Category — genetics
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.
December 3, 2012 No Comments
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.
November 19, 2012 No Comments
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.
Claus M. Azzalin, Eidgenössische Technische Hochschule Zürich, Switzerland
Susan M. Bailey, Colorado State University, USA
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: email@example.com
October 3, 2012 No Comments
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.
October 3, 2012 No Comments
Mouse lifespan extended up to 24 percent with a single treatment.
A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals’ genes permanently from the embryonic stage – an approach impracticable in humans. Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director María Blasco, have proved that mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal’s genes. And they have done so using gene therapy, a strategy never before employed to combat ageing. The therapy has been found to be safe and effective in mice.
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May 15, 2012 No Comments
The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder
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).
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.
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.
Modest sample size and cross-sectional design.
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.
September 13, 2011 No Comments
In 1984, University of California, Berkeley biology professor Elizabeth Blackburn and then grad student Carol Greider made the discovery that a quarter century later would win them the Nobel Pnze: They identified telomerase as the enzyme that protects the DNA in our chromosomes, in effect keeping our cells-and, to some degree, us-young. But telomerase is naturally produced only minimally and intermittently in some of our cells-just enough to grt. disposable us a maximum life span of around 120 years. Unless, that is, someone figures out how to increase the telomerase inside our bodies. Such tinkering with the basic machinery of life has been a theoretical possibility since the 1990s, when scientists
at the Bay Area biotech firm Geron and elsewhere identified the human telomerase gene.
July 19, 2011 No Comments
Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study
1 Division of Cardiology, San Francisco General Hospital, San Francisco, California, United States of America, 2 Department of Medicine, University of California San Francisco, San Francisco, California, United States of America, 3 Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America, 4 Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America, 5 Veterans Affairs Medical Center, San Francisco, California, United States of America, 6 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America
Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality. However, the natural history of telomere length in patients with coronary artery disease has not been studied. We sought to investigate the longitudinal trajectory of telomere length, and to identify the independent predictors of telomere shortening, in persons with coronary artery disease.
In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0).
Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening. The mechanisms and reversibility of telomeric aging in cardiovascular disease deserve further study.
June 1, 2011 No Comments
Masayuki Kimura, Jacob v. B. Hjelmborg, Jeffrey P. Gardner, Lise Bathum, Michael Brimacombe, Xiaobin Lu, Lene Christiansen, James W. Vaupel, Abraham Aviv, and Kaare Christensen; American Journal of Epidemiology Advance Access
Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73-94 years, of whom 204 pairs experienced the death of one or both co-twins during 9-10 years of follow-up (1997-2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL50) and shortest 25% (mTRFL25) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL50: 0.59, 95% CI: 0.52, 0.66; mTRFL25: 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3-4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters.
February 18, 2008 No Comments
Stephanie L. Bakaysa, Lorelei A. Mucci, P. Eline Slagboom, Dorret I. Boomsma, Gerald E. McClearn, Boo Johansson and Nancy L. Pedersen. Aging Cell, 2007.
Telomeres prevent the loss of coding genetic material during chromosomal replication. Previous research suggests that shorter telomere length may be associated with lower survival. Because genetic factors are important for individual differences in both telomere length and mortality, this association could reflect genetic or environmental pleiotropy rather than a direct biological effect of telomeres. We demonstrate through within-pair analyses of Swedish twins that telomere length at advanced age is a biomarker that predicts survival beyond the impact of early familial environment and genetic factors in common with telomere length and mortality. Twins with the shortest telomeres had a three times greater risk of death during the follow-up period than their co-twins with the longest telomere measurements [hazard ratio (RR) = 2.8, 95% confidence interval 1.1-7.3, P = 0.03].
December 6, 2007 No Comments