Hematopoietic stem cell transplantation of aplastic anemia by relative with mutations and normal telomere length: A case report

BACKGROUND Immunosuppressive therapy and matched sibling donor hematopoietic stem cell transplantation(MSD-HSCT)are the preferred treatments for aplastic anemia(AA).CASE SUMMARY In this report,we describe a 43-year-old male patient with severe AA who carried BRIP1(also known as FANCJ),TINF2,and TCIRG1 mutations.Screening of the family pedigree revealed the same TINF2 mutation in his mother and older brother,with his older brother also carrying the BRIP1 variant and demonstrating normal telomere length and hematopoietic function.The patient was successfully treated with oral cyclosporine A,eltrombopag,and acetylcysteine,achieving remission 4 years after receiving MSD-HSCT from his older brother.CONCLUSION This case provides a valuable clinical reference for individuals with suspected pathogenic gene mutations,normal telomere length,and hematopoietic function,highlighting them as potential donors for patients with AA.

Association between Dietary Collagen Consumption and Telomere Length: National Health and Nutrition Examination Survey

Background: Bioactive peptides derived from hydrolyzed collagen have broad physiological functions and beneficial effects on human health, ranging from reducing skin aging to modifying lipid metabolism. Telomere length shortening is an established biomarker of cellular aging. It is not known if collagen consumption is associated with telomere length protection. Our purpose was to investigate the relationship between dietary collagen consumption and telomere length in a nationally representative US adult population. Methods: We analyzed the data of 6173 adults aged 20 - 84 from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Multivariable linear regression and a generalized additive model with smoothing plot were used to assess the association between the total collagen consumption and log-transformed leukocyte telomere length (LTL). Results: Compared with the lowest quartile of total collagen (Q1), we found that the second quartile of collagen (Q2) consumption (1.36 - 3.40 g/1000kcal) was positively associated with telomere length (β: 0.017;95% CI: 0.006, 0.028;P = 0.022) in the females while no association in the males (β: −0.003;95% CI: −0.019, 0.012;P = 0.678) and overall population (β: 0.008;95% CI: −0.002, 0.018;P = 0.141). The association in the females is nonlinear with an inflection point of 2.5 g/1000kcal (P for non-linearity: Conclusion: In conclusion, moderate dietary collagen has a positive and nonlinear association with telomere length in US females, while no significant associations were found in the males and the overall population.

Association between Physical Activity and Telomere Length in a North Chinese Population： A China Suboptimal Health Cohort Study

Several studies have demonstrated an association between physical activity and telomere length; however, the association remains inconsistent. A cross-sectional study consisting of 588 participants （375 females, median age of 33.8 years） was carried out to investigate the association between telomere length and physical activity in a general population from North China. The results show that relative telomere length is not significantly different in participants in the northern Chinese population with different levels of physical activity, either in the model only adjusted for age （F = 2.127, P = 0.120） or in the model adjusted for demographics and lifestyle （F = 1.227, P = 0.294）. The gender-stratified analysis also produced insignificant results. Our study confirmed a non-significant association between physical activity and telomere length in the northern Chinese population, which adds to the inconsistent association between physical activity and telomere length across different ethnic populations.

Antipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injury

Antipsychotics may prolong or retain telomere length,affect mitochondrial function,and then affect the metabolism of nerve cells.To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury,leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient.The mononuclear cells layer was resuspended in cell culture medium.Oxidative stress was induced with hydrogen peroxide in cultured leukocytes.Four days later,leukocytes were treated with aripiprazole,haloperidol or clozapine for 7 days.Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23%and 20%in peripheral blood mononuclear cells after acute oxidative stress injury.These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress.The experiment procedure was approved by the Ethics Committee of Faculty of Medicine of the University of Sao Paulo(FMUSP/CAAE approval No.52622616.8.0000.0065).

Measuring Telomere Length in Proliferating Cells by Flow-FISH Method

The purpose of present work is a measurement of telomere length dynamic in proliferating cells in vitro by modified flow-FISH method. This method is a combination of two modifications： telomere length measurement in differentiated cells by surface antigen and analysis of cells divisions＇ number by vital dye dilution. Lymphocytes were activated by anti-CD3 Abs with IL-2 presents and grown in vitro for 7 days. Cells division＇s number was measured by dilution of CFSE vital dye which cells were stained previously activation. For telomere length measurement we used flow-FISH method with Cy3 labeled telomere PNH probe. Using this method we evaluated the dynamic of telomere length in CD4＋ and CD8＋ T-cells after 7 days culturing in vitro and revealed the difference in telomere lengthening and shortening versus division rounds in cell subsets. In CD8＋ cells telomeres start lengthen on a second division with the maximum on 4th division round becoming more that 20% longer compared with undividing cells. In CD4＋ cells telomeres did not have any length peculiarities through all division rounds demonstrating different telomere regulation in subsets. This probably occurs due to the higher level ofhTERT protein expression in CD8＋ than CD4＋ cells do.

U-shaped association between telomere length and esophageal squamous cell carcinoma risk： a case-control study in Chinese population

Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma （ESCC） was still uncertain. Several telomere length-related single nucleotide polymorphisms （TL- SNPs） in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study （1045 ESCC cases and 1433 controls） to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length （RTL） （median： 1.34） than controls （median： 1.50, P 〈 0.001）. More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk （P 〈 0.001）, with odds ratios （95% confidence interval） equal to 2.40 （1.84- 3.14）, 1.36 （1.03-1.79）, 1.01 （0.76-1.35）, and 1.37 （1.03-1.82） for individuals in the 1st （the shortest）, 2nd, 3rd, and 5th （the longest） quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.

Association between Long Interspersed Nuclear Element-1 Methylation and Relative Telomere Length in Wilms Tumor

Background： DNA hypomethylation of long interspersed nuclear elements- 1 （LINEs- 1 ） occurs during carcinogenesis, whereas intbmaation addressing LINE-1 methylation in Wilms tumor （WT） is limited. The main purpose of our study was to quantity, LINE-1 methylation levels and evaluate their relationship with relative telomere length （TL） in WT. Methods： We investigated LINE-1 methylation and relative TL using bisulfite-polymerase chain reaction （PCR） pyrosequencing and quantitative PCR, respectively, in 20 WT tissues, 10 normal kidney tissues and a WT cell line. Significant changes were analyzed by t-tests. Results： LINE-1 methylation levels were significantly lower （P 〈 0.05） and relative TLs were sigmificantly shorter （P 〈 0.05） in WT compared with normal kidney. There was a significant positive relationship between LINE- 1 methylation and relative TL in WT （r = 0.671, P = 0.001 ）. LINE- 1 Methylation levels were significantly associated with global DNA methylation （r = 0.332, P 〈 0.01 ）. In addition, relative TL was shortened and LINE- 1 methylation was decreased in a WT cell line treated with the hypomethylating agent 5-aza-2＇-deoxycytidine compared with untreated WT cell line. Conclusion： These results suggest that LINE-1 hypomethylation is common and may be linked to telomere shortening in WT.

Association Analysis of Four Single Nucleotide Polymorphisms with Leukocyte Telomere Length in Two Chinese Populations

Telomeres are protein--DNA complex structure at the ends of chromosomes, which are involved in genomic stability （Blackburn, 2010）. In most human cells, telomere erosion with each round of cell division eventually limits cell proliferation and tissue renewal, thereby impacting age-dependent pathol- ogies （Lundblad, 2012）. Leukocyte telomere length （LTL） undertakes a slow loss throughout life across human pop- ulations in general （Blackburn, 2010）. Telomerase is a ribo- nucleoprotein that adds telomeric DNA to chromosomal ends and contains two essential components：

Ultrasound deep brain stimulation decelerates telomere shortening in Alzheimer’s disease and aging mice

Telomere length is a reliable biomarker for health and longevity prediction in both humans and animals.The common neuromodulation techniques,including deep brain stimulation(DBS)and optogenetics,have excellent spatial resolution and depth penetration but require implementation of electrodes or optical fibers.Therefore,it is important to develop methods for noninvasive modulation of telomere length.Herein,we reported on a new method for decelerating telomere shortening using noninvasive ultrasound deep brain stimulation(UDBS).Firstly,we found that UDBS could activate the telomerase-associated proteins in normal mice.Then,in the Alzheimer’s disease mice,UDBS was observed to decelerate telomere shortening of the cortex and myocardial tissue and to effectively improve spatial learning and memory abilities.Similarly,UDBS was found to significantly slow down telomere shortening of the cortex and peripheral blood,and improve motor and cognitive functions in aging mice.Finally,transcriptome analysis revealed that UDBS upregulated the neuroactive ligand-receptor interaction pathway.Overall,the present findings established the critical role of UDBS in delaying telomere shortening and indicated that ultrasound modulation of telomere length may constitute an effective therapeutic strategy for aging and aging-related diseases.

The Influence of Oxygen on the Development of Nanorana parkeri Tadpoles

Ectothermic animals are tolerant of variable oxygen availability, whether low-oxygen levels constrain the fitness of ectotherms remains unclear. Nanorana parkeri, an anuran endemic to the southern Tibetan plateau, is an excellent model with which to answer this question. In this study, we raised tadpoles ofN. parkeri in oxygenated water （high-oxygen group） and deoxygenated unchlorinated tap water （low-oxygen group） and monitored their growth, mortality, and telomere length. The growth rate for body length and body weight was higher in the low-oxygen group than in the high-oxygen group. However, dissolved oxygen did not affect development time, mortality, and telomere length of the tadpoles. These results suggest that although the oxygen concentration influenced some phenotype traits of plateau tadpoles, but it didn＇t influence the telomere length and survival rate, potential explanations are the local adaptation and N. parkeri tadpoles＇ wide oxygen tolerance, and fluctuant toxic content that resulted in little oxidative stress on tadpoles. These results indicated that low oxygen was not a stress to N. parkeri tadpoles＇ fitness and survival. This study is helpful in understanding the adaptation mechanisms of Tibetan plateau amphibians.

Telomere shortening in patients on long-term hemodialysis

Background:Leukocyte telomere length shortening is a characteristic of premature senescence,a process that can be accelerated by oxidative stress.In general,patients with end-stage renal disease undergoing regular hemodialysis(HD)are repeatedly exposed to oxidative stress.Patients undergoing HD tend to have cardiovascular diseases associated with oxidative stress and inflammation.Therefore,we assumed that telomere length is associated with HD vintage and the degree of vascular calcification.Methods:A total of 144 patients undergoing regular HD before kidney transplantation and 62 patients on hemodialysis,but not undergoing kidney transplantation,were enrolled.We measured common laboratory values,such as calcium,phosphate,and hemoglobin levels,and assessed the degree of vascular calcification in the patients.The leukocyte telomere length was measured using reverse transcription polymerase chain reaction,and Spearman correlation was used for correlation analysis.Results:The leukocyte telomere length was negatively associated with age(rho=-0.306,P<0.01);it was shorter in middle-aged patients than in young patients(13.48±4.80 vs.15.86±4.51,P<0.01).The telomere length was significantly different among patients aged 52-74 years in groups with different HD vintages.Additionally,the telomere length was positively associated with serum hemoglobin(Hb)levels in all patients(rho=0.290,P<0.01).There was a significant difference among patients divided into three groups according to the degree of anemia(17.09±5.64 vs.14.40±4.07 vs.13.99±3.95,P<0.01).Further,a significant difference was observed in the telomere length among patients with different degrees of vascular calcification(16.79±4.91 vs.13.61±2.82 vs.14.62±3.63 vs.10.71±3.74,P<0.01).The telomere length was shorter in the patients on hemodialysis who did not receive a kidney transplant than in the surgical patients(8.12±1.83 vs.14.33±4.63,P<0.01).Conclusion:This study demonstrated that the telomere length was significantly correlated with HD vintage in patients of a certain age group.The telomere length was shorter in patients on hemodialysis who matched for age and dialysis vintage with kidney transplant patients.It was also associated with vascular calcification and serum Hb levels in all patients undergoing HD.

Developmental origins of health and disease: Impact of paternal nutrition and lifestyle

Most epidemiological and experimental studies have focused on maternal influences on offspring’s health.The impact of maternal undernutrition,overnutrition,hypoxia,and stress is linked to adverse offspring outcomes across a range of systems including cardiometabolic,respiratory,endocrine,and reproduction among others.During the past decade,it has become evident that paternal environmental factors are also linked to the development of diseases in offspring.In this article,we aim to outline the current understanding of the impact of male health and environmental exposure on offspring development,health,and disease and explore the mechanisms underlying the paternal programming of offspring health.The available evidence suggests that poor paternal pre-conceptional nutrition and lifestyle,and advanced age can increase the risk of negative outcomes in offspring,via both direct(genetic/epigenetic)and indirect(maternal uterine environment)effects.Beginning at preconception,and during utero and the early life after birth,cells acquire an epigenetic memory of the early exposure which can be influential across the entire lifespan and program a child’s health.Potentially not only mothers but also fathers should be advised that maintaining a healthy diet and lifestyle is important to improve offspring health as well as the parental health status.However,the evidence is mostly based on animal studies,and well-designed human studies are urgently needed to verify findings from animal data.

Anti-senescence effect and molecular mechanism of the major royal jelly proteins on human embryonic lung fibroblast(HFL-I) cell line

Royal jelly (R J)from honeybee has been widely used as a health promotion supplement.The major royal jelly proteins (MRJPs)have been identified as the functional component of RJ.However,the question of whether MRJPs have anti-senescence activity for human cells remains.Human embryonic lung fibroblast (HFL-I)cells were cultured in media containing no MRJPs (A),MRJPs at 0.1mg/ml (B),0.2mg/ml (C),or 0.3mg/ml (D),or bovine serum albumin (BSA)at 0.2mg/ml (E).The mean population doubling levels of cells in media B,C,D,and E were increased by 12.4%,31.2%,24.0%,and 10.4%,respectively,compared with that in medium A.The cells in medium C also exhibited the highest relative proliferation activity,the lowest senescence,and the longest telomeres.Moreover, MRJPs up-regulated the expression of superoxide dismutase-1(SOD1)and down-regulated the expression of mammalian target of rapamycin (MTOR),catenin beta like-1(CTNNB1),and tumor protein p53(TP53).Raman spectra analysis showed that there were two unique bands related to DNA synthesis materials,amide carbonyl group vibrations and aromatic hydrogens.These results suggest that MRJPs possess anti-senescence activity for the HFL-I cell line,and provide new knowledge illustrating the molecular mechanism of MRJPs as anti-senescence factors.