Category — telomere length

Telomeres are specialized structures providing chromosome integrity during cellular division along with protection against premature senescence and apoptosis. Accelerated telomere attrition in patients with Myelodysplastic Syndrome (MDS) occurs by an undefined mechanism. Although the MDS clone originates within the myeloid compartment, T-lymphocytes display repertoire contraction and loss of naïve T-cells. The replicative lifespan of T-cells is stringently regulated by telomerase activity. In MDS cases, we show that purified CD3+ T-cells have significantly shorter telomere length and reduced proliferative capacity upon stimulation compared to controls. To understand the mechanism, telomerase enzymatic activity and telomerase reverse transcriptase (hTERT) gene expression were compared in MDS cases (n=35) and healthy controls (n=42) within different T-cell compartments. Telomerase activity is greatest in naïve T-cells illustrating the importance of telomere repair in homeostatic repertoire regulation. Compared to healthy controls, MDS cases had lower telomerase induction (P<0.0001) that correlated with significantly lower hTERT mRNA (P<0.0001), independent of age and disease stratification. hTERT mRNA deficiency affected naïve but not memory T-cells, and telomere erosion in MDS occurred without evidence of an hTERT-promoter mutation, copy number variation or deletion. Telomerase insufficiency may undermine homeostatic control within the hematopoietic compartment and promote a change in the T-cell repertoire in MDS.

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Background
The development of peripheral arterial disease (PAD) is heterogeneous even in the presence of similar risk factors. Our aim was to determine whether inter-individual differences in leukocyte telomere length contribute to the susceptibility of PAD.

Methods
A total of 485 patients with PAD (defined by the ankle-brachial index) and 970 age- and gender-matched controls were recruited from seven rural communities in Henan Province in China. The relative leukocyte telomere length was determined by a quantitative PCR-based method. Two common promoter variants of the hTERT gene were genotyped to assess their effects on telomere length and the risk of PAD. In vivo luciferase assay was performed to study the transcriptional activity.

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Background: Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening. Methods: The Heart and Soul Study is a longitudinal study of patients with stable coronary heart disease. Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFR(CKD-EPI)), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (n = 954) and 5 years later (n = 608). Linear regression models were used to test the association of kidney function with (i) baseline telomere length and (ii) change in telomere length over 5 years. Results: At baseline, mean eGFR(CKD-EPI) was 72.6 (±21.5) ml/min/1.73 m(2), eGFRcys was 71.0 (±23.1) ml/min/1.73 m(2) and ACR was 8.6 (±12.3) mg/g. Only lower baseline eGFR(CKD-EPI) was associated with shorter baseline telomere length (9.1 (95% CI 1.2-16.9) fewer base pairs for every 5 ml/min/1.73 m(2) lower eGFR(CKD-EPI)). Lower baseline eGFR(CKD-EPI) (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 (95% CI 4.3-17.3) decrease in base pairs over 5 years for every 5 ml/min/1.73 m(2) lower eGFR(CKD-EPI)). After adjustment for age, these associations were no longer statistically significant. Conclusions: In patients with coronary heart disease, reduced kidney function is associated with (i) shorter baseline telomere length and (ii) more rapid telomere shortening over 5 years; however, these associations are entirely explained by older age.

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The shorter the DNA sequences found at the end of a person’s chromosomes — known as telomeres — the higher the risk for death, a large investigation into the microscopic underpinnings of mortality contends.

The finding stems from a fresh look at the role of telomeres, and the degree to which they serve as so-called “biomarkers” of aging.

More than 100,000 participants volunteered both saliva samples and medical records for analysis and review.

Ilaria Chiodi and Chiara Mondello*
Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
Telomerase canonical activity at telomeres prevents telomere shortening, allowing chromosome stability and cellular proliferation. To perform this task, the catalytic subunit (telomerase reverse transcriptase, TERT) of the enzyme works as a reverse transcriptase together with the telomerase RNA component (TERC), adding telomeric repeats to DNA molecule ends. Growing evidence indicates that, besides the telomeric-DNA synthesis activity, TERT has additional functions in tumor development and is involved in many different biological processes, among which cellular proliferation, gene expression regulation, and mitochondrial functionality. TERT has been shown to act independently of TERC in the Wnt-β-catenin signaling pathway, regulating the expression of Wnt target genes, which play a role in development and tumorigenesis. Moreover, TERT RNA-dependent RNA polymerase activity has been found, leading to the genesis of double-stranded RNAs that act as precursor of silencing RNAs. In mitochondria, a TERT TERC-independent reverse transcriptase activity has been described that could play a role in the protection of mitochondrial integrity. In this review, we will discuss some of the extra-telomeric functions of telomerase.
Keywords: telomerase, TERT, telomere, transformation, cancer, apoptosis, mitochondria, RNA interference
Citation: Chiodi I and Mondello C (2012) Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria. Front. Oncol. 2:133. doi: 10.3389/fonc.2012.00133
Received: 31 July 2012; Accepted: 18 September 2012;
Published online: 28 September 2012.
Edited by:
Claus M. Azzalin, Eidgenössische Technische Hochschule Zürich, Switzerland
Susan M. Bailey, Colorado State University, USA
Reviewed by:
Xu-Dong Zhu, McMaster University, Canada
Yongmei Song, Chinese Academy of Medical Sciences and Peking Union Medical College, China
Copyright: © 2012 Chiodi and Mondello. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Chiara Mondello, Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy. e-mail: mondello@igm.cnr.it

A team of researchers from the Spanish National Cancer Research Centre (CNIO), headed by CNIO Director Mar-a Blasco, has demonstrated in a pioneering study on mammals that longevity is defined at a molecular level by the length of telomeres. The work-which is published today in the online edition of the journal Cell Reports-opens the door to further study of these cellular components in order to calculate the rate at which cells age and thus be able to determine life expectancy for a particular organism.

Chromosomes-the cellular containers holding the genetic information in living creatures-have repetitive sequences of DNA at their extremities called telomeres. These sequences act as hoods that protect the genetic material in the face of any external agent which might damage it and compromise the function of the cells.

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Abstract:
Telomere length (TL) in circulating leukocytes relates to the chronological age
of the individual but it is believed to reflect also the cumulative burden of oxidative stress and
inflammation over the life-time. Shortening of TL has been reported in several chronic conditions
characterized by oxidative stress and inflammation, such as diabetes and atherosclerosis.
Because these conditions also occur in patients with Obstructive Sleep Apnea Syndrome
(OSAS), we hypothesized that TL would be reduced in patients with OSAS.

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Abstract

Background

It has recently been hypothesized that bipolar disorders are associated with accelerated aging. Telomere dysfunction, a biomarker of aging, is determined by the load of short telomeres, rather than by the mean telomere length. To our knowledge, the load of short telomeres has not been reported in any psychiatric disorder. The aims of the study were to examine the load of short telomeres and the mean telomere length and their relationships with illness duration and lifetime number of depressive episodes in bipolar II disorder (BD-II).

Methods

Twenty-eight patients (mean age = 34.8 ± 7.7) with a DSM-IV diagnosis of BD-II and 28 healthy control subjects (mean age = 34.8 ± 9.2) matched for age, sex, and education participated. The load of short telomeres (percentage of telomeres < 3 kilobases) and mean telomere length in peripheral blood mononuclear cells were measured using high-throughput quantitative fluorescence in situ hybridization.

Results

The load of short telomeres was significantly increased in patients with BD-II relative to healthy controls and may represent 13 years of accelerated aging. The load of short telomeres and the mean telomere length were associated with lifetime number of depressive episodes, but not with illness duration.

Limitations

Modest sample size and cross-sectional design.

Conclusions

Our results suggest that BD-II is associated with an increased load of short telomeres. Depressive episode-related stress may accelerate telomere shortening and aging. However, longitudinal studies are needed to fully clarify telomere shortening and its relationship with clinical variables in BD-II.

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Telomeres, the body’s own cellular clocks, may be a crucial factor underlying the development of emphysema, according to research from Johns Hopkins University.

“We found that in mice that have short telomeres, there was a significant increased risk of developing emphysema after exposure to cigarette smoke,” said Mary Armanios, MD, assistant professor of oncology at the Johns Hopkins School of Medicine.

The study appears online ahead of the print edition of the American Journal of Respiratory and Critical Care Medicine.

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Pauline Abdallah, Pierre Luciano, Kurt W. Runge, Michael Lisby, Vincent Géli, Eric Gilson and M. Teresa Teixeira

Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence.

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