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      Telomere length in COPD: Relationships with physical activity, exercise capacity, and acute exacerbations

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          Abstract

          Rationale

          Shorter leukocyte telomere length (LTL) is associated with reduced health-related quality of life and increased risk for acute exacerbations (AEs) and mortality in chronic obstructive pulmonary disease (COPD). Increased physical activity and exercise capacity are associated with reduced risk for AEs and death. However, the relationships between LTL and physical activity, exercise capacity, and AEs in COPD are unknown.

          Methods

          Data from 3 COPD cohorts were examined: Cohort 1 (n = 112, physical activity intervention trial), Cohorts 2 and 3 (n = 182 and 294, respectively, separate observational studies). Subjects completed a 6-minute walk test (6MWT) and provided blood for LTL assessment using real-time PCR. Physical activity was measured as average daily step count using an accelerometer or pedometer. Number of self-reported AEs was available for 1) the year prior to enrollment (Cohorts 1 and 3) and 2) prospectively after enrollment (all cohorts). Multivariate models examined associations between LTL and average daily step count, 6MWT distance, and AEs.

          Results

          A significant association between longer LTL and increased 6MWT distance was observed in the three combined cohorts (β = 3x10 -5, p = 0.045). No association between LTL and average daily step count was observed. Shorter LTL was associated with an increased number of AEs in the year prior to enrollment (Cohorts 1 and 3 combined, β = -1.93, p = 0.04) and with prospective AEs (Cohort 3, β = -1.3388, p = 0.0003).

          Conclusions

          Among COPD patients, increased LTL is associated with higher exercise capacity, but not physical activity. Shorter LTL was associated with AEs in a subgroup of cohorts.

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          Most cited references 23

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          Telomeres and aging.

          Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must "cap" each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or "uncapped" telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many "uncapped" telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.
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            COPD as a disease of accelerated lung aging.

            There is increasing evidence for a close relationship between aging and chronic inflammatory diseases. COPD is a chronic inflammatory disease of the lungs, which progresses very slowly and the majority of patients are therefore elderly. We here review the evidence that accelerating aging of lung in response to oxidative stress is involved in the pathogenesis and progression of COPD, particularly emphysema. Aging is defined as the progressive decline of homeostasis that occurs after the reproductive phase of life is complete, leading to an increasing risk of disease or death. This results from a failure of organs to repair DNA damage by oxidative stress (nonprogrammed aging) and from telomere shortening as a result of repeated cell division (programmed aging). During aging, pulmonary function progressively deteriorates and pulmonary inflammation increases, accompanied by structural changes, which are described as senile emphysema. Environmental gases, such as cigarette smoke or other pollutants, may accelerate the aging of lung or worsen aging-related events in lung by defective resolution of inflammation, for example, by reducing antiaging molecules, such as histone deacetylases and sirtuins, and this consequently induces accelerated progression of COPD. Recent studies of the signal transduction mechanisms, such as protein acetylation pathways involved in aging, have identified novel antiaging molecules that may provide a new therapeutic approach to COPD.
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              Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema.

              Different anatomic and physiological changes occur in the lung of aging people that can affect pulmonary functions, and different pulmonary diseases, including deadly diseases such as chronic obstructive pulmonary disease (COPD)/emphysema and idiopathic pulmonary fibrosis (IPF), can be related to an acceleration of the aging process. The individual genetic background, as well as exposure to a variety of toxic substances (cigarette smoke in primis) can contribute significantly to accelerating pulmonary senescence. Premature aging can impair lung function by different ways: by interfering specifically with tissue repair mechanisms after damage, thus perturbing the correct crosstalk between mesenchymal and epithelial components; by inducing systemic and/or local alteration of the immune system, thus impairing the complex mechanisms of lung defense against infections; and by stimulating a local and/or systemic inflammatory condition (inflammaging). According to recently proposed pathogenic models in COPD and IPF, premature cellular senescence likely affects distinct progenitors cells (mesenchymal stem cells in COPD, alveolar epithelial precursors in IPF), leading to stem cell exhaustion. In this review, the large amount of data supporting this pathogenic view are discussed, with emphasis on the possible molecular and cellular mechanisms leading to the severe parenchymal remodeling that characterizes, in different ways, these deadly diseases. Copyright © 2013 Mosby, Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Formal analysisRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Funding acquisitionRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: MethodologyRole: SoftwareRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 October 2019
                2019
                : 14
                : 10
                Affiliations
                [1 ] VA Boston Healthcare System, Boston, MA, United States of America
                [2 ] Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States of America
                [3 ] Harvard Medical School, Boston, MA, United States of America
                [4 ] VA Puget Sound, Seattle, WA, United States of America
                [5 ] University of Washington, Seattle, WA, United States of America
                [6 ] Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States of America
                [7 ] Harvard T.H. Chan School of Public Health, Boston, MA, United States of America
                [8 ] Brigham & Women’s Hospital, Boston, MA, United States of America
                University of Newcastle, UNITED KINGDOM
                Author notes

                Competing Interests: Dr. Moy reports receiving an honorarium for consulting from AstraZeneca, outside the submitted work. This does not impact our compliance with PLOS ONE policies on sharing data and materials.

                Article
                PONE-D-19-14110
                10.1371/journal.pone.0223891
                6797105
                31622416

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                Page count
                Figures: 1, Tables: 6, Pages: 12
                Product
                Funding
                Funded by: United States Department of Veterans Affairs Rehabilitation Research and Development
                Award ID: I21RX002197
                Award Recipient :
                Funded by: United States Department of Veterans Affairs Rehabilitation Research and Development
                Award ID: IK2RX002165
                Award Recipient :
                Funded by: National Institutes of Health – National Heart Lung Blood Institute
                Award ID: R01HL093146
                Award Recipient :
                Funded by: National Center for Research Resources
                Award ID: UL1RR025014
                This study was supported by the United States Department of Veterans Affairs Rehabilitation Research and Development ( https://www.research.va.gov/): merit award I21RX002197 (M.L.M.) and Career Development Award 2 IK2RX002165 (E.S.W.); National Institutes of Health – National Heart Lung Blood Institute ( https://www.nhlbi.nih.gov/): R01HL093146 (H.Q.N. and V.S.F.); National Center for Research Resources UL1RR025014 (PI: M.L. Disis). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Pulmonology
                Chronic Obstructive Pulmonary Disease
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromosomes
                Chromosome Structure and Function
                Telomeres
                Telomere Length
                Biology and Life Sciences
                Physiology
                Biological Locomotion
                Walking
                Medicine and Health Sciences
                Physiology
                Biological Locomotion
                Walking
                Medicine and Health Sciences
                Public and Occupational Health
                Physical Activity
                Physical Fitness
                Exercise
                Medicine and Health Sciences
                Sports and Exercise Medicine
                Exercise
                Biology and Life Sciences
                Sports Science
                Sports and Exercise Medicine
                Exercise
                Medicine and Health Sciences
                Public and Occupational Health
                Physical Activity
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Chromosomes
                Chromosome Structure and Function
                Telomeres
                Research and Analysis Methods
                Research Design
                Observational Studies
                Custom metadata
                Summary-level statistics and data are available within the manuscript and its Supporting Information files. However, due to restrictions in the original Informed Consent mandated by United States Veterans Affairs research policy, we are unable to deposit individual-level data included in the manuscript into public repositories. Release of de-identified, individual-level data requires Institutional Board Review approval and will be made available to qualified investigators on a case-by-case basis. All inquiries should be directed to the principal investigator, Marilyn Moy, MD, or to the VA Boston Institutional Review Board at VHABHSIRB@ 123456va.gov .

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