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

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          Abstract

          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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          Most cited references 19

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          Oxidative stress shortens telomeres.

          Telomeres in most human cells shorten with each round of DNA replication, because they lack the enzyme telomerase. This is not, however, the only determinant of the rate of loss of telomeric DNA. Oxidative damage is repaired less well in telomeric DNA than elsewhere in the chromosome, and oxidative stress accelerates telomere loss, whereas antioxidants decelerate it. I suggest here that oxidative stress is an important modulator of telomere loss and that telomere-driven replicative senescence is primarily a stress response. This might have evolved to block the growth of cells that have been exposed to a high risk of mutation.
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            Obesity, cigarette smoking, and telomere length in women.

            Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.
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              The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability.

              Loss of telomere function can induce cell cycle arrest and apoptosis. To investigate the processes that trigger cellular responses to telomere dysfunction, we crossed mTR-/- G6 mice that have short telomeres with mice heterozygous for telomerase (mTR+/-) that have long telomeres. The phenotype of the telomerase null offspring was similar to that of the late generation parent, although only half of the chromosomes were short. Strikingly, spectral karyotyping (SKY) analysis revealed that loss of telomere function occurred preferentially on chromosomes with critically short telomeres. Our data indicate that, while average telomere length is measured in most studies, it is not the average but rather the shortest telomeres that constitute telomere dysfunction and limit cellular survival in the absence of telomerase.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                8 January 2010
                : 5
                : 1
                Affiliations
                [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
                University of Valencia, Spain
                Author notes

                Conceived and designed the experiments: RFF EE EB MAW. Performed the experiments: JL KL. Analyzed the data: RFF MAW. Contributed reagents/materials/analysis tools: RFF JL MAW. Wrote the paper: RFF EE EB MAW.

                Article
                09-PONE-RA-13801R1
                10.1371/journal.pone.0008612
                2797633
                20072607
                Farzaneh-Far et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 7
                Categories
                Research Article
                Cardiovascular Disorders/Coronary Artery Disease
                Cardiovascular Disorders/Geriatric Cardiology
                Geriatrics/Geriatric Cardiology
                Public Health and Epidemiology/Epidemiology

                Uncategorized

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