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      Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies

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          Key Points

          Question

          Is leukocyte telomere length associated with the natural life span of contemporary humans?

          Findings

          This cohort study included 3259 participants from 3 longitudinal studies, of whom 1525 died during the follow-up period. Leukocyte telomere length–associated mortality from noncancer causes increased as participants aged, approaching their age at death.

          Meaning

          These data suggest that leukocyte telomere length is associated with a life span limit among contemporary humans.

          Abstract

          This cohort study examines whether leukocyte telomere length is associated with the life span of contemporary humans.

          Abstract

          Importance

          Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span.

          Objective

          To examine whether LTL is associated with the life span of contemporary humans.

          Design, Setting, and Participants

          This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women’s Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019.

          Main Outcomes and Measures

          Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees.

          Results

          The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77).

          Conclusions and Relevance

          The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

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          Most cited references20

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          Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths.

          In this protocol we describe a method to obtain telomere length parameters using Southern blots of terminal restriction fragments (TRFs). We use this approach primarily for epidemiological studies that examine leukocyte telomere length. However, the method can be adapted for telomere length measurements in other cells whose telomere lengths are within its detection boundaries. After extraction, DNA is inspected for integrity, digested, resolved by gel electrophoresis, transferred to a membrane, hybridized with labeled probes and exposed to X-ray film using chemiluminescence. Although precise and highly accurate, the method requires a considerable amount of DNA (3 μg per sample) and it measures both the canonical and noncanonical components of telomeres. The method also provides parameters of telomere length distribution in each DNA sample, which are useful in answering questions beyond those focusing on the mean length of telomeres in a given sample. A skilled technician can measure TRF length in ∼130 samples per week.
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            The plateau of human mortality: Demography of longevity pioneers

            Theories about biological limits to lifespan and evolutionary shaping of human longevity depend on facts about mortality at extreme ages. The facts have remained in dispute. Do hazard curves typically ultimately level out into high plateaus, as seen in other species, or do exponential increases go on and on? Here we estimate hazard rates from data on all Italian inhabitants aged over 105 between 2009 and 2015 (born 1896–1910), 3836 carefully documented cases. We find level hazard curves, essentially constant beyond age 105. The estimates are free from artifacts of aggregation limiting earlier studies and provide the best evidence so far for the existence of extreme-age mortality plateaus in humans. Above age 105 human mortality appears constant over age at levels that are slowly declining across cohorts.
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              Telomere length in white blood cell DNA and lung cancer: a pooled analysis of three prospective cohorts.

              We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex qPCR assay. We used conditional logistic regression models to calculate ORs and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis [OR (95% CI) by quartile: 1.00; 1.24 (0.90-1.71); 1.27 (0.91-1.78); and 1.86 (1.33-2.62); P trend = 0.000022]. Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length [OR (95% CI)] in the upper half of the fourth quartile were 2.41 (1.28-4.52), 2.16 (1.11-4.23), and 3.02(1.39-6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than 6 years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                26 February 2020
                February 2020
                26 February 2020
                : 3
                : 2
                : e200023
                Affiliations
                [1 ]Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina
                [2 ]Groningen Institute for Evolutionary Life Sciences, University of Groningen, the Netherlands
                [3 ]Epidemiology, Biostatistics, and Biodemography, Institute of Public Health, University of South Denmark, Odense, Denmark
                [4 ]Epidemiology Unit, Hebrew University–Hadassah School of Public Health and Community Medicine, Jerusalem, Israel
                [5 ]Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
                [6 ]Department of Epidemiology, University of Washington, Seattle
                [7 ]Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
                [8 ]The Framingham Heart Study, Framingham, Massachusetts
                [9 ]Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
                [10 ]Danish Aging Research Center, University of Southern Denmark, Odense, Denmark
                [11 ]Center of Human Development and Aging, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark
                Author notes
                Article Information
                Accepted for Publication: December 19, 2019.
                Published: February 26, 2020. doi:10.1001/jamanetworkopen.2020.0023
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Arbeev KG et al. JAMA Network Open.
                Corresponding Author: Konstantin G. Arbeev, PhD, Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, 2024 W Main St, Durham, NC 27705 ( ka29@ 123456duke.edu ).
                Author Contributions: Dr Arbeev and Ms Bagley had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Arbeev, Kark, Reiner, Christensen, Aviv.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Arbeev, Verhulst, Kark, Bagley, Aviv.
                Critical revision of the manuscript for important intellectual content: Arbeev, Steenstrup, Kark, Kooperberg, Reiner, Hwang, Levy, Fitzpatrick, Christensen, Yashin, Aviv.
                Statistical analysis: Arbeev, Verhulst, Steenstrup, Bagley, Hwang, Christensen.
                Obtained funding: Fitzpatrick, Yashin, Aviv.
                Administrative, technical, or material support: Yashin, Aviv.
                Supervision: Arbeev, Aviv.
                Conflict of Interest Disclosures: Drs Hwang and Levy reported being employees of the National Heart, Lung, and Blood Institute and that their research is supported by its Division of Intramural Research. Dr Fitzpatrick reported receiving grants from National Institutes of Health during the conduct of the study. Dr Yashin reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Aviv reported receiving grants from National Institutes of Health during the conduct of the study. No other disclosures were reported.
                Funding/Support: This work was supported in part by contract N01-HC-25195 from the National Heart, Lung, and Blood Institute for the Framingham Heart Study. The Cardiovascular Health Study research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute, with additional contributions from the National Institute of Neurological Disorders and Stroke. Additional support was provided by grant R01AG023629 from the National Institute on Aging. The Women’s Health Initiative program is funded through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C from the National Heart, Lung, and Blood Institute. Drs Arbeev and Yashin and Ms Bagley were partially supported by grant P01AG043352 from the National Institutes of Health. Dr Aviv was supported by grants R01HL116446, R01HD071180, and R01HL13840 from the National Institutes of Health and grants 262700 and 262043 from the Norwegian Institute of Public Health. Drs Fitzpatrick and Aviv were supported by R01 HL80698 from the National Institutes of Health.
                Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services.
                Additional Contributions: A full list of principal Cardiovascular Health Study investigators and institutions can be found at https://chs-nhlbi.org/. A full list of Women’s Health Initiative investigators who contributed to Women’s Health Initiative science can be found at https://www.whi.org/researchers/SitePages/Principal%20Investigators.aspx.
                Additional Information: We dedicate this article to Jeremy D. Kark, MD, MPH—the epitome of a clinical researcher—who inspired his colleagues and students in his uncompromised quest for the truth. Jeremy sadly died while working on this study.
                Article
                zoi200004
                10.1001/jamanetworkopen.2020.0023
                7137690
                32101305
                b4c848af-0905-49fa-b0f7-6cca4359d2a8
                Copyright 2020 Arbeev KG et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 8 August 2019
                : 19 December 2019
                Funding
                Funded by: National Heart, Lung, and Blood Institute
                Funded by: National Heart, Lung, and Blood Institute
                Funded by: National Institute of Neurological Disorders and Stroke
                Funded by: National Institute on Aging
                Funded by: National Heart, Lung, and Blood Institute
                Funded by: National Institutes of Health
                Funded by: National Institutes of Health
                Funded by: Norwegian Institute of Public Health
                Funded by: National Institutes of Health
                Categories
                Research
                Original Investigation
                Online Only
                Genetics and Genomics

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