days, 73.5% required IMV, and 38.8% required a prone position. Patients with longer ICU-LOS or who required IMV showed greater RTL shortening during follow-up. Patients who required pronation had a greater RTL shortening during follow-up. IMV patients who developed pulmonary fibrosis showed greater RTL reduction and shorter RTL at the 1-year visit. Patients with longer ICU-LOS and those who required IMV had a shorter RTL in peripheral blood, as observed 1 year after hospital discharge. Additionally, patients who required IMV and developed pulmonary fibrosis had greater telomere shortening, showing shorter telomeres at the 1-year visit. These patients may be more prone to develop cellular senescence and lung-related complications; therefore, closer monitoring may be needed.

DNA damage (8-OHdG) and telomere length in captive Psittacidae birds with different longevity.

Aging is a complex process influenced by internal and external factors. Oxidative stress damages DNA, leading to 8-hydroxy-2' deoxyguanosine formation (8-OHdG). Telomere shortening is considered a biomarker of aging and oxidative stress may enhance its attrition. The ability to manage and repair oxidative stress varies among species and life histories. Avian species, such as Psittacidae birds, exhibit exceptional lifespans despite their physiological characteristics that might suggest otherwise. This study investigates 8-OHdG levels in serum samples from long- and short-lived birds of the order Psittaciformes, examining their relationship with telomere length and antioxidant capacity based on lifespan strategies. Among 43 individuals analyzed 26 belonged to the "long-lived species" group and 17 belonged to the "short-lived species" one. Relative telomere length (rTL) was measured in DNA isolated from whole blood by qPCR, and oxidative stress markers, such as Total Antioxidant Capacity (TAC) and 8-OHdG, were determined by spectrophotometry in serum samples. Long-lived birds had longer rTL than short-lived ones [1.308 ± 0.11 vs. 0.565 ± 0.13, (p < 0.001)]. On the contrary, short-lived birds showed more DNA damage than their counterparts [3.847 ± 0.351 vs. 2.012 ± 0.308, respectively, (p < 0.001)]. Old birds had shorter rTL than young ones, for both longevity groups (p < 0.001). Although no correlation was found between 8-OHdG levels and age, nor 8-OHdG and telomere length, long-lived birds exhibited 75.42-unit increased TAC levels when increased 8-OHdG concentrations (p = 0.046). These findings highlight distinct patterns of telomere length and oxidative stress influenced by lifespan strategies among avian longevity groups.

Are urbanization and brood parasitism associated with differences in telomere lengths in song sparrows?

Urbanization reflects a major form of environmental change impacting wild birds globally. Whereas urban habitats may provide increased availability of water, some food items, and reduced predation levels compared to rural, they can also present novel stressors including increased light at night, ambient noise, and reduced nutrient availability. Urbanization can also alter levels of brood parasitism, with some host species experiencing elevated levels of brood parasitism in urban areas compared to rural areas. Though the demographic and behavioral consequences of urbanization and brood parasitism have received considerable attention, their consequences for cellular‐level processes are less understood. Telomeres provide an opportunity to understand the cellular consequences of different environments as they are a well‐established metric of biological state that can be associated with residual lifespan, disease risk, and behavior, and are known to be sensitive to environmental conditions. Here we examine the relationships between urbanization, brood parasitism, and blood telomere lengths in adult and nestling song sparrows Melospiza melodia. Song sparrows are a North American songbird found in both urban and rural habitats that experience high rates of brood parasitism by brown‐headed cowbirds Molothrus ater in the urban, but not the rural, sites in our study system. Among adults and nestlings from non‐parasitized nests, we found no differences in relative telomere lengths between urban and rural habitats. However, among urban nestlings, the presence of a brood parasite in the nest was associated with significantly shorter relative telomere lengths compared to when a brood parasite was absent. Our results suggest a novel, indirect, impact of urbanization on nestling songbirds through the physiological impacts of brood parasitism.

Aging, Cancer, and Inflammation: The Telomerase Connection.

Understanding the complex dynamics of telomere biology is important in the strong link between aging and cancer. Telomeres, the protective caps at the end of chromosomes, are central players in this connection. While their gradual shortening due to replication limits tumors expansion by triggering DNA repair mechanisms, it also promotes oncogenic changes within chromosomes, thus sustaining tumorigenesis. The enzyme telomerase, responsible for maintaining telomere length, emerges as a central player in this context. Its expression in cancer cells facilitates the preservation of telomeres, allowing them to circumvent the growth-limiting effects of short telomeres. Interestingly, the influence of telomerase extends beyond telomere maintenance, as evidenced by its involvement in promoting cell growth through alternative pathways. In this context, inflammation accelerates telomere shortening, resulting in telomere dysfunction, while telomere elements also play a role in modulating the inflammatory response. The recognition of this interplay has promoted the development of novel therapeutic approaches centered around telomerase inhibition. This review provides a comprehensive overview of the field, emphasizing recent progress in knowledge and the implications in understanding of cancer biology.

Impact of childhood maltreatment on aging: a comprehensive Mendelian randomization analysis of multiple age-related biomarkers

BackgroundChildhood maltreatment (CM) is linked to long-term adverse health outcomes, including accelerated biological aging and cognitive decline. This study investigates the relationship between CM and various aging biomarkers: telomere length, facial aging, intrinsic epigenetic age acceleration (IEAA), GrimAge, HannumAge, PhenoAge, frailty index, and cognitive performance.MethodsWe conducted a Mendelian randomization (MR) study using published GWAS summary statistics. Aging biomarkers included telomere length (qPCR), facial aging (subjective evaluation), and epigenetic age markers (HannumAge, IEAA, GrimAge, PhenoAge). The frailty index was calculated from clinical assessments, and cognitive performance was evaluated with standardized tests. Analyses included Inverse-Variance Weighted (IVW), MR Egger, and Weighted Median (WM) methods, adjusted for multiple comparisons.ResultsCM was significantly associated with shorter telomere length (IVW: β = − 0.1, 95% CI − 0.18 to − 0.02, pFDR = 0.032) and increased HannumAge (IVW: β = 1.33, 95% CI 0.36 to 2.3, pFDR = 0.028), GrimAge (IVW: β = 1.19, 95% CI 0.19 to 2.2, pFDR = 0.040), and PhenoAge (IVW: β = 1.4, 95% CI 0.12 to 2.68, pFDR = 0.053). A significant association was also found with the frailty index (IVW: β = 0.31, 95% CI 0.13 to 0.49, pFDR = 0.006). No significant associations were found with facial aging, IEAA, or cognitive performance.ConclusionsCM is linked to accelerated biological aging, shown by shorter telomere length and increased epigenetic aging markers. CM was also associated with increased frailty, highlighting the need for early interventions to mitigate long-term effects. Further research should explore mechanisms and prevention strategies.

High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder.

Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD). As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD. This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel. Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.

Mixture analysis of associations between environmental and workplace toxins and liver damage and telomere length, stratified by race/ethnicity

This study aimed to identify the worst “bad actors” in mixtures of pollutants contributing to liver damage and shorter telomeres in the U.S. population, using Weighted Quantile Sum (WQS) modeling with stratification by race/ethnicity. We conducted a comprehensive cross-sectional analysis of mixtures of pollutants in National Health and Nutrition Examination Survey datasets: a) 33,979 adults with blood levels of cadmium (Cd), lead (Pb), and mercury, including subsets with measurements of per-/polyfluoroalkyl substances (PFAS), and polychlorinated biphenyls (PCBs)/polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs); and b) 7360 adults with measurements of telomeres, Cd, and Pb. Multivariable-adjusted WQS regression examined associations between WQS mixture indices and liver injury [alanine aminotransferase (ALT)-elevation], advanced liver-fibrosis (LF), and telomere length. WQSmetal indices were associated with advanced-LF in all racial/ethnic groups. The top contributor was Cd in the total population and in non-Hispanic Whites (NHW), while Pb was the top contributor in non-Hispanic Blacks (NHB). The WQSmetal-PCB-PCDD/F index was associated with ALT-elevation, with PCB126, Cd and Pb as main contributors; the odds ratio (OR) per decile was 1.50 (95%CI, 1.26-1.78), while the OR per decile of the WQSmetal-PFAS index was 1.03 (95%CI, 0.98-1.05), not significant. WQSmetal indices were associated with shorter telomeres. Cd was main contributor associated with advanced-LF in NHW, while Pb was the major bad actor in NHB, suggesting that NHB may be especially susceptible to Pb toxicity. Metals were associated with shorter telomeres. Metal and PCB/PCDD/F mixtures were associated with ALT-elevation. Heavy metals and organic chemicals may contribute to liver-related morbidity and healthcare disparities.

Research progress on the regulatory mechanism of cell senescence in arsenic toxicity: a systematic review.

As an element with metalloid properties, arsenic is pervasively present in the environment and is recognized as a potent carcinogen. Consequently, the issue of human arsenic exposure has become a significant concern within the global public health sector. Numerous studies have indicated that arsenic induces cellular senescence through various mechanisms, including triggering epigenetic alterations, inducing the senescence-associated secretory phenotype (SASP), promoting telomere shortening, and causing mitochondrial dysfunction. This article collates and summarizes the latest research advancements on the involvement of cellular senescence in arsenic toxicity and explores the mechanisms of arsenic-induced toxicity. This study aims to provide new perspectives and directions for future research on arsenic toxicity and the development of prevention and treatment strategies.

Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

Investigating the differential therapeutic efficacy and mechanisms of human umbilical cord mesenchymal stem cells at various passages in osteoarthritis treatment

This study aimed to assess the clinical efficacy of umbilical cord mesenchymal stem cells (hUC-MSCs) from different passages (P3, P8, and P13) in the treatment of knee osteoarthritis (OA) and explore the underlying mechanisms. The hUC-MSCs from each passage were characterized and evaluated for their stemness, migration, proliferation, and marker expression. Rats with OA were treated with hUC-MSCs from each passage, and the therapeutic effects were assessed based on knee swelling, discomfort, and pathological examination of the knee joint. Co-culture experiments were conducted to examine the ability of hUC-MSCs to stimulate type II collagen synthesis and inhibit MMP13 expression in chondrocytes. Telomere length and telomerase activity of hUC-MSCs from each passage were measured to investigate the reasons for the observed differences in clinical efficacy. The results revealed that P3 and P8 hUC-MSCs exhibited superior osteogenic and chondrogenic differentiation potential compared to P13, while P13 demonstrated stronger adipogenic differentiation. The wound healing rate was significantly higher in the P3 and P8 groups compared to P13. All hUC-MSC groups expressed high levels of CD90 and CD105, indicating their mesenchymal stem cell characteristics, while CD31 and CD45 were not expressed. CD105 expression was significantly reduced in the P13 group. In the treatment of rat osteoarthritis, there were no significant differences in knee swelling, discomfort, Mankin scores, and pathological findings between P3 and P8 hUC-MSC treatments. However, there was a significant difference between the 8th and 13th passages. Co-culture experiments showed that hUC-MSCs from P3 and P8 enhanced type II collagen synthesis and reduced MMP13 expression in chondrocytes. Although no significant difference was observed between the P3 and P8 groups, a significant difference was found between the P13 and P8 groups. Telomere length analysis revealed that P13 samples had significantly shorter telomeres compared to both P3 and P8. The telomerase activity was positive in P3 and P8 hUC-MSCs, indicating no significant difference between these passages, while it was negative in P13 hUC-MSCs. In conclusion, P3 and P8 hUC-MSCs exhibited superior therapeutic potential for knee osteoarthritis compared to P13, possibly due to their enhanced differentiation capacity and telomerase activity.

Clinical utility of relative telomere length analysis in pediatric bone marrow failure

IntroductionTelomere length related studies are limited in pediatric marrow failure cases due to difficulty in establishing population specific age related normograms. Moreover, there is paucity of data related to clinical relevance of telomere length in idiopathic aplastic anemia (IAA) and non telomere biology inherited bone marrow failure syndrome (IBMFS) cases. Methodology: Hence, in current study we investigated Relative telomere length (RTL) by RQ-PCR in 83 samples as: healthy controls (n = 44), IAA (n = 15) and IBMFS (n = 24). In addition, we performed chromosomal breakage studies and targeted NGS to screen for pathogenic variants. Results & Conclusion: Median RTL was significantly different between control vs. IBMFS (p-0.002), IAA vs. IBMFS (p-0.0075) and DC vs. non-DC IBMFS (p-0.011) but not between control vs. IAA (p-0.46). RTL analysis had clinical utility in differentiating BMF cases as 75 % (9/12) of DC had short/very short telomeres compared to only 17 % (2/12) of non-DC IBMFS, 7 % (1/15) of IAA and 7 % (3/44) of controls (p < 0.001).

Maternal smoking during pregnancy could accelerate aging in the adulthood: evidence from a perspective study in UK Biobank

BackgroundMaternal smoking during pregnancy (MSDP) is significantly linked to the short- or long-term health of offspring. However, little research has examined whether MSDP affect the aging rate of offspring. MethodsThis study used questionnaires to determine out whether the participants' mothers smoked when they were pregnant. For evaluating aging rate, we used the following several outcome measures: telomere length, frailty index, cognitive function, homeostatic dysregulation score, KDM-age, age-related hospitalization rate, premature death, and life expectancy. ResultAfter adjusting for covariates, we found that the offspring of the MSDP group had significantly shorter telomere length in adulthood by 0.8 % (β = −0.008,95%CI:−0.009 to −0.006) compared with non-MSDP group. Compared to the non-MSDP group, participants in MSDP group showed higher levels of homeostatic dysregulation (β = 0.015,95%CI: 0.007–0.024) and were frailer (β = 0.008,95%CI:0.007–0.009). The KDM age increased by 0.100 due to MSDP (β = 0.100,95 % CI:0.018–0.181), and the age acceleration of KDM algorithm also increases significantly (β = 0.101, 95%CI:0.020–0.183). Additionally, we found that the risk of aging-related hospitalizations was significantly higher than the non-MSDP group by 10.4 %(HR = 1.104,95%CI:1.066–1.144). Moreover, MSDP group had a 12.2 % increased risk of all-cause premature mortality (HR = 1.122,95%CI:1.064–1.182) and a significant risk of lung cancer-specific premature mortality increased by 55.4 %(HR = 1.554,95%CI:1.346–1.793). In addition, participants in the MSDP group had significantly decreased cognitive function and shorter life expectancies than those in non-MSDP group. ConclusionOur findings indicated a significant association between MSPD and accelerated aging, elevated hospitalization rates, increased premature mortality rates, and reduced life expectancies in offspring.