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      HIV Infection Is Associated with Shortened Telomere Length in Ugandans with Suspected Tuberculosis

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          Abstract

          Introduction

          HIV infection is a risk factor for opportunistic pneumonias such as tuberculosis (TB) and for age-associated health complications. Short telomeres, markers of biological aging, are also associated with an increased risk of age-associated diseases and mortality. Our goals were to use a single cohort of HIV-infected and HIV-uninfected individuals hospitalized with pneumonia to assess whether shortened telomere length was associated with HIV infection, TB diagnosis, and 2-month mortality.

          Methods

          This was a sub-study of the IHOP Study, a prospective observational study. Participants consisted of 184 adults admitted to Mulago Hospital in Kampala, Uganda who underwent evaluation for suspected TB and were followed for 2 months. Standardized questionnaires were administered to collect demographic and clinical data. PBMCs were isolated and analyzed using quantitative PCR to determine telomere length. The association between HIV infection, demographic and clinical characteristics, and telomere length was assessed, as were the associations between telomere length, TB diagnosis and 2-month mortality. Variables with a P≤0.2 in bivariate analysis were included in multivariate models.

          Results

          No significant demographic or clinical differences were observed between the HIV-infected and HIV-uninfected subjects. Older age ( P<0.0001), male gender ( P = 0.04), total pack-years smoked ( P<0.001), alcohol consumption in the past year ( P = 0.12), and asthma ( P = 0.08) were all associated ( P≤0.2) with shorter telomere length in bivariate analysis. In multivariate analysis adjusting for these five variables, HIV-positive participants had significantly shorter telomeres than HIV-negative participants (β = -0.0621, 95% CI -0.113 to -0.011, P = 0.02). Shortened telomeres were not associated with TB or short-term mortality.

          Conclusions

          The association between HIV infection and shorter telomeres suggests that HIV may play a role in cellular senescence and biological aging and that shorter telomeres may be involved in age-associated health complications seen in this population. The findings indicate a need to further research the impact of HIV on aging.

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          Most cited references37

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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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              Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study.

              Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease. We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS. Mean telomere length decreased with age by 9% per decade (95% CI 3.6-14.1; p=0.001) in controls; much the same trend was seen in cases (-5.9% per decade, -3.1 to 14.1; p=0.1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1.51, 95% CI 1.15-1.98; p=0.0029 in the middle tertile; 1.44, 1.10-1.90, p=0.0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1.93, 1.33-2.80, p=0.0005 in the middle tertile; 1.94, 1.33-2.84, p=0.0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1.12, 0.75-1.69, p=0.5755 in the middle tertile; 1.02, 0.68-1.52, p=0.9380 in the lowest). Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk--and variability in age of onset--of coronary heart disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 September 2016
                2016
                : 11
                : 9
                : e0163153
                Affiliations
                [1 ]Division of HIV/AIDS, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America
                [2 ]Department of Biophysics and Biochemistry, University of California San Francisco, San Francisco, California, United States of America
                [3 ]Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America
                [4 ]Makerere University – University of California, San Francisco (MU-UCSF) Research Collaboration, Kampala, Uganda
                [5 ]Department of Medicine, Mulago Hospital, Makerere University, Kampala, Uganda
                [6 ]Department of Pulmonary, Critical Care & Sleep Medicine, Yale University, New Haven, Connecticut, United States of America
                [7 ]Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America
                University of North Carolina at Chapel Hill, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: EA JL EB LH.

                • Data curation: EA JL EC PB EM LH.

                • Formal analysis: EA EC MS LH.

                • Funding acquisition: EB LH.

                • Investigation: EA JL PB EM IA JD LH.

                • Methodology: EA JL EC PB EB LH.

                • Supervision: IA WW EB LH.

                • Writing – original draft: EA JL EC EB LH.

                • Writing – review & editing: EA JL EC PB IA EM WW JD MS EB LH.

                Article
                PONE-D-16-16571
                10.1371/journal.pone.0163153
                5031464
                27655116
                e97a4f54-bd76-4df8-85dd-12878dc62025
                © 2016 Auld 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.

                History
                : 24 April 2016
                : 2 September 2016
                Page count
                Figures: 1, Tables: 3, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NIH K24 HL087713
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NIH R01 HL090335
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NIH R01 HL128156
                Award Recipient :
                This research was supported by grants from the National Institutes of Health (K24 087713, L.H., R01 128156, L.H. and R01 090335, L.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromosomes
                Chromosome Structure and Function
                Telomeres
                Telomere Length
                Medicine and health sciences
                Infectious diseases
                Viral diseases
                HIV infections
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                Cell Biology
                Chromosome Biology
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