Median Telomere Length Research Articles

Telomere Length Is Associated with Increased Risk of Cardiovascular Events in Patients with End-Stage Kidney Disease on Hemodialysis

Introduction: Patients with chronic kidney disease, especially those with end-stage kidney disease (ESKD) on hemodialysis (HD), are at increased risk for cardiovascular disease (CVD), including myocardial infarction and ischemic stroke. A shortening in telomere length, as a parameter for accelerated vascular aging, is an established biomarker for CVD in the general population. We aimed to elucidate the role of telomere length in ESKD patient on HD and its association with cardiovascular outcomes. Methods: Telomere length was measured in a prospective population-based cohort study of prevalent HD patients. DNA was isolated from whole blood, sampled at baseline, and analyzed for telomere length via a qPCR-based approach. The risk for the occurrence of the independently adjudicated three-point major adverse cardiovascular event outcome (myocardial infarction, ischemic stroke, and cardiovascular death) was statistically analyzed considering the competing risk of non-cardiovascular death. Results: In the cohort of 308 patients with ESKD (115 [37.3%] women, median [25th–75th percentile] age: 67.0 [56.8–76.0]), the median telomere length was 1.51 kb (25th–75th percentile 0.6–3.2 kb). The 3P-MACE outcome occurred with an incidence rate of 9.4 per 100 patient-years. Patients with longer telomere length more frequently had vascular nephropathy compared to patients with shorter telomere length. Interestingly, patients in the highest quartile of telomere length had a 1.8-fold increased risk for 3P-MACE (95% CI: 1.051–3.201, p = 0.033), after multivariable adjustment for age, history of stroke, myocardial infarction, venous thromboembolism, presence of heart valve replacement, atrial fibrillation, smoking, anticoagulation, or immunosuppressive use. Conclusion: Surprisingly, in this high-risk cohort of patients with ESKD on HD, longer telomere lengths were associated with increased risk of cardiovascular events.

A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study.

Telomeres are ribonucleoprotein structures that form a protective buffer at the ends of chromosomes, maintaining genomic integrity during the cell cycle. A decrease in average telomere length is associated with with age and with aging-related diseases such as cancer and cardiovascular disease. In this study, we conducted a randomized, double-blind, placebo-controlled trial over six months to compare the effects of the Astragalus-based supplement versus a placebo on telomere length (TL) in 40 healthy volunteers (mean age 56.1 ± 6.0 years). Twenty subjects received the supplement, and 20 received placebo capsules. All participants completed the study, and no adverse side effects were reported at six months. Subjects taking the Astragalus-based supplement exhibited significantly longer median TL (p = 0.01) and short TL (p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change in TL. This trial confirmed that the supplement significantly lengthens both median and short telomeres by increasing telomerase activity and reducing the percentage of short telomeres (<3 Kbp) in a statistically and possibly clinically significant manner. These results align with a previous open prospective trial, which found no toxicity associated with the supplement's intake. These findings suggest that this Astragalus-based supplement warrants further investigation for its potential benefits in promoting health, extending life expectancy, and supporting healthy aging.

Telomere length and clonal chromosomal alterations in peripheral blood of patients with severe aplastic anaemia.

Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.

Comparison of telomere length in patients with bone marrow failure syndromes and healthy controls.

During normal aging, telomeric DNA is gradually lost in dividing somatic cells, and critically short telomeres lead to replicative senescence, apoptosis, or chromosomal instability. We studied telomere length in bone marrow failure syndromes (BMFS) compared to normal healthy population. Peripheral blood was collected from the participants, and genomic DNA was extracted. Relative telomere length was measured using a quantitative polymerase chain reaction. Statistical analysis was performed using SPSS and GraphPad Prism 8.2 software. The median age of normal Indian population was 31 (0-60) years. As expected, telomere length (TL) showed a decline with age and no difference in TL between males and females. The median age of 650 patients with aplastic anemia (AA) was 30 (1-60) years. TL was significantly shorter in patients with AA compared to healthy controls (p < .001). In FA and MDS patients, TL was significantly shorter than age-matched healthy controls (p = .028; p < .001), respectively. There was no difference between the median TL in age-matched AA and FA patients (p = .727). However, patients with MDS had shorter TL than age-matched AA (p = .031). TL in BMF syndrome patients was significantly shorter than age-matched healthy controls.

Telomeres are associated with markers and regions sensitive to aging and not Alzheimer’s disease in cognitively unimpaired older adults

AbstractBackgroundTelomeres (protective chromosomal ends) gradually shorten over the lifespan and have been associated with the development of age‐related diseases such as Alzheimer’s disease (AD). Most studies use median telomere length as a biomarker of cellular aging, but their dysfunction is rather reflected by the load of short telomere. No study to date has assessed the links between the percentage of short telomeres (ST) and blood, neuroimaging markers of aging, neurodegeneration, amyloid and tau pathologies in healthy elderly.MethodBaseline data from 125 cognitively unimpaired older adults (65 to 83 years old; mean ± SD: 68.9 ± 2.8) from the Age‐Well trial (NCT02977819), who completed multimodal neuroimaging and blood sampling, were analyzed. Neuroimaging data included structural T1‐weighted MRI, T2‐weighted high‐resolution scan of the hippocampus, DKI, FDG‐PET and AV45‐PET (perfusion and amyloid load). ST, as well as neurodegeneration, amyloid, and tau biomarkers (NFL, GFAP, Aß42/40 ratio and pTau181) were measured in blood samples. Multiple linear regressions between ST and each marker were conducted corrected for age, sex, education and body mass index. Additional adjustments for APOE and amyloid status were made. Statistical significance was set to p&lt;0.05, except for voxelwise analyses (puncorrected&lt;0.005, kuncorrected = 500 voxels).ResultST was associated with lower white matter integrity (measured by kurtosis fractional anisotropy (kFA)) in prefrontal and temporal regions (Fig.1), and with the hippocampal subiculum volume, but not with total gray matter volume, mean kurtosis, glucose metabolism, brain perfusion or amyloid load; nor with blood markers of neurodegeneration, amyloid, or tau. Additional adjustments for APOE/amyloid status gave similar results.ConclusionTelomere dysfunctions were associated with lower white matter integrity in regions vulnerable to aging, but not to AD, nor with neurodegeneration, amyloid or tau biomarkers, and neither with AD risk factors (APOE or amyloid status). When we focused on the hippocampus, a specific link was found with the subiculum volume, an hippocampal subfield known to be the most sensitive to aging, which is not the case in AD. These results give further evidence for the tight connection between cellular and cerebral aging, but not with AD in cognitively unimpaired older adults.

Telomeres are associated with markers and regions sensitive to aging and not Alzheimer’s disease in cognitively unimpaired older adults

AbstractBackgroundTelomeres (protective chromosomal ends) gradually shorten over the lifespan and have been associated with the development of age‐related diseases such as Alzheimer’s disease (AD). Most studies use median telomere length as a biomarker of cellular aging, but their dysfunction is rather reflected by the load of short telomere. No study to date has assessed the links between the percentage of short telomeres (ST) and blood, neuroimaging markers of aging, neurodegeneration, amyloid and tau pathologies in healthy elderly.MethodBaseline data from 125 cognitively unimpaired older adults (65 to 83 years old; mean ± SD: 68.9 ± 2.8) from the Age‐Well trial (NCT02977819), who completed multimodal neuroimaging and blood sampling, were analyzed. Neuroimaging data included structural T1‐weighted MRI, T2‐weighted high‐resolution scan of the hippocampus, DKI, FDG‐PET and AV45‐PET (perfusion and amyloid load). ST, as well as neurodegeneration, amyloid, and tau biomarkers (NFL, GFAP, Aβ42/40 ratio and pTau181) were measured in blood samples. Multiple linear regressions between ST and each marker were conducted corrected for age, sex, education and body mass index. Additional adjustments for APOE and amyloid status were made. Statistical significance was set to p&lt;0.05, except for voxelwise analyses (puncorrected&lt;0.005, kuncorrected = 500 voxels).ResultST was associated with lower white matter integrity (measured by kurtosis fractional anisotropy (kFA)) in prefrontal and temporal regions (Fig.1), and with the hippocampal subiculum volume, but not with total gray matter volume, mean kurtosis, glucose metabolism, brain perfusion or amyloid load; nor with blood markers of neurodegeneration, amyloid, or tau. Additional adjustments for APOE/amyloid status gave similar results.ConclusionTelomere dysfunctions were associated with lower white matter integrity in regions vulnerable to aging, but not to AD, nor with neurodegeneration, amyloid or tau biomarkers, and neither with AD risk factors (APOE or amyloid status). When we focused on the hippocampus, a specific link was found with the subiculum volume, an hippocampal subfield known to be the most sensitive to aging, which is not the case in AD. These results give further evidence for the tight connection between cellular and cerebral aging, but not with AD in cognitively unimpaired older adults.

The mediating role of telomere length in multi-pollutant exposure associated with metabolic syndrome in adults.

Metabolic syndrome is a chronic and complex disease characterized by environmental and genetic factors. However, the underlying mechanisms remain unclear. This study assessed the relationship between exposure to a mixture of environmental chemicals and metabolic syndrome (MetS) and further examined whether telomere length (TL) moderated these relationships. A total of 1265 adults aged > 20years participated in the study. Data on multiple pollutants (polycyclic aromatic hydrocarbons, phthalates, and metals), MetS, leukocyte telomere length (LTL), and confounders were provided in the 2001-2002 National Health and Nutrition Examination Survey. The correlations between multi-pollutant exposure, TL, and MetS in the males and females were separately assessed using principal component analysis (PCA), logistic and extended linear regression models, Bayesian kernel machine regression (BKMR), and mediation analysis. Four factors were generated in PCA that accounted for 76.2% and 77.5% of the total environmental pollutants in males and females, respectively. The highest quantiles of PC2 and PC4 were associated with the risk of TL shortening (P < 0.05). We observed that the relationship between PC2, PC4, and MetS risk was significant in the participants with median TL levels (P for trend = 0.04 for PC2, and P for trend = 0.01 for PC4). Furthermore, mediation analysis revealed that TL could explain 26.1% and 17.1% of the effects of PC2 and PC4 associated with MetS in males, respectively. The results of BKMR model revealed that these associations were mainly driven by 1-PYE (cPIP = 0.65) and Cd (cPIP = 0.29) in PC2. Meanwhile, TL could explain 17.7% of the mediation effects of PC2 associated with MetS in the females. However, the relationships between pollutants and MetS were sparse and inconsistent in the females. Our findings suggest that the effects of the risk of MetS associated with mixed exposure to multiple pollutants are mediated by TL, and this mediating effect in the males is more pronounced than that in the females.

A Multivitamin Mixture Protects against Oxidative Stress-Mediated Telomere Shortening

Telomeres are nucleotide repeat sequences located at the end of chromosomes that protect them from degradation and maintain chromosomal stability. Telomeres shorten with each cell division; hence telomere length is associated with aging and longevity. Numerous lifestyle factors have been identified that impact the rate of telomere shortening; high vitamin consumption has been associated with longer telomere length, whereas oxidative stress is associated with telomere shortening. In this paper, we sought to determine if a multivitamin mixture containing both vitamins and a blend of polyphenolic compounds, could reduce telomere shortening consequent to an oxidative stress (10 uM H2O2 for 8 weeks) in a primary fibroblast cell culture model. Under conditions of oxidative stress, the median and 20th percentile telomere length were significantly greater (p < 0.05), and the percentage of critically short telomeres (<3000 bp) was significantly less (p < 0.05) in cells treated with the multivitamin mixture at 4, 15 and 60 ug/ml compared to control (0 ug/ml). Median and 20th percentile telomere shortening rate was also reduced under the same conditions (p < 0.05). Taken together, these findings demonstrate that the multivitamin mixture protects against oxidative stress-mediated telomere shortening in cell culture, findings which may have implications in human health.

Association of longer telomere length in cancer cells and cancer-associated fibroblasts withworse prognosis.

Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appearing duct cells at initiation and then continues during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression. TL in both cancer cells and cancer-associated fibroblasts (CAFs) was analyzed by high-throughput quantitative fluorescence in situ hybridization using a previously reported cohort comprising 1434 cases of adenocarcinoma (ADC), squamous cell carcinoma (SCC), adenosquamous carcinoma, hepatocellular carcinoma, and renal cell carcinoma (RCC), which are known cancers with a statistically significantly low incidence of alternative lengthening of telomeres. Cases were divided into 2 groups as follows: longer and shorter telomeres, according to the median TL of cancer cells and CAFs. The statistical significance of TL in cancer cells and CAFs on clinicopathological characteristics and prognosis was analyzed. There was a close association between TL in cancer cells and CAFs. Longer telomeres in cancer cells and CAFs were associated with aggressive features such as advanced stage, high mitosis score and nuclear score, poorly differentiated cancer, and desmoplastic stroma in ADC. Furthermore, a longer TL was an independent prognostic factor for ADC, SCC, and RCC. Longer telomeres are associated with worse prognosis in ADC, SCC, and RCC. Thus, TL is a novel biomarker for the diagnosis of aggressive cancers with poor prognoses.

In Vitro Determination of the Skin Anti-Aging Potential of Four-Component Plant-Based Ingredient.

The beauty industry is actively searching for solutions to prevent skin aging. Some of the crucial elements protecting cells from the aging process are telomere shortening, telomerase expression, cell senescence, and homeostasis of the redox system. Modification of these factors using natural antioxidants is an appealing way to support healthy skin aging. Therefore, in this study, we sought to investigate the antiaging efficacy of a specific combination of four botanical extracts (pomegranate, sweet orange, Cistanche and Centella asiatica) with proven antioxidant properties. To this end, normal human dermal fibroblasts were used as a cell model and the following studies were performed: cell proliferation was established by means of the MTT assay and the intracellular ROS levels in stress-induced premature senescence fibroblasts; telomere length measurement was performed under standard cell culture conditions using qPCR and under oxidative stress conditions using a variation of the Q-FISH technique; telomerase activity was examined by means of Q-TRAP; and AGE quantification was completed by means of ELISA assay in UV-irradiated fibroblasts. As a result, the botanical blend significantly reversed the H2O2-induced decrease in cell viability and reduced H2O2-induced ROS. Additionally, the presence of the botanical ingredient reduced the telomere shortening rate in both stressed and non-stressed replicating fibroblasts, and under oxidative stress conditions, the fibroblasts presented a higher median and 20th percentile telomere length, as well as a lower percentage of short telomeres (&lt;3 Kbp) compared with untreated fibroblasts. Furthermore, the ingredient transiently increased relative telomerase activity after 24 h and prevented the accumulation of UVR-induced glycated species. The results support the potential use of this four-component plant-based ingredient as an antiaging agent.

Telomere Length and Mitochondrial DNA Copy Number Variations in Patients with Obesity: Effect of Diet-Induced Weight Loss-A Pilot Study.

Background: Telomere length (TL) and mitochondrial DNA (mtDNA) copy number shifts are linked to metabolic abnormalities, and possible modifications by diet-induced weight loss are poorly explored. We investigated the variations before (T0) and after a 1-year (T12) lifestyle intervention (diet + physical activity) in a group of outpatients with obesity. Methods: Patients aged 25–70 years with BMI ≥ 30 kg/m2 were enrolled. Clinical and biochemical assessments (including a blood sample for TL, mtDNA copy number and total antioxidant capacity, and TAC determinations) were performed at T0 and T12. Results: The change in TL and the mtDNA copy number was heterogeneous and not significantly different at T12. Patients were then divided by baseline TL values into lower than median TL (L-TL) and higher than median TL (H-TL) groups. The two groups did not differ at baseline for anthropometric, clinical, and laboratory characteristics. At T12, the L-TL group when compared to H-TL showed TL elongation (respectively, +0.57 ± 1.23 vs. −2.15 ± 1.13 kbp, p = 0.04), higher mtDNA copy number (+111.5 ± 478.5 vs. −2314.8 ± 724.2, respectively, p < 0.001), greater weight loss (−8.1 ± 2.7 vs. −6.1 ± 4.6 Kg, respectively, p = 0.03), fat mass reduction (−1.42 ± 1.3 vs. −1.22 ± 1.5%, respectively, p = 0.04), and increased fat-free mass (+57.8 ± 6.5 vs. +54.9 ± 5.3%, respectively, p = 0.04) and TAC levels (+58.5 ± 18.6 vs. +36.4 ± 24.1 µM/L, respectively, p = 0.04). Conclusions: TL and the mtDNA copy number significantly increased in patients with obesity and with lower baseline TL values after a 1-year lifestyle intervention. Larger longitudinal studies are needed to confirm the results of this pilot study.

An Open-Label Clinical Trial Analyzing the Efficacy of a Novel Telomere-Protecting Antiaging Face Cream

Telomere length, a hallmark of cellular senescence, decreases with age and is associated with age-related diseases. Environmental factors, including dietary and lifestyle factors, can affect the rate at which telomeres shorten, and telomere protection prevents this from happening. The protection of telomeres by natural molecules has been proposed as an antiaging strategy that may play a role in treating age-related diseases. This study investigated the effect of a cycloartane-type triterpene glycoside (astragaloside IV). Astragaloside IV is one of the primary compounds from the aqueous extract of Astragalus membranaceus, and it provides telomere protection both in vitro and in vivo. In a study cohort with 13 participants, telomere length in human skin samples was analyzed after daily treatment for 4 weeks. A comparison of the average median telomere length between the treatment and control groups (5342 bp vs. 4616 bp p = 0.0168) showed significant results. In the second clinical cohort with 20 participants, skin parameters at baseline and after 4 and 8 weeks were measured in vivo. The results show that the product improved hydration by 95%, the skin appeared brighter by 90%, and wrinkle visibility was reduced by 70%. The combination of biologically active compounds in the cream possesses telomere-protecting properties and notable antioxidant activity in vitro and in vivo.

Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study

The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3–4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case–control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52–5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First-degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.

Abstract 14025: Atrial Fibrillation is Associated With Reduced Telomere Length

Background: Atrial Fibrillation (AF) is common pathophysiologically complex. Age is among the most important AF risk factors. However, some young patients develop early-onset AF, whereas many others do not despite an advanced age. Advanced biological aging as opposed to advanced calendar age may be an explanation. Telomere length is associated with age and may be considered a measurable marker of biological age. AF and telomere length have previously been associated, but results remained inconclusive. Hypothesis: AF is age-related and associates with telomere length in a large case-control cohort. Methods: Between 2005 and 2018, we enrolled 2475 early-onset AF patients into the prospective AFLMU cohort. 3077 AF-free individuals from the community-based KORA study (enrollment 2006-08) served as controls. Clinical characteristics, an electrocardiogram, and a blood sample was obtained in all participants. We determined telomere length by a qPCR-based method using a multiplex TaqMan assay. Telomere length was expressed as delta-CT referenced to the single copy gene 36B4 .Lower CT values indicate shorter telomere length. Telomere length in cases vs. controls was assessed using multi-variably adjusted logistic regression. Results: Mean age was 58 years in AFLMU and 56 years in KORA. Men accounted for 72.3% in AFLMU and for 51.7% in KORA. For quality control, we confirmed a reduction of telomere length with age and demonstrated shorter telomere length in men compared to women. Median telomere length was also significantly shorter in AF patients compared to controls (9.81 [5.98, 13.1] vs. 13,10 [12.60, 13.63], p&lt;0,001). The association remained significant after adjustment for sex, body mass index, hypertension, and diabetes (odds ratio per telomere length unit 0.77 [95% confidence interval 0.74-0.77], p&lt;0.001). Conclusion: In a large case-control cohort, AF significantly associates with telomere length. Information on telomere length may help to inform if a patient develops AF due to premature biological aging. The underlying pathomechanisms for premature aging remain to be elucidated.

Germline Variants Contribute Significantly to the Pathogenesis of Aplastic Anemia in India

IntroductionAplastic anemia (AA) is characterized by a hypoplastic marrow and bone marrow failure (BMF), leading to peripheral pancytopenia. The treatment for AA currently consists of either hematopoietic stem cell transplant (HSCT) or immunosuppressive therapy (IST) with anti-thymocyte globulin and cyclosporine. We have previously reported poor responses to IST in Indian children with AA while adults (>15 years) show responses of 60%. Therefore, we wanted to study if we could identify constitutional variants in children and young adults with AA.MethodsWe included 102 young patients (≤40 years of age) diagnosed to have AA between year Jan 2006 to April 2021. Genomic DNA was extracted from peripheral blood and relative telomere length (rTL) was measured using quantitative real-time PCR (qPCR). The DNA was used to perform targeted gene capture using a custom capture kit which covered 2196 genes associated with various hematological disorders. Among the 2196 genes, the analysis was restricted to 96 genes associated with AA/IBMFS. Bioinformatics analysis was carried out using Genome Analysis ToolKit (GATK) best practices pipeline. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the variants were labelled as pathogenic/likely pathogenic/variant of uncertain significance (VUS)/likely benign/benign. The candidate variants were validated by Sanger sequencing.ResultsThe median age of patients was 9 (0-40) years, including 56 males (55%) and 46 females (45%). There were 15 patients with non-severe AA (NSAA) (15%), 63 with severe AA (SAA) (62%) and 24 with very severe AA (VSAA) (23%). The median relative telomere length of the entire cohort was 0.85 (0.21-3.10). The characteristics of patients age-wise are mentioned in Table 1. Genetic variants were identified in 34 patients (33.3%). This included germline pathological (PAT) genetic variants in 12.7%, variants of limited significance in 9.8% and variants of uncertain significance (VUS) in 10.7% patients. Of the 13 patients who had PAT variants, 6 patients had variants in telomere associated genes. This includes 2 patients with splice site and missense mutation in TINF2 (c.1221+5G>A & R282H); 2 patients with missense mutation in TERT (C828W & S947C); and 2 patients with frameshift and nonsense mutation in RTEL1 (L962S & R1010X). Homozygous MPL mutations [L79Q, R522T & P530L(n=3)] were observed in 5 patients. Two patients had PAT variants in DNAJC21 and NLRP12. Eleven VUS variants were present in the following genes, ATM (n=3), TINF2 (n=1), WRAP53 (n=1), BRCA2 (n=1), AK2 (n=1), FANCA (n=1), FANCN (n=1), ERCC6L2 (n=1) & PRF1 (n=1). The incidence of mutations in the age group ≤5, 6-10, 11-15 and 16-30 years were 51.8%, 25.6%, 27.8% & 33.4% respectively. There was significant difference in median rTL between patients with variants and no variants in the age-group 11-15 years (p=0.043).DiscussionGenetic analyses studies in aplastic anemia patients were confined to single genes or limited gene sets. Keel et al., reported 5.1% of AA patients carried pathogenic variants in inherited BMF/MDS genes. We observed a high frequency of causative genetic variants (37%) in children (<10 years). Our study results highlight the importance of recognizing pathogenic and VUS genetic variants contributing to the pathogenesis of AA in the lower age group. [Display omitted] DisclosuresMathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

Telomere Length and Preterm Birth in Pregnant Mexican-Origin Women.

Despite the obstacles of limited education and employment opportunities-and the stress associated with immigration and pregnancy-Mexican immigrant women have low rates of preterm birth (PTB) compared to the US national average for all races and ethnicities. Stressors during pregnancy, and stressors associated with acculturation, may accelerate cellular aging manifested by shortened telomere length (TL) in pregnant women. Our objectives were to: (1) determine whether women with PTBs had shorter telomere lengths compared to women who had full term births; (2) assess the association of acculturation with TL and PTB. This prospective pilot study collected data from 100 self-identified Mexican-origin pregnant women. Survey data included self-administered sociodemographic and acculturation measures and was collected from participants via paper and pen, while biologic data was collected via a single blood draw during a regularly scheduled prenatal visit between 26 and 36weeks gestation. PTB data was collected from the participant's medical record after delivery. TL was significantly associated with PTB; the median TL of the women with PTB was less than the median TL for the full sample (p = 0.02). Based on regression analysis for PTB vs acculturation, we found no significant associations between acculturation and PTB or TL. This study provides important evidence of the association between shortened maternal TL and adverse birth outcomes. By linking social, clinical and biologic data, we can enhance our understanding of social determinants that may affect racial and ethnic disparities in preterm birth.

Obesity and telomere status in the prognosis of patients with colorectal cancer submitted to curative intention surgical treatment.

The risk of colorectal cancer (CRC) development has been associated with telomere dysfunction and obesity. However, clinical relevance of these parameters in CRC prognosis is not clear. Therefore, the aim of the present study was to evaluate the impact of obesity and telomere status in the prognosis of patients affected by CRC and submitted to curative surgical treatment. According to published data, this is the first work in which obesity and telomere status are jointly considered in relation to CRC prognosis. A prospective study including 162 patients with CRC submitted to curative surgical treatment was performed. Subjects were classified according to their BMI. Telomere status was established through telomere length and telomerase activity evaluation. Statistical analyses were performed using the SPSS software package version 22. Telomere shortening was inversely associated with BMI in patients with CRC. Notably, among patients with CRC, subjects with obesity exhibited less shortening of tumor telomeres than non-obese patients (P=0.047). Patients with shorter telomeres, both in the tumor (median telomere length <6.5 kb) and their non-tumor paired tissues (median telomere length <7.1 kb), had the best clinical evolution, regardless of the Dukes' stage of cancers (P=0.025, for tumor samples; P=0.003, for non-tumor samples). Additionally, subjects with a BMI >31.85 kg/m2 showed the worse clinical outcomes compared with subjects with other BMI values. Interestingly, the impact of BMI showed sex dependence, since only the group of men displayed significant differences in CRC prognosis in relation to obesity status (P=0.037). From the results of the present study, based on a multivariate prediction model to establish prognosis, it was concluded that telomere length is a useful biomarker to predict prognosis in patients with CRC. Regardless of BMI values, the improved clinical evolution was associated with shorter telomeres. The impact of BMI seems to be associated with other factors, such as sex.

Dynamic of Telomeric Parameters in Relapsing or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL), an Analysis of the Filo ICLL001 Bomp Trial

Dynamic of Telomeric Parameters in Relapsing or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL), an Analysis of the Filo ICLL001 Bomp Trial

Analysis of the Hematopoietic System in Long-Term Survivors of Allogeneic Stem Cell Transplantation and Their Respective Donors

For a variety of malignant and non-malignant hematopoietic disorders, allogeneic stem cell transplantation (HSCT) is the only curative treatment option. Over the past decades, the outcome of patients undergoing HSCT continuously improved. However, there is limited knowledge about the hematopoietic system of long-time survivors of HSCT in comparison to their respective donors. Telomere length shortening reflects the proliferation history of cells. With respect to HSCT, seminal studies have demonstrated that accelerated telomere length shortening occurs during the early post-transplant phase but the rate of telomere shortening then slows down and becomes indistinguishable between recipients and donors thereafter, leading to a parallel decline. This results in an overall pre-mature ageing of the hematopoietic system in HSCT recipients. We here analyzed blood counts and telomere length of 45 long-time survivors of HSCT and their respective donors.Blood counts were analyzed at the University Hospital Zurich. Telomere length was measured by Flow-FISH at RWTH Aachen. The study was approved by the local ethics committee. Patients and donors gave informed consent.Of the 45 donor-recipient pairs enrolled in this study, three recipients showed hematological diseases (donor-derived Thalassemia minor, MDS, relapsed Multiple Myeloma) and were thus excluded from this analysis. All remaining 42 analyzed patients were considered to be cured from their underlying hematological disease. The sex ratio was 1:1 in donors and 1:1.1 in recipients in favor of male recipients. The median age of donors and recipients at the time of HSCT was 36 and 35 years, and the age at presentation for this study was 59 and 56 years, respectively. The median time since HSCT was 16 years (range 9-33 years). When comparing donors and recipients, we did not detect any relevant differences in hemoglobin concentration (donors: 139±12g/L, recipients: 143±15g/l, p=0.54) or erythrocyte counts (donors: 4.73±0.49T/L, recipients 4.55±0.47T/L, p=0.32). Recipients showed significantly higher MCV values (donors: 91.6±4.4fL, recipients 94.1±3.8fL, p=0.03) and significantly higher MCH (donors 30.5±1.3pg, recipients 31.3±1.3pg, p<0.001), while MCHC did not differ (donors: 329±11g/L, recipients 333±9g/L, p=0.20). Recipients showed a trend to higher relative but not absolute reticulocyte counts (donor: 1.02±0.38%, 50±17G/L, recipients: 1.23±0.40%, 56±18G/L, p=0.08 and p=0.18). Also, we did not observe significant alterations in platelet counts (donors: 248±62G/L, recipients 234±70G/L, p=0.31). In the leukocyte compartment, neutrophil counts were not altered (donors: 3.8±1.5G/L, recipients 4.2±1.6G/L, p=0.87), while recipients had significantly more monocytes (donors: 0.52±0.17G/L, recipients 0.62±0.20G/L, p<0.001). Eosinophil and basophil counts did not show differences, while recipients had higher lymphocyte counts (donors: 1.7±0.6G/L, recipients 2.2±5G/L, p=0.007).In 28 of 42 pairs, telomere length analysis was logistically possible. Telomere length was measured separately in lymphocytes as well as in granulocytes. The median telomere length of granulocytes was 8.00±1.30kb in donors and 7.46±1.16kb in recipients, respectively (p=0.043). The median difference in granulocyte telomere length between donors and recipients was 0.38±0.82kb reflecting a hypothetical age difference of 14.2 years assuming a loss in telomere length of 27bp per year. In lymphocytes, the median telomere length was 7.13±1.06kb in donors and 6.43±1.02kb in recipients (p<0.001). The median difference in telomere length between donors' and recipients' lymphocytes was 0.48±0.99kb corresponding to a longer proliferation history of approximately 17.8 years in the recipients.Peripheral blood counts are stable and widely inconspicuous in long-time HSCT-survivors. Telomere length is significantly shorter in recipients' lymphocytes and granulocytes. This telomere shortening is most likely due to increased HSC proliferation (reflected by granulocyte telomere length) and inflammatory stimuli (affecting both HSCs and lymphocytes) in HSCT recipients. However, it does not have a clinically relevant effect on blood counts in this small group of long-term HSCT-survivors. In how far the increased proliferative history of donor HSCs in allo-HSCT recipients is of biologic relevance needs further investigation. DisclosuresBrümmendorf:Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Telomere Length Is Significantly Reduced in Patients with Aplastic Anemia and Is Not Influenced By Gender and Severity

Telomeres are nucleotide repeats at the ends of the chromosomes that function as protective caps to prevent erosion of genomic DNA during cell division. With each mitotic division, telomeric DNA becomes shorter and at a critically short length, cells become senescent or undergo apoptosis. Idiopathic aplastic anemia (AA) is a bone marrow failure disorder characterized by peripheral blood pancytopenia and bone marrow aplasia. Studies have shown that 30-50% of patients with aplastic anaemia will have short telomeres and these short telomeres are associated with relapse, clonal evolution and poor survival following immunosuppressive therapy. We analysed the telomere length in patients with aplastic anaemia from a single centre in India..MethodWe analysed telomere length in patients with aplastic anaemia [either newly diagnosed or those who underwent haematopoietic stem cell transplantation (HSCT) between 2001 and 2017]. This was compared with healthy controls which included healthy donors for HSCT and age matched healthy subjects. Clinical parameters were documented in a standard format. DNA from patients with AA and healthy controls was extracted. Telomere length (TL) was measured using quantitative real-time PCR (qPCR) using relative quantitation method. Analysis was carried out using SPSS software.ResultsTwo hundred and fifty three patients with AA were included in this analysis and was compared with 328 healthy controls. This included 45 patients with non-severe aplastic anaemia [NSAA] [18%), 159 with severe aplastic anaemia [SAA] (64%) and 46 with very severe aplastic anaemia [VSAA] (18%). The clinical and demographic details are tabulated in the Table.1. The TL was significantly shorter in AA patients as compared to healthy controls [0.78 (Range: 0.07 - 4.08) and 1.59 (range: 0.19 - 11.59); p=0.000]. The median TL was 1.02; 67% of AA patients had shorter telomeres (n=169/253). The TL was not influenced by gender (p=0.186). In AA patients, there was no correlation between age and TL whereas it had a significant negative correlation with age in the healthy controls (r=-0.474, p=0.000). In 62 AA subjects, a paired BM sample was also available. A significant positive correlation was observed between the PBTL and BMTL (r=0.399, p=0.001). There was no significant association seen between the severity of AA and TL.DiscussionTelomere length was significantly shorter in patients with aplastic anemia. An age related decrease in TL was noted in healthy subjects but not in patients with AA. The TL did not differ significantly in the subtypes of AA [Display omitted] DisclosuresSrivastava:Bayer Healthcare, Shire, Novo Nordisk, Roche Genentech, LFB: Other: Educational grants / Advisory Board / Grants Review / Data Monitoring Committee, Research Funding.