Telomere Length In Cells Research Articles

Inflamm-Aging Is Associated with Lower Plasma PTX3 Concentrations and an Impaired Capacity of PBMCs to Express hTERT following LPS Stimulation.

Age-related elevations in proinflammatory cytokines, known as inflamm-aging, are associated with shorter immune cell telomere lengths. Purpose. This study examined the relationship of plasma PTX3 concentrations, a biomarker of appropriate immune function, with telomere length in 15 middle-aged (40-64 years) and 15 young adults (20-31 years). In addition, PBMCs were isolated from middle-aged and young adults to examine their capacity to express a key mechanistic component of telomere length maintenance, human telomerase reverse transcriptase (hTERT), following ex vivo cellular stimulation. Methods. Plasma PTX3 and inflammatory cytokines (i.e., IL-6, IL-10, TGF-β, and TNF-α), PBMC telomere lengths, and PBMC hTERT gene expression and inflammatory protein secretion following exposure to LPS, PTX3, and PTX3+LPS were measured. Results. Aging was accompanied by the accumulation of centrally located visceral adipose tissue, without changes in body weight and BMI, and alterations in the systemic inflammatory milieu (decreased plasma PTX3 and TGF-β; increased TNF-α (p ≤ 0.050)). In addition, shorter telomere lengths in middle-aged compared to young adults (p = 0.011) were negatively associated with age, body fat percentages, and plasma TNF-α (r = −0.404, p = 0.027; r = −0.427, p = 0.019; and r = −0.323, p = 0.041, respectively). Finally, the capacity of PBMCs to increase hTERT gene expression following ex vivo stimulation was impaired in middle-aged compared to young adults (p = 0.033) and negatively associated with telomere lengths (r = 0.353, p = 0.028). Conclusions. Proinflammation and the impaired hTERT gene expression capacity of PBMCs may contribute to age-related telomere attrition and disease.

Shorter telomere length of white blood cells is associated with higher rates of aneuploidy in women undergoing in vitro fertilization

Telomeres are tandem repeats of the sequence TTAGGG located at the ends of chromosomes. Telomere shortening is a key mechanism of cell senescence and aging. Telomere shortening has been associated with decreased oocyte quality through disruption of chromosome alignment and spindle structure. In this study, we sought to evaluate whether the telomere length of cumulus cells (CC) or white blood cells (WBC) in an infertile population is associated with reproductive aging. Prospective cohort study. Women undergoing IVF between July 2017 and December 2018 were recruited for the study under Institutional Review Board approval. Blood and CC were collected at the time of oocyte retrieval. Genomic DNA was isolated and stored at -80°C. Telomere DNA length was measured by quantitative real-time PCR and normalized to AluYa5 sequence as an endogenous control for each sample. Linear regression was applied to determine if telomere length (TL) of WBC or CC was associated with patient age, number of oocytes retrieved, number of mature (M2) oocytes retrieved, blastulation rate, aneuploidy rate, serum anti-mullerian hormone (AMH), and serum estrogen (E2) level on day of hCG or GnRHa administration. TL data was available for WBC samples from 156 individuals and for CC samples from 142 patients. Data was available for both tissue types in 139 patients (age range 25.7 to 45.0 years, mean 35.0 ± 4.0 years). As expected, WBC telomere length declined with increasing age (p=0.006). In contrast, CC TL was equivalent in patients of all ages and failed to show anticipated age-related shortening. As such, CC TL was unrelated to any index of ovarian performance including number of oocytes retrieved (p=0.95), M2 oocytes retrieved (p=0.81), blastulation rate (p=0.98), aneuploidy rate (p=0.30), AMH level (p=0.32), or mid-cycle E2 level (p=0.77). Consistent with these data, CC TL was not associated with patient age (p=0.99). While WBC TL declined with increasing maternal age, it was a poor predictor of quantitative ovarian performance [total oocytes retrieved (p=0.47), number of M2 oocytes retrieved (p=0.30), AMH level (p=0.13), E2 level (p=0.36), and blastulation rate (p=0.48)]. However, TL of WBC samples was associated with embryonic competence as evidenced by aneuploidy rate (p=0.02), with shorter TL associated with higher aneuploidy. The TL of CC was not associated with patient age or any index of ovarian or embryonic performance. Declining WBC TL was associated with increasing maternal age and increasing rates of embryonic aneuploidy. Further studies are necessary to determine if changes in peripheral somatic cell TL are truly prognostic for aneuploidy rate within a given maternal age group or if this finding is simply reflective of a simultaneous change which occurs with age.

Telomere length and aging-related outcomes in humans: A Mendelian randomization study in 261,000 older participants.

Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging‐related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40–70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow‐up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate‐adjusted p‐values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92–0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06–1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age‐related health outcomes. Telomere lengthening may offer little gain in later‐life health status and face increasing cancer risks.

Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB.

Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.

Amyloid β and Tumorigenesis: Amyloid β-Induced Telomere Dysfunction in Tumor Cells

Amyloid β and Tumorigenesis: Amyloid β-Induced Telomere Dysfunction in Tumor Cells

Exposure–Response Associations of Household Air Pollution and Buccal Cell Telomere Length in Women Using Biomass Stoves.

Background:Telomere shortening is associated with early mortality and chronic disease. Recent studies indicate that environmental exposures, including urban and traffic-related air pollution, may shorten telomeres. Associations between exposure to household air pollution from solid fuel stoves and telomere length have not been evaluated.Methods:Among 137 rural Chinese women using biomass stoves ( of age), we measured 48-h personal exposures to fine particulate matter [PM in aerodynamic diameter ()] and black carbon and collected oral DNA on up to three occasions over a period of 2.5 y. Relative telomere length (RTL) was quantified using a modified real-time polymerase chain reaction protocol. Mixed effects regression models were used to investigate the exposure–response associations between household air pollution and RTL, adjusting for key sociodemographic, behavioral, and environmental covariates.Results:Women’s daily exposures to air pollution ranged from for () and for black carbon (). Natural cubic spline models indicated a mostly linear association between increased exposure to air pollution and shorter RTL, except at very high concentrations where there were few observations. We thus modeled the linear associations with all observations, excluding the highest 3% and 5% of exposures. In covariate-adjusted models, an interquartile range (IQR) increase in exposure to black carbon () was associated with shorter RTL [all observations: (95% CI: , ); excluding highest 5% exposures: (95% CI: , )]. Further adjustment for outdoor temperature brought the estimates closer to zero [all observations: (95% CI: , 0.06); excluding highest 5% exposures: (95% CI: , )]. Models with as the exposure metric followed a similar pattern.Conclusion:Telomere shortening, which is a biomarker of biological aging and chronic disease, may be associated with exposure to air pollution in settings where household biomass stoves are commonly used. https://doi.org/10.1289/EHP4041

Downregulation of mTOR Signaling Increases Stem Cell Population Telomere Length during Starvation of Immortal Planarians.

SummaryReduction of caloric intake delays and prevents age-associated diseases and extends the life span in many organisms. It may be that these benefits are due to positive effects of caloric restriction on stem cell function. We use the planarian model Schmidtea mediterranea, an immortal animal that adapts to long periods of starvation by shrinking in size, to investigate the effects of starvation on telomere length. We show that the longest telomeres are a general signature of planarian adult stem cells. We also observe that starvation leads to an enrichment of stem cells with the longest telomeres and that this enrichment is dependent on mTOR signaling. We propose that one important effect of starvation for the rejuvenation of the adult stem cell pool is through increasing the median telomere length in somatic stem cells. Such a mechanism has broad implications for how dietary effects on aging are mediated at the whole-organism level.

The approximate formulas predicting personal somatic telomere length using patient blood test data.

Biological aging underlies lifestyle-related diseases. It can be assessed by measuring personal somatic cell telomere length. However, measuring the telomere length is laborious, and its clinical surrogate parameters have not been developed. This study analyzed the correlation between telomere length in peripheral leukocytes and laboratory data to select test items relating closely to biological aging. We established formulas from these clinical data to predict the personal telomere length. The subjects were patients having visited Kyushu University Beppu Hospital from 2012 to 2015. Two hundred and thirty-two patients were enrolled. The blood data were collected and telomere lengths were measured by Southern blotting method. The patients showed significant correlations between the telomere length and several blood test data with a sex-related difference. Candidate formulas are as follows: Predicted telomere length (kb) in men = 8.59 - 0.037 × Age (years) + 0.024 × Hemoglobin (g/dL); Predicted telomere length (kb) in women = 4.83 - 0.019 × Age (years) + 0.23 × Albumin (g/dL) + 0.0001 × White blood cells (/mm3) + 0.0020 × Red blood cells (× 104/mm3) + 0.0032 × Total cholesterol (mg/dL). Thus, the derived formulas allow for the accurate differential prediction of telomeric length in male and female patients.

Cellular aging over 13 years associated with incident antinuclear antibody positivity in the Baltimore Longitudinal Study of Aging

Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals from the Baltimore Longitudinal Study of Aging (BLSA). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals of ANA positivity comparing the shorter tertiles of telomere length to the longest tertile for two cross-sectional points in time and then longitudinally to assess the association between shorter telomere length and incident ANA positivity. Cross-sectional analyses were adjusted for sex, race and BMI (N = 368 baseline, N = 370 follow-up) and longitudinal analyses were adjusted for sex, race, BMI and time between baseline and follow-up (N = 246). No statistically significant cross-sectional associations were observed at baseline or follow-up. Among those where ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes.

TSPYL5 Depletion Induces Specific Death of ALT Cells through USP7-Dependent Proteasomal Degradation of POT1.

A significant fraction (∼10%) of cancer cells maintain their telomere length via a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). There are no known molecular, ALT-specific, therapeutic targets. We have identified TSPYL5 (testis-specific Y-encoded-like protein 5) as a PML body component, co-localizing with ALT telomeres and critical for ALT+ cell viability. TSPYL5 was described as an inhibitor of the USP7 deubiquitinase. We report that TSPYL5 prevents the poly-ubiquitination of POT1-a shelterin component-and protects POT1 from proteasomal degradation exclusively in ALT+ cells. USP7 depletion rescued POT1 poly-ubiquitination and loss, suggesting thatthe deubiquitinase activates POT1 E3 ubiquitin ligase(s). Similarly, PML depletion suppressed POT1 poly-ubiquitination, suggesting an interplay between USP7 and PML to trigger POT1 degradation in TSPYL5-depleted ALT+ cells. We demonstrate that ALT telomeres need to be protected from POT1 degradation in ALT-associated PML bodies and identify TSPYL5 as an ALT+ cancer-specific therapeutic target.

Abstract 3110: Shorter naïve T cell telomere length is associated with thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study (CCSS)

Abstract Introduction: Reduced blood telomere content has been associated with an increased risk for subsequent malignant neoplasms of the thyroid (thyroid SMN) in survivors of childhood cancer (PMID 24277454). Here, we further investigate this association by examining telomere length (TL) in leukocyte subsets. Methods: Survivors were enrolled to the CCSS, a multicenter, retrospective cohort of 5-year + survivors of childhood cancer. Cases were survivors with thyroid SMN, and matched (1:1) to survivor controls without SMN by primary diagnosis, year of primary diagnosis (decade), chemotherapy (yes/no), radiation field, and follow-up time (exceeding time to SMN for the case). Stem cell transplant recipients were excluded. Absolute TL was determined from viably frozen leukocytes (lymphocytes, naïve T, memory T, B, and NK cells) by telomere flow cytometry fluorescence in situ hybridization (telomere flow FISH, Repeat Diagnostics), and transformed to age-adjusted percentiles based on age at sample collection. For each leukocyte subset, we used McNemar’s test to compare frequency of very low (VL, ≤1st age-adjusted percentile) or low (L, &amp;gt;1st to ≤10th percentile), and a paired t-test to compare age-adjusted TL between cases and controls. Odds ratios were determined by conditional logistic regression. Results: Of the 52 matched pairs identified, 46 pairs (92 survivors) had sufficient cell recovery for flow FISH: primary diagnoses included Hodgkin lymphoma (20 pairs), acute lymphoblastic leukemia (13 pairs), CNS tumors (7 pairs), neuroblastoma (2 pairs), non-Hodgkin lymphoma (3 pairs), and kidney tumor (1 pair). All survivors had age-adjusted TL below the population median. Cases had shorter age-adjusted TL than controls in 4 out of 5 leukocyte subsets: lymphocytes (p=0.04), naïve T cells (p=0.02), B cells (p=0.01), and NK cells (p=0.01). Naïve T cells had an overrepresentation of VL TL (cases with VL TL in 9/46 pairs vs. controls with VL TL in 2/46 pairs, p=0.04). The odds of L or VL naïve T cell TL was significantly higher in cases compared with controls (OR=2.8, 1.11-7.19, p=0.03), an observation that did not change after adjusting for age at diagnosis. Conclusions: Survivors of childhood cancer had shorter age-adjusted leukocyte TL than the general population. This negative deviation was more pronounced among survivors with thyroid SMN than in survivors without SMN, which may reflect a differential risk among survivors for excess premature aging in the hematopoietic compartment. The effect of SMN treatment on TL is unlikely to be a factor, as treatment for thyroid SMN is primarily surgical. In cancer-naïve populations, VL lymphocyte TL is a sensitive and specific indicator of underlying defects in telomere maintenance. In survivors of childhood cancer, VL TL in naïve T cells may reflect an association between SMN risk and defects in T cell-mediated cancer surveillance. Citation Format: Maria M. Gramatges, Geraldine Aubert, Elmira Hariri, Yan Chen, John A. Whitton, Wendy M. Leisenring, Michael A. Arnold, Joseph P. Neglia, Yutaka Yasui, Leslie L. Robison, Gregory T. Armstrong, Smita Bhatia. Shorter naïve T cell telomere length is associated with thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study (CCSS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3110.

Telomere length in cervical exfoliated cells, interaction with HPV genotype, and cervical cancer occurrence among high-risk HPV-positive women.

BackgroundAlthough high‐risk human papillomavirus (HR‐HPV) infection is recognized as the main cause of cervical cancer, only a minority of HPV‐infected women develop this malignancy. Increasing evidence suggests that alterations of telomere length might be implicated in carcinogenesis. However, the association between cervical cancer and telomere length remains unknown.MethodsThis case‐control study included 591 cervical cancer patients and 373 cancer‐free controls, all of whom were infected with HR‐HPV. Relative telomere length (RTL) in cervical cancer exfoliated cells was measured by quantitative PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis.ResultsHPV16, 18, 52, and 58 were common in both case and control groups. The proportion of HPV16 infection tended to increase across the quartiles of RTL (P trend < 0.001). There was no statistically significant association of RTL with tumor differentiation, histological type, and FIGO stage. After adjustment for age and HPV types, the lowest quartile of RTL presented a 49% lower risk (OR = 0.51, 95% CI: 0.35, 0.76; P < 0.001) than those with the highest quartile of RTL. There was also a dose‐response relationship of shorter RTL on lower risk of cervical cancer (P trend < 0.001).ConclusionShortened telomere length in cervical exfoliated cells was related to the lower risk of cervical cancer among HR‐HPV‐positive women, which might help to improve cervical cancer screening and surveillance. Further prospective studies with large sample should be designed to validate our preliminary findings, and evaluate the potential efficacy of telomere length for cervical cancer screening.

Correlation Between Differentiation of Adrenocortical Zones and Telomere Lengths Measured by Q-FISH.

Adrenocortical zonation is associated with a markedly complex developmental process, and the pathogenesis and/or etiology of many disorders of adrenocortical zonal development have remained unknown. Cells from the three adrenocortical zones are morphologically and functionally differentiated, and the mature stage of cell development or senescence has been recently reported to be correlated with telomere length. However, the telomere length of each adrenocortical zonal cell has not yet been studied in human adrenal glands. We aimed to study the telomere lengths of adrenocortical parenchymal cells from three different zones of the adrenal glands present during childhood, adolescence, and adulthood. Adrenal glands of 30 autopsied subjects, aged between 0 and 68 years, were retrieved from pathology files. The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined in the parenchymal cells of the zona glomerulosa, zona fasciculata, and zona reticularis (ZR), using quantitative fluorescence in situ hybridization. NTCR of ZR cells was the longest, followed in decreasing order by that of zona glomerulosa and zona fasciculata cells in subjects aged 20 to 68 years, but no substantial differences in NTCR were detected among these three zones in the group <20 years of age. NTCR of ZR increased with age in subjects aged 20 to 68 years, whereas no important age-dependent changes in NTCR were detected in the group <20 years of age. The telomere lengths for three zones in adrenal cortex were correlated with their differentiation in adulthood but not in childhood and adolescence.

Effects of continuous high-dose G-CSF administration on hematopoietic stem cell mobilization and telomere length in patients with amyotrophic lateral sclerosis – a pilot study

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34+ hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34+ HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients’ leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34+ HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.

Association Between Leukocyte Telomere Length and Colorectal Cancer Risk in the Singapore Chinese Health Study.

OBJECTIVES:Telomeres and telomerase play important roles in maintaining chromosome integrity and genomic stability. To address a lack of consensus about the association between leukocyte telomere length and colorectal cancer, we investigated this association in the Singapore Chinese Health Study.METHODS:Relative telomere length in white blood cells was quantified using a validated quantitative polymerase chain reaction method in 26,761 participants, including 776 incident colorectal cancer cases. The Cox proportional hazard regression method was used to calculate the hazard ratio and the corresponding 95% confidence interval (CI) for colorectal cancer associated with longer telomeres.RESULTS:Longer telomeres were significantly associated with a higher risk of colorectal cancer (Ptrend = 0.02). Compared with the lowest quartile, subjects with the highest quartile of telomere length had a hazard ratio of 1.32 (95% CI: 1.08–1.62) for developing colorectal cancer. The corresponding elevation in rectal cancer risk for the highest quartile of telomere length was 71% (95% CI: 22–140, Ptrend = 0.02). There was no statistically significant association between telomere length and risk of colon cancer.DISCUSSION:This large cohort study of Singapore Chinese, the first study using a cohort study design with more than 26,000 participants that yielded 776 incidence colorectal cancer cases during 12 years of follow-up, provides evidence in support of longer telomeres being associated with a higher risk of colorectal cancer, particularly rectal cancer.

Association of telomere length with chronic exposure to ionizing radiation among inhabitants of natural high background radiation areas of Ramsar, Iran

Purpose: There are few areas in the world where ionizing radiation (IR) dose received by the public from radon gas and other radioactive elements are much higher than recommended limits. Telomere length is a potential biomarker of genomic instability due to oxidative stress from IR exposure. In this study, we investigated the impact of chronic exposure to environmental IR on relative telomere length (RTL) in white blood cells (WBC) among inhabitants of high background radiation areas (HBRA) of Ramsar, Iran.Materials and methods: One hundred and four individuals from HBRAs of Ramsar and 104 age-matched subjects from normal background radiation areas (NBRA) of Iran were enrolled in the study. The RTLs of WBC DNA samples were measured by a quantitative polymerase chain reaction (q-PCR) approach.Results: Mean RTL in HBRA and NBRA groups did not show any significant difference (1.21 ± 0.71 versus 1.22 ± 0.66, p = .306). After controlling for all demographic variables, less than 1% of the variances in RTL values were related to background radiation exposure.Conclusion: We conclude that chronic exposure to natural IR has no statistically significant effect on RTL among the inhabitants of HBRAs of Ramsar compared with a control group.

Mitochondrial DNA copy number and telomere length in peripheral blood mononuclear cells in comparison with whole blood in three different age groups

There are more and more studies on telomere length (TL) and mitochondrial DNA (mtDNA), and it has been proven that these factors play a significant role in the aging of the immune system thereby it is important to understand how it varies in different cell types for more accurate conclusions. The aim of this study was to look into dynamics of mtDNA amount in conjunction with TL in peripheral blood mononuclear cells (PBMC) during aging in comparison with whole blood (WB) cells.Overall, 53 samples were divided into three age groups: 20–39 year age group, 40–59 year age group and 60–79 year age group. MtDNA amount was determined by qPCR TaqMan, and TL was measured by Southern blotting of terminal restriction fragments (TRFs).PBMC had much higher mtDNA copy number (CN) amount than WB samples. Furthermore, with age, it increased in PBMC, while in WB mtDNA CN count did not change. TL in the elderly group was shorter in PBMC fraction than in WB cells. It also looked like that in PBMC TL shortened faster than in WB.In conclusions, it appears that during the aging process both mtDNA CN and TL were more stable in WB than in PBMC fraction where changes were more drastically pronounced, but more studies using larger sample cohorts should be performed to confirm this observation.

Compromised Chondrocyte Differentiation Capacity in TERC Knockout Mouse Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer.

Mammalian telomere lengths are primarily regulated by telomerase, consisting of a reverse transcriptase protein (TERT) and an RNA subunit (TERC). We previously reported the generation of mouse Terc+/− and Terc−/− embryonic stem cells (ntESCs) by somatic cell nuclear transfer. In the present work, we investigated the germ layer development competence of Terc−/−, Terc+/− and wild-type (Terc+/+) ntESCs. The telomere lengths are longest in wild-type but shortest in Terc−/− ntESCs, and correlate reversely with the population doubling time. Interestingly, while in vitro embryoid body (EB) differentiation assay reveals EB size difference among ntESCs of different genotypes, the more stringent in vivo teratoma assay demonstrates that Terc−/− ntESCs are severely defective in differentiating into the mesodermal lineage cartilage. Consistently, in a directed in vitro chondrocyte differentiation assay, the Terc−/− cells failed in forming Collagen II expressing cells. These findings underscore the significance in maintaining proper telomere lengths in stem cells and their derivatives for regenerative medicine.

Replicative senescence of hematopoietic cells in patients with idiopathic cytopenia of undetermined significance

We hypothesized that a subset of idiopathic cytopenia of undetermined significance (ICUS) is associated with an increased autonomous proliferation with exhaustion of hematopoiesis. The aim of this study was to investigate the cell turnover rate and replicative history of the bone marrow cells of ICUS patients. To this end, we examined telomere length (TL), proliferation, and apoptosis of the bone marrow cells of ICUS patients and healthy controls (HCs) using telomere quantitative fluorescence in situ hybridization and immunohistochemical staining for Ki-67 and cleaved caspase-3. We also performed targeted sequencing of 88 myeloid-associated genes. A total of 37 patients with ICUS were enrolled in this study, with a median age of 66 years (range: 31–83). TLs were significantly shorter in patients with ICUS than in the HCs (8.8, interquartile range [IQR] 6.8–12.1 vs 18.4, IQR 14.4–22.0, p < 0.0001). Proliferation (Ki-67-positive) and apoptosis (cleaved caspase-3-positive) were significantly increased in patients with ICUS compared to HCs (median = 20.0% vs 5.0%, p = 0.0003; 45.0% vs 22.5%, p = 0.0005, respectively). The shortening of TL and the increased proliferation and apoptotic activity was also prominent in patients with ICUS without mutation and dysplasia than in HCs (p < 0.0001, p < 0.0001, and p = 0.0093, respectively). TL was not associated with mutational profile and clinical characteristics as well in patients with ICUS. To our knowledge, this is the first study to show that ICUS is associated with premature replicative senescence with increased proliferation and apoptosis of bone marrow cells. Further study is needed to address the cause of replicative exhaustion in ICUS patients.

Stochastic Telomere Shortening and the Route to Limitless Replicative Potential.

In human tissues, the replicative potential of stem cells is limited by the shortening of telomere, limitless replicative potential is a hallmark of cancer. Telomere length changes stochastically during cell division mainly due to the competition between the end replication problem and telomerase, short telomere can lead to replicative senescence and cell apoptosis. Here, we investigate how stochastic changes of telomere length in individual cells may affect the population dynamics of clonal growth. We established a computational model that couples telomerase-regulated stochastic telomere length changes with the replicative potential of clones. Model simulations reveal qualitative dependence of clone proliferation potential with activities of telomerase; mutations in cells to alter the activities of telomerase and its inhibitors can induce abnormal tissue growth and lead to limitless replicative potential.