Telomere Science Library

The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder

dan — Tue, 13 Sep 2011 16:48:17 +0000

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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Anti-Aging (Elle Magazine, 2011)

dan — Tue, 19 Jul 2011 19:48:50 +0000

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.

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Telomere length linked to emphysema risk

dan — Fri, 15 Jul 2011 18:43:05 +0000

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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Shortened Telomere Length Is Associated with Increased Risk of Cancer: A Meta-Analysis

dan — Tue, 21 Jun 2011 21:38:19 +0000

Abstract

Background

Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting.

Methods

A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the χ²-based Q statistic test and Egger’s test, respectively.

Results

The results showed that shorter telomeres were significantly associated with cancer risk (OR = 1.35, 95% CI = 1.14–1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR = 1.84, 95% CI = 1.38–2.44), lung cancer (OR = 2.39, 95% CI = 1.18–4.88), smoking-related cancers (OR = 2.25, 95% CI = 1.83–2.78), cancers in the digestive system (OR = 1.69, 95% CI = 1.53–1.87) and the urogenital system (OR = 1.73, 95% CI = 1.12–2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Egger’s test suggested that there was no publication bias in the current meta-analysis (P = 0.532).

Conclusions

The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings.

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The Axis Of Aging

dan — Mon, 20 Jun 2011 15:00:25 +0000

Telomere dysfunction activates p53-mediated cellular growth arrest, senescence, and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart, and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1 and PGC-1 , also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1 expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1 and PGC-1 promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.

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Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study

dan — Wed, 01 Jun 2011 19:05:11 +0000

Ramin Farzaneh-Far¹^,²^*, Jue Lin³, Elissa Epel⁴, Kyle Lapham³, Elizabeth Blackburn³, Mary A. Whooley²^,⁵^,⁶

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

Abstract Top

Background

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.

Methodology/Principal Findings

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).

Conclusions/Significance

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.

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The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men

dan — Wed, 01 Jun 2011 19:00:26 +0000

Elissa S. Epel¹, Sharon Stein Merkin², Richard Cawthon³, Elizabeth H. Blackburn⁴, Nancy E. Adler¹, Mark J. Pletcher⁵ and Teresa E. Seeman²

¹University of California, San Francisco, Department of Psychiatry, San Francisco, CA, 94143, USA
²University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 90095-1687, USA
³University of Utah, Human Genetics, Salt Lake City, UT 84112, USA
⁴University of California, San Francisco, Department of Biochemistry & Biophysics, San Francisco, CA, 94158, USA
⁵University of California, San Francisco, Department of Epidemiology & Biostatistics, San Francisco, CA, 94107, USA
Running title:: Telomere Shortening and Mortality
Key words:: aging, longevity, telomere length, cardiovascular disease, mortality
Received:: 11/05/08; accepted: 12/01/08; published on line: 12/19/08

Correspondence:: Elissa S. Epel, PhD, University of California, San Francisco, Department of Psychiatry, 3333 California St, Ste. 465, San Francisco, CA, 94143, USA; e-mail: EEpel@lppi.ucsf.edu

Abstract

Telomere length (TL) has been proposed as a marker of mitotic cell age and as a general index of human organismic aging. Short absolute leukocyte telomere length has been linked to cardiovascular-related morbidity and mortality. Our aim was to test whether the rate of change in leukocyte TL is related to mortality in a healthy elderly cohort. We examined a subsample of 236 randomly selected Caucasian participants from the MacArthur Health Aging Study (aged 70 to 79 years). DNA samples from baseline and 2.5 years later were assayed for mean TL of leukocytes. Percent change in TL was calculated as a measure of TL change (TLC). Associations between TL and TLC with 12-year overall and cardiovascular mortality were assessed. Over the 2.5 year period, 46% of the study participants showed maintenance of mean bulk TL, whereas 30% showed telomere shortening, and, unexpectedly, 24% showed telomere lengthening. For women, short baseline TL was related to greater mortality from cardiovascular disease (OR = 2.3; 95% CI:1.0-5.3). For men, TLC (specifically shortening), but not baseline TL, was related to greater cardiovascular mortality, OR = 3.0 (95% CI: 1.1-8.2). This is the first demonstration that rate of telomere length change (TLC) predicts mortality and thus may be a useful prognostic factor for longevity.

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Telomerase is not an oncogene

dan — Wed, 01 Jun 2011 18:55:53 +0000

In the decade since the telomere hypothesis of cellular aging was proposed, the two essential genes for human telomerase were cloned and characterized, allowing experimental proof of the causal relationships between telomere loss and replicative senescence, and telomerase activation and immortalization. These relationships were established using a variety of cultured human cell types from both normal and tumor tissues, and were largely confirmed in the telomerase knockout mouse. Taken together, the data provide strong support for the potential utility of telomerase detection and inhibition for cancer, and telomerase activation for degenerative diseases. The specificity of the promoter for the telomerase catalytic gene and the antigenicity of the protein product, hTERT, provide additional strategies for killing telomerase-positive tumor cells. Unfortunately, the strong link between telomerase and cancer has led some to confuse telomerase activation with cancer, and others to overstate the cancer risk of telomerase activation therapies for degenerative diseases. This review clarifies the difference between telomerase, which does not cause growth deregulation, and oncogenes, which do. It also addresses the concept of telomerase repression as a tumor suppressor mechanism early in life, with detrimental tissue degeneration and tumor-promoting consequences late in life. This extended view of the telomere hypothesis helps explain how telomerase inhibition can be therapeutic in cancer patients, while controlled telomerase activation for degenerative diseases may actually reduce, rather than increase, the frequency of age-related tumorigenesis.

Oncogene (2002) 21, 494-502 DOI: 10.1038/sj/onc/1205076

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Telomeres Tell Future in Aplastic Anemia

janey — Tue, 21 Sep 2010 16:09:30 +0000

By John Gever, Senior Editor, MedPage Today
Published: September 21, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Shortened telomeres in peripheral blood leukocytes may predict relapse, malignant progression, and poorer survival in patients with severe aplastic anemia, researchers at the National Institutes of Health (NIH) reported.

An analysis of average pretreatment telomere length in almost 200 patients with severe aplastic anemia treated at the NIH, revealed that patients in the first quartile for telomere length — the shortest telomeres — had an overall six-year survival rate of 66% (95% CI 52.9% to 82.5%) compared with 83.8% (95% CI 77.3% to 90.0%) among those in the other three quartiles (P=0.008), according to the Sept. 22 issue of the Journal of the American Medical Association.

Having the shortest telomeres was also associated with greater risk of progression to malignancy (24.5% versus 8.4%, P=0.009) and with evolution to monosomy 7 or complex cytogenetics (18.8% versus 4.5%, P=0.002), wrote Phillip Scheinberg, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Md., and colleagues.

“Clonal evolution to myelodysplasia is a major adverse event in severe aplastic anemia; it cannot be routinely predicted and usually signals a poor prognosis,” Scheinberg and colleagues noted.

They suggested their findings point toward a practical method of identifying patients at heightened risk for progression who might receive more aggressive treatment.

“Higher-risk protocols such as stem cell transplants in older patients and alternative sources of stem cells might be considered earlier in younger patients,” the researchers wrote.

They also indicated that androgen treatment may lengthen telomeres, potentially altering patients’ risk profiles.

Telomeres are the protective end-caps on chromosomes. Portions are lopped off with each round of cell division, although they may be restored by the telomerase enzyme complex.

Cell senescence has been associated with critically short telomeres, but mutations in telomerase genes that result in extremely short telomeres have been found in some patients with severe aplastic anemia.

Scheinberg and colleagues measured telomere lengths in pretreatment peripheral blood samples from 183 patients treated for severe aplastic anemia at the NIH from 2000 to 2008.

They found no relationship between telomere length and initial treatment responses. Hematologic response rates were nearly identical in each quartile of telomere length, ranging from 54% to 60%.

But the subsequent course for patients in the first quartile — those with the shortest telomeres — differed significantly over as long as six years from patients in the second to fourth quartiles — those with longer telomeres.

By far the worst survival outcomes were in first-quartile patients who also had absolute reticulocyte counts below 25,000 per μL.

With four years of follow-up, just over 50% of these patients were still alive. The four-year survival rate among those in the first quartile but higher reticulocyte counts, and those with low counts but longer telomeres, was close to 80%.

Nearly all of those with longer telomeres and high reticulocyte counts survived at least four years. Few deaths occurred in study patients after year four irrespective of telomere or reticulocyte status.

For other outcomes — hematologic relapse, clonal evolution, progression to monosomy 7 or complex cytogenetics — differences according to telomere length were apparent in about two years.

Scheinberg and colleagues asserted that truncated telomeres are “not simply a biomarker,” but may play a direct role in the disease process.

“Ample in vitro and animal experimentation indicate that critical shortening of telomeres causes chromosome instability, tumor formation, and cancer progression,” they wrote.

Although short telomeres would ordinarily lead to senescence, the chromosomal damage that may result from defective end-caps may instead allow cells to turn malignant, especially if they also lack functional p53 or other tumor suppressor mechanisms, the researchers suggested.

Scheinberg and colleagues noted some limitations of their study. Its retrospective nature was one; another was the relatively small number of patients that precluded assembling a separate validation cohort. They also noted that the NIH patient pool may not be representative of patients elsewhere.

“Our results need to be replicated to validate the observed associations and to determine reliable telomere length thresholds that could be incorporated in treatment algorithms,” the researchers concluded.

The study was funded by the National Heart, Lung, and Blood Institute.

One author obtained salary support from a training program partially funded by Pfizer.

The authors declared they had no relevant financial interests.

Primary source: Journal of the American Medical Association
Source reference:
Scheinberg P, et al “Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia” JAMA 2010; 304: 1358-1364.

Telomere Length and Risk of Incident Cancer and Cancer Mortality

janey — Sun, 11 Jul 2010 16:42:50 +0000

Peter Willeit, MD; Johann Willeit, MD; Agnes Mayr, MD; Siegfried Weger, MD; Friedrich Oberhollenzer, MD; Anita Brandstätter, PhD; Florian Kronenberg, MD; Stefan Kiechl, MD

JAMA. 2010;304(1):69-75.

Context Telomeres are essential to preserve the integrity of the genome. Critically short telomeres lead to replicative cell senescence and chromosomal instability and may thereby increase cancer risk.

Objective To determine the association between baseline telomere length and incident cancer and cancer mortality.

Results A total of 92 of 787 participants (11.7%) developed cancer (incidence rate, 13.3 per 1000 person-years). Short telomere length at baseline was associated with incident cancer independently of standard cancer risk factors (multivariable hazard ratio [HR] per 1-SD decrease in loge-transformed telomere length, 1.60; 95% confidence interval [CI], 1.30-1.98; P < .001). Compared with participants in the longest telomere length group, the multivariable HR for incident cancer was 2.15 (95% CI, 1.12-4.14) in the middle length group and 3.11 (95% CI, 1.65-5.84) in the shortest length group (P < .001). Incidence rates were 5.1 (95% CI, 2.9-8.7) per 1000 person-years in the longest telomere length group, 14.2 (95% CI, 10.0-20.1) per 1000 person-years in the middle length group, and 22.5 (95% CI, 16.9-29.9) per 1000 person-years in the shortest length group. The association equally applied to men and women and emerged as robust under a variety of circumstances. Furthermore, short telomere length was associated with cancer mortality (multivariable HR per 1-SD decrease in loge-transformed telomere length, 2.13; 95% CI, 1.58-2.86; P < .001) and individual cancer subtypes with a high fatality rate.

Conclusion In this study population, there was a statistically significant inverse relationship between telomere length and both cancer incidence and mortality.

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