Telomere Science Library

Telomeres in Disease

dan — Mon, 03 Dec 2012 21:55:33 +0000

The ends of linear chromosomes have attracted serious scientific study—and Nobel Prizes—since the early 20th century. Called telomeres, these ends serve to protect the coding DNA of the genome. When a cell’s telomeres shorten to critical lengths, the cell senesces. Thus, telomeres dictate a cell’s life span—unless something goes wrong. Work over the past several decades has revealed an active, though limited, mechanism for the normal enzymatic repair of telomere loss in certain proliferative cells.[1. E.H. Blackburn et al., “Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging,” Nat Med, 12:1133-38, 2006.] Telomere lengthening in cancer cells, however, confers an abnormal proliferative ability.

Naïve T-cells in myelodysplastic syndrome display intrinsic human telomerase reverse transcriptase (hTERT) deficiency

dan — Mon, 19 Nov 2012 20:35:46 +0000

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.

Functional Haplotypes of the hTERT Gene, Leukocyte Telomere Length Shortening, and the Risk of Peripheral Arterial Disease

dan — Mon, 19 Nov 2012 20:33:34 +0000

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.

The Long and Short of It: The Role of Telomeres in Fetal Origins of Adult Disease

dan — Mon, 19 Nov 2012 20:31:18 +0000

Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.

Association between Kidney Function and Telomere Length: The Heart and Soul Study.

dan — Mon, 19 Nov 2012 20:29:27 +0000

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.

Biologic function and clinical potential of telomerase and associated proteins in cardiovascular tissue repair and regeneration

dan — Mon, 19 Nov 2012 20:26:46 +0000

Telomeres comprise long tracts of double-stranded TTAGGG repeats that extend for 9–15 kb in humans. Telomere length is maintained by telomerase, a specialized ribonucleoprotein that prevents the natural ends of linear chromosomes from undergoing inappropriate repair, which could otherwise lead to deleterious chromosomal fusions. During the development of cardiovascular tissues, telomerase activity is strong but diminishes with age in adult hearts. Dysfunction of telomerase is associated with the impairment of tissue repair or regeneration in several pathologic conditions, including heart failure and infarction. Under both physiologic and pathophysiologic conditions, telomerase interacts with promyogenic nuclear transcription factors (e.g. myocardin, serum response factor) to augment the potency of cardiovascular cells during growth, survival, and differentiation.

DNA ‘Telomere’ Length Tied to Aging, Death Risk

dan — Mon, 19 Nov 2012 20:24:40 +0000

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.

Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria

dan — Wed, 03 Oct 2012 22:16:57 +0000

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

Increase in rates of short telomeres predicts longevity in mammals

dan — Wed, 03 Oct 2012 22:14:42 +0000

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.

Work-Related Exhaustion and Telomere Length: A Population-Based Study

dan — Tue, 24 Jul 2012 18:12:43 +0000

Background
Psychological stress is suggested to accelerate the rate of biological aging. We investigated whether work-related exhaustion, an indicator of prolonged work stress, is associated with accelerated biological aging, as indicated by shorter leukocyte telomeres, that is, the DNA-protein complexes that cap chromosomal ends in cells.

Methods
We used data from a representative sample of the Finnish working-age population, the Health 2000 Study. Our sample consisted of 2911 men and women aged 30–64. Work-related exhaustion was assessed using the Maslach Burnout Inventory – General Survey. We determined relative leukocyte telomere length using a quantitative real-time polymerase chain reaction (PCR) -based method.

Results
After adjustment for age and sex, individuals with severe exhaustion had leukocyte telomeres on average 0.043 relative units shorter (standard error of the mean 0.016) than those with no exhaustion (p = 0.009). The association between exhaustion and relative telomere length remained significant after additional adjustment for marital and socioeconomic status, smoking, body mass index, and morbidities (adjusted difference 0.044 relative units, standard error of the mean 0.017, p = 0.008).

Conclusions
These data suggest that work-related exhaustion is related to the acceleration of the rate of biological aging. This hypothesis awaits confirmation in a prospective study measuring changes in relative telomere length over time.