Telomere Length in Pig Sperm Is Related to In Vitro Embryo Development Outcomes

Telomere length has attracted much interest as a topic of study in human reproduction; furthermore, the link between sperm telomere length and fertility outcomes has been investigated in other species. This biomarker, however, has not been much explored in other animals, such as pigs, and whether it is related to sperm quality and fertility outcomes remains unknown. The present work aimed to determine the absolute value of telomere length in pig sperm, as well as its relationship to sperm quality parameters and embryo development. Telomere length was determined through quantitative fluorescence in situ hybridization (qFISH) in 23 pig sperm samples and data were correlated to quality parameters (motility, morphology, and viability) and in vitro fertilization outcomes. We found that the mean telomere length in pig sperm was 22.1 ± 3.6 kb, which is longer than that previously described in humans. Whilst telomere length was not observed to be correlated to sperm quality variables (p > 0.05), a significant correlation between telomere length and the percentage of morulae 6 days after in vitro fertilization was observed (rs = 0.559; 95%C.I. = (−0.007 to 0.854); p = 0.047). Interestingly, this correlation was not found when percentages of early blastocysts/blastocysts (rs = 0.410; 95%C.I. = (−0.200 to 0.791); p = 0.164) and of hatching/hatched blastocysts (rs = 0.356; 95%C.I. = (− 0.260 to 0.766); p = 0.233) were considered. Through the separation of the samples into two groups by the median value, statistically significant differences between samples with shorter telomeres than the median and samples with longer telomeres than the median were found regarding development to morula (11.5 ± 3.6 vs. 21.8 ± 6.9, respectively) and to early blastocyst/blastocysts (7.6 ± 1.4 vs. 17.9 ± 12.2, respectively) (p < 0.05). In the light of these results, sperm telomere length may be a useful biomarker for embryo development in pigs, as sperm with longer telomeres lead to higher rates of morulae and blastocysts.

Relationship between five Epigenetic Clocks, Telomere Length and Functional Capacity assessed in Older Adults: Cross-sectional and Longitudinal Analyses

DNA methylation age acceleration (DNAmAA, derived from an epigenetic clock) and relative leukocyte telomere length (rLTL) are widely accepted biomarkers of aging. Nevertheless, it is still unclear which aspects of aging they represent best. Here we evaluated longitudinal associations between baseline rLTL and DNAmAA (estimated with 7-CpG clock) and functional assessments covering different domains of aging. Additionally, we made use of cross-sectional data on these assessments and examined their association with DNAmAA estimated by five different DNAm age measures. Two-wave longitudinal data was available for 1,083 participants of the Berlin Aging Study II (BASE-II) who were re-examined on average 7.4 years after baseline as part of the GendAge study. Functional outcomes were assessed with Fried’s frailty score, Tinetti mobility test, falls in the past 12 months (yes/no), Finger-floor distance, Mini Mental State Examination (MMSE), Center for Epidemiologic Studies Depression Scale (CES-D), Activities of Daily Living (ADL), Instrumented ADL (IADL) and Mini Nutritional Assessment (MNA). Overall, we found no evidence for an association between the molecular biomarkers measured at baseline, rLTL and DNAmAA (7-CpG clock), and functional assessments assessed at follow-up. Similarly, a cross-sectional analyses of follow-up data did also not show evidence for associations of the various DNAmAA measures (7-CpG clock, Horvath’s clock, Hannum’s clock PhenoAge, and GrimAge) with functional assessments. In conclusion, neither rLTL nor 7-CpG DNAmAA were able to predict impairment in the analyzed assessments over a ~7-year time-course. Similarly, DNAmAA estimated from five epigenetic clocks was not a good cross-sectional marker of health deterioration either.

Dietary Exposure to Polychlorinated Biphenyls and Dioxins and Its Relationship to Telomere Length in Subjects Older Than 55 Years from the SUN Project

Exposure to persistent organic pollutants (POPs) may influence telomere length (TL), which is considered as a marker of biological age associated with the risk of chronic disease. We hypothesized that dietary exposure to polychlorinated biphenyls (PCBs) and dioxins could affect TL. Our aim was to evaluate the association of dietary exposure to PCBs and dioxins with TL. In this cross-sectional study of 886 subjects older than 55 y (mean age: 67.7; standard deviation (SD): 6.1; 27% women) from the “Seguimiento Universidad de Navarra” (SUN) project. TL was determined by real-time quantitative polymerase chain reaction and dietary PCBs and dioxins exposure was collected using a validated 136-item Food Frequency Questionnaire. Multivariable linear regression models were used to control for potential confounding factors. Shorter TL was associated with dietary total PCBs (SD of T/S ratio/(ng/day) = −0.30 × 10−7; 95% CI, −0.55 × 10−7 to −0.06 × 10−7), dioxin-like PCBs (DL-PCBs) (SD of T/S ratio/(pg WHO TEQ (Toxic Equivalents)/day) = −6.17 × 10−7; 95% CI, −11.30 × 10−7 to −1.03 × 10−7), and total TEQ exposure (SD of T/S ratio/(pg WHO TEQ/day) = −5.02 × 10−7; 95% CI, −9.44 × 10−7 to −0.61 × 10−7), but not with dioxins (SD of T/S ratio/(pg WHO TEQ/day) = −13.90 × 10−7; 95% CI, −37.70 × 10−7 to 9.79 × 10−7). In this sample of middle-aged and older Spanish adults, dietary exposure to total PCBs and DL-PCBs alone and together with dioxins was associated with shorter TL. Further longitudinal studies, preferably with POPs measured in biological samples, are needed to confirm this finding.

Leukocyte telomere length and response to antiangiogenic therapy in patients with neovascular age-related macular degeneration

Возрастная макулярная дегенерация (ВМД) становится основной причиной потери зрения людьми старше 60 лет. Неоваскулярная форма ВМД характеризуется хориоидальной неоваскуляризацией, основным триггером которой является фактор роста эндотелия сосудов (VEGF), ингибирование которого - современный стандарт лечения. Значительная вариабельность ответа на анти-VEGF-терапию определяет актуальность поиска биологических маркеров - прогностических критериев ответа на лечение. Проведен анализ зависимости ответа 110 пациентов с нВМД на анти-VEGF-терапию от функциональных и анатомических параметров сетчатки (по данным оптической когерентной томографии) и длины теломер лейкоцитов (ДТЛ, оценивали методом количественной ПЦР). В 100 % глаз наблюдали положительную динамику максимально корригированной остроты зрения (МКОЗ). Центральная толщина сетчатки (ЦТС) снизилась после третьей инъекции до 265 [234-306] мкм, к концу периода наблюдения - до 211 [190-262] мкм. Сохранение активности субретинальной неоваскулярной мембраны (СНМ) в конце периода наблюдения коррелировало с более низкими показателями исходной МКОЗ и высокими значениями исходной ЦТС. Выявлена ассоциация ДТЛ с ответом на лечение: у пациентов с большей ДТЛ чаще наблюдали переход активной формы СНМ в неактивную уже после трех инъекций, в то время как при меньшей ДТЛ чаще сохранялась активность СНМ, что определяло потребность в большем числе интравитреальных инъекций. Age-related macular degeneration (AMD) is becoming the leading cause of vision loss in people over 60 years of age. The neovascular form of AMD (nVMD) is characterized by choroidal neovascularization (CNV), the main trigger of which is vascular endothelial growth factor (VEGF), the inhibition of which is the current standard of treatment. Significant variability of response to anti-VEGF therapy determines the relevance of the search for biological markers - prognostic criteria of treatment response. We analyzed the response of 110 nVMD patients to anti-VEGF therapy depending on the functional and anatomical parameters of the retina (according to optical coherence tomography, OCT) and leukocyte telomere length (LTL, was assessed by quantitative PCR). Positive dynamics of best corrected visual acuity (BCVA) was observed in 100 % of eyes. The central retinal thickness (CRT) decreased after the 3rd injection to 265 [234-306] µm, by the end of the observation period - to 211 [190-262] µm. The retention of activity of the subretinal neovascular membrane (SNM) at the end of the observation period correlated with lower values of the initial BCVA and high values of the initial CRT. An association of LTL with response to treatment was revealed: in patients with higher LTL the active form of SNM was more often switched to inactive after three injections, while with lower LTL, the activity of SNM was more often preserved, which determined the need for more intravitreal injections.

Combined Effect of Telomere Length and Mitochondrial DNA Copy Number As a Potential Biomarker Indicating PE Risk: a Case-Control Study in a Chinese Population

Purpose To explore changes of Telomere length (TL) and mitochondrial copy number (mtDNA-CN) in preeclampsia (PE) and to evaluatethe combined effect of maternal TL and mtDNA-CN on PE risk.Methods A case-control study of 471 subjects (130 PE cases and 341 age frequency matched controls) was conducted in Nanjing Drum Tower Hospital, Jiangsu Province of China. Relative telomere length (RTL) and mtDNA-CN were measured using quantitative polymerase chain reaction (qPCR) and PE risk was calculated between groups by logistic regression analyses.Results PE patients displayed longer RTL (0.48 versus 0.30) and higher mtDNA-CN (3.02 versus 2.00) in maternal bloodas well as longer cord blood RTL(0.61 versus 0.35) but lower mtDNA-CN (1.69 versus 5.49) in cord blood (all p<0.001). Exercise during pregnancy exerted an obvious effect of prolonging maternal telomere length. Multiparous, women with folic acid intake during early pregnancy and those delivered vaginally showed longer telomere length while those factors imposed no or opposite effect on RTL in PE cases. Furthermore, RTL and mtDNA-CN were positively correlated in controls (in maternal blood r=0.18, p<0.01; in cord blood r=0.19, p<0.001), but this correlation was disrupted in PE cases, no matter in maternal blood or in cord blood. Longer maternal RTL and higher mtDNA-CN were associated with higher risk of PE, and the ROC curve of RTL and mtDNA-CN in predicting PE risk presented an AUC of 0.755(95%CI: 0.698-0.812).Conclusions Interaction of TL and mtDNA-CN may play an important role in pathogenesis of PE and it could be a potential biomarker indicating PE risk.

Effect of Human Disturbance on Bird Telomere Length: An Experimental Approach

Human recreational activities increase worldwide in space and frequency leading to higher rates of encounter between humans and wild animals. Because wildlife often perceive humans as predators, this increase in human disturbance may have negative consequences for the individuals and also for the viability of populations. Up to now, experiments on the effects of human disturbance on wildlife have mainly focused on individual behavioral and stress-physiological reactions, on breeding success, and on survival. However, the effects on other physiological parameters and trans-generational effects remain poorly understood. We used a low-intensity experimental disturbance in the field to explore the impacts of human disturbance on telomere length in great tit (Parus major) populations and found a clear effect of disturbance on telomere length. Adult males, but not females, in disturbed plots showed shorter telomere lengths when compared to control plot. Moreover, variation in telomere length of adult great tits was reflected in the next generation, as we found a positive correlation between telomere length of the chicks and of their fathers. Given that telomere length has been linked to animal lifespan, our study highlights that activities considered to be of little concern (i.e., low levels of disturbance) can have a long-lasting impact on the physiology and survival of wild animals and their next generation.

Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects

Inherited bone marrow failure syndromes (IBMFS) represent a group of disorders typified by impaired production of one or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant Høyeraal-Hreidarsson (HH) syndrome are rare IBMFS characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. Here we identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in three unrelated patients presenting with a DC/HH phenotype consisting of early onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly and/or intrauterine growth retardation. All three patients carry a homozygous or compound heterozygous (in combination with a null-allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were however not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080-cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS combining clinical hallmarks of DC/HH with normal telomere length.

Association Between Baseline Buccal Telomere Length and Progression of Kidney Function: The Health and Retirement Study

We aimed to evaluate associations of baseline telomere length with overall and annual change in estimated glomerular filtration rate (eGFR) and trajectory of kidney function during an 8-year follow-up. A total of 3,964 participants of the Health and Retirement Study (HRS) were included. We identified three trajectory groups of kidney function: consistently normal (n=1,163 or 29.3%), normal to impaired (n=2,306 or 58.2%), and consistently impaired groups (n=495 or 12.5%). After controlling for age, sex, race, education, smoking, drinking, diabetes, heart disease, blood pressure, body mass index, total cholesterol, and hemoglobin A1c, participants with longer telomere length were 20% less likely (odds ratio [OR]=0.80, 95% confidence interval [CI]: 0.69-0.93, P=0.003) to have a normal to impaired kidney function trajectory than a consistently normal function trajectory. Telomere length was not associated with changing rate of eGFR over 8 years (P=0.45). Participants with longer telomere length were more likely to have consistently normal kidney function.