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      The age‐dependent association between aortic pulse wave velocity and telomere length

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          Abstract

          Key points

          • Age significantly modifies the relationship between aortic pulse wave velocity and telomere length.

          • The differential relationships observed between aortic pulse wave velocity and telomere length in younger and older individuals suggest that the links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life‐course.

          Abstract

          Ageing is associated with marked large artery stiffening. Telomere shortening, a marker of cellular ageing, is linked with arterial stiffening. However, the results of existing studies are inconsistent, possibly because of the confounding influence of variable exposure to cardiovascular risk factors. Therefore, we investigated the relationship between telomere length (TL) and aortic stiffness in well‐characterized, younger and older healthy adults, who were pre‐selected on the basis of having either low or high aortic pulse wave velocity (aPWV), a robust measure of aortic stiffness. Demographic, haemodynamic and biochemical data were drawn from participants in the Anglo‐Cardiff Collaborative Trial. Two age groups with an equal sex ratio were examined: those aged <30 years (younger) or >50 years (older). Separately for each age group and sex, DNA samples representing the highest ( n = 125) and lowest ( n = 125) extremes of aPWV (adjusted for blood pressure) were selected for analysis of leukocyte TL. Ultimately, this yielded complete phenotypic data on 904 individuals. In younger subjects, TL was significantly shorter in those with high aPWV vs. those with low aPWV ( P = 0.017). By contrast, in older subjects, TL was significantly longer in those with high aPWV ( P = 0.001). Age significantly modified the relationship between aPWV and TL ( P < 0.001). Differential relationships are observed between aPWV and TL, with an inverse association in younger individuals and a positive association in older individuals. The links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life‐course.

          Key points

          • Age significantly modifies the relationship between aortic pulse wave velocity and telomere length.

          • The differential relationships observed between aortic pulse wave velocity and telomere length in younger and older individuals suggest that the links between cellular and vascular ageing reflect a complex interaction between genetic and environmental factors acting over the life‐course.

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          Most cited references25

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          Telomeres and human disease: ageing, cancer and beyond.

          Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.
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            Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms.

            Higher levels of physical activity are associated with fewer cardiovascular disease (CVD) events. Although the precise mechanisms underlying this inverse association are unclear, differences in several cardiovascular risk factors may mediate this effect. In a prospective study of 27,055 apparently healthy women, we measured baseline levels of hemoglobin A1c, traditional lipids (total, low-density lipoprotein, and high-density lipoprotein cholesterol), novel lipids [lipoprotein(a) and apolipoprotein A1 and B-100], creatinine, homocysteine, and inflammatory/hemostatic biomarkers (high-sensitivity C-reactive protein, fibrinogen, soluble intracellular adhesion molecule-1) and used women's self-reported physical activity, weight, height, hypertension, and diabetes. Mean follow-up was 10.9+/-1.6 years, and 979 incident CVD events occurred. The risk of CVD decreased linearly with higher levels of activity (P for linear trend or = 1500 kcal/wk of 27%, 32%, and 41%, respectively. Differences in known risk factors explained a large proportion (59.0%) of the observed inverse association. When sets of risk factors were examined, inflammatory/hemostatic biomarkers made the largest contribution to lower risk (32.6%), followed by blood pressure (27.1%). Novel lipids contributed less to CVD risk reduction compared with traditional lipids (15.5% and 19.1%, respectively). Smaller contributions were attributed to body mass index (10.1%) and hemoglobin A1c/diabetes (8.9%), whereas homocysteine and creatinine had negligible effects (< 1%). The inverse association between physical activity and CVD risk is mediated in substantial part by known risk factors, particularly inflammatory/hemostatic factors and blood pressure.
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              Senescence induced by altered telomere state, not telomere loss.

              Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.
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                Author and article information

                Contributors
                bmcdonnell@cardiffmet.ac.uk
                Journal
                J Physiol
                J. Physiol. (Lond.)
                10.1111/(ISSN)1469-7793
                TJP
                jphysiol
                The Journal of Physiology
                John Wiley and Sons Inc. (Hoboken )
                0022-3751
                1469-7793
                24 January 2017
                01 March 2017
                24 January 2017
                : 595
                : 5 ( doiID: 10.1113/tjp.2017.595.issue-5 )
                : 1627-1635
                Affiliations
                [ 1 ] Cardiff School of Health SciencesCardiff Metropolitan University CardiffUK
                [ 2 ] Division of Experimental Medicine & ImmunotherapeuticsUniversity of Cambridge CambridgeUK
                [ 3 ] Division of Cardiology, New York‐Presbyterian HospitalColumbia University New York NYUSA
                Author notes
                [*] [* ] Corresponding author B. J. McDonnell: Cardiff School of Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, UK. Email: bmcdonnell@ 123456cardiffmet.ac.uk
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-5912-1278
                Article
                TJP12157
                10.1113/JP273689
                5330867
                28247509
                c1936a0b-c170-468d-ae27-02397da24265
                2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 October 2016
                : 28 November 2016
                Page count
                Figures: 2, Tables: 3, Pages: 9, Words: 5638
                Funding
                Funded by: British Heart Foundation
                Award ID: FS/12/8/29377
                Funded by: National Institute for Health Research
                Categories
                Ageing and Degeneration
                Cardiovascular Physiology
                Research Paper
                Cardiovascular
                Custom metadata
                2.0
                tjp12157
                1 March 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.7 mode:remove_FC converted:28.02.2017

                Human biology
                ageing,aortic stiffness,telomere length
                Human biology
                ageing, aortic stiffness, telomere length

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