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      A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: the iESRD study

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          Abstract

          Background

          Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of the immune system. Nevertheless, the etiology and impact of these changes in ESRD patients remain unknown.

          Results

          Compared to healthy individuals, ESRD patients exhibit accelerated immunosenescence in both T cell and monocyte compartments, characterized by a dramatic reduction in naïve CD4+ and CD8+ T cell numbers but increase in CD8+ T EMRA cell and proinflammatory monocyte numbers. Notably, within ESRD patients, aging-related immune changes positively correlated not only with increasing age but also with longer dialysis vintage. In multivariable-adjusted logistic regression models, the combination of high terminally differentiated CD8+ T cell level and high intermediate monocyte level, as a composite predictive immunophenotype, was independently associated with prevalent coronary artery disease as well as cardiovascular disease, after adjustment for age, sex, systemic inflammation and presence of diabetes. Levels of terminally differentiated CD8+ T cells also positively correlated with the level of uremic toxin p-cresyl sulfate.

          Conclusions

          Aging-associated adaptive and innate immune changes are aggravated in ESRD and are associated with cardiovascular diseases. For the first time, our study demonstrates the potential link between immunosenescence in ESRD and duration of exposure to the uremic milieu.

          Electronic supplementary material

          The online version of this article (10.1186/s12979-018-0131-x) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography.

          The aim of this study was to analyze the yet ill-defined relationship of distinct human monocyte subsets with cardiovascular outcomes in a broad patient population at cardiovascular risk. Monocytes, the most abundant immune cell type found in atherosclerotic plaques, are crucial promoters of atherogenesis. Three distinct human monocyte subsets exist: classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. Immunomodulation of distinct monocyte subsets has recently been discussed as a new therapeutic avenue in atherosclerosis. Cardiovascular events in 951 subjects referred for elective coronary angiography were prospectively analyzed. Monocyte subset analysis was performed using flow cytometry, blinded to patients' clinical characteristics, and patients were categorized according to quartiles of total monocyte and monocyte subset counts. The primary endpoint was defined a priori as the first occurrence of cardiovascular death, acute myocardial infarction, or nonhemorrhagic stroke. Endpoint adjudication was done blinded to monocyte subset distribution. During a mean follow-up period of 2.6 ± 1.0 years, 93 patients experienced the primary endpoint. In univariate Kaplan-Meier analysis, counts of total (p = 0.010), classical CD14++CD16- (p = 0.024), and intermediate CD14++CD16+ (p < 0.001) monocytes predicted the primary endpoint, whereas nonclassical monocytes did not (p = 0.158). After full adjustment for confounders, CD14++CD16+ monocytes remained the only monocyte subset independently related to cardiovascular events (fourth vs. first quartile: hazard ratio: 3.019; 95% confidence interval: 1.315 to 6.928; p = 0.009). CD14++CD16+ monocytes independently predicted cardiovascular events in subjects referred for elective coronary angiography. Future studies will be needed to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies in atherosclerosis. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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            Chronic kidney disease and premature ageing.

            Chronic kidney disease (CKD) shares many phenotypic similarities with other chronic diseases, including heart failure, chronic obstructive pulmonary disease, HIV infection and rheumatoid arthritis. The most apparent similarity is premature ageing, involving accelerated vascular disease and muscle wasting. We propose that in addition to a sedentary lifestyle and psychosocial and socioeconomic determinants, four major disease-induced mechanisms underlie premature ageing in CKD: an increase in allostatic load, activation of the 'stress resistance response', activation of age-promoting mechanisms and impairment of anti-ageing pathways. The most effective current interventions to modulate premature ageing-treatment of the underlying disease, optimal nutrition, correction of the internal environment and exercise training-reduce systemic inflammation and oxidative stress and induce muscle anabolism. Deeper mechanistic insight into the phenomena of premature ageing as well as early diagnosis of CKD might improve the application and efficacy of these interventions and provide novel leads to combat muscle wasting and vascular impairment in chronic diseases.
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              Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans.

              The impact of intrinsic aging upon human peripheral blood T cell subsets remains incompletely quantified and understood. This impact must be distinguished from the influence of latent persistent microorganisms, particularly CMV, which has been associated with age-related changes in the T cell pool. In a cross-sectional cohort of 152 CMV-negative individuals, aged 21-101 y, we found that aging correlated strictly to an absolute loss of naive CD8, but not CD4, T cells but, contrary to many reports, did not lead to an increase in memory T cell numbers. The loss of naive CD8 T cells was not altered by CMV in 239 subjects (range 21-96 y), but the decline in CD4(+) naive cells showed significance in CMV(+) individuals. These individuals also exhibited an absolute increase in the effector/effector memory CD4(+) and CD8(+) cells with age. That increase was seen mainly, if not exclusively, in older subjects with elevated anti-CMV Ab titers, suggesting that efficacy of viral control over time may determine the magnitude of CMV impact upon T cell memory, and perhaps upon immune defense. These findings provide important new insights into the age-related changes in the peripheral blood pool of older adults, demonstrating that aging and CMV exert both distinct and joint influence upon blood T cell homeostasis in humans.
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                Author and article information

                Contributors
                yenlingchiu@ntu.edu.tw
                khshu.laclo@gmail.com
                fongrong@ntu.edu.tw
                selenechou@gmail.com
                ptmin0722@gmail.com
                lfylily1990@gmail.com
                gpsforeveryoung@gmail.com
                lincj@mmh.org.tw
                n.litjens@erasmusmc.nl
                m.g.h.betjes@erasmusmc.nl
                doc.sel@gmail.com
                rickykckao@gmail.com
                chiajs@ntu.edu.tw
                gwang7@jhmi.edu
                taan70@gmail.com
                +886-2-2826-7982 , chuangy@ym.edu.tw
                Journal
                Immun Ageing
                Immun Ageing
                Immunity & Ageing : I & A
                BioMed Central (London )
                1742-4933
                8 November 2018
                8 November 2018
                2018
                : 15
                : 27
                Affiliations
                [1 ]ISNI 0000 0004 0604 4784, GRID grid.414746.4, Division of Nephrology, Department of Medicine, , Far Eastern Memorial Hospital, ; Taipei, Taiwan
                [2 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Graduate Institute of Clinical Medicine, , College of Medicine, National Taiwan University , ; Taipei, Taiwan
                [3 ]ISNI 0000 0004 1770 3669, GRID grid.413050.3, Graduate Program in Biomedical Informatics, , Yuan Ze University, ; Taoyuan, Taiwan
                [4 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Graduate Institute of Immunology, , College of Medicine, National Taiwan University , ; Taipei, Taiwan
                [5 ]ISNI 0000 0004 0572 7815, GRID grid.412094.a, Department of Medicine, , National Taiwan University Hospital Yun Lin Branch, ; Douliu, Taiwan
                [6 ]ISNI 0000 0004 0573 007X, GRID grid.413593.9, Division of Nephrology, Department of Internal Medicine, , Mackay Memorial Hospital, ; Taipei, Taiwan
                [7 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, , University Medical Center Rotterdam, ; Rotterdam, Netherlands
                [8 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, International Health Program, , National Yang Ming University School of Public Health, ; Taipei, Taiwan
                [9 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Biology of Healthy Aging Program, Division of Geriatric Medicine and Gerontology, , Johns Hopkins University School of Medicine, ; Baltimore, MD USA
                [10 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, Institute of Public Health, , National Yang Ming University School of Public Health, ; Taipei, Taiwan
                [11 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, Preventive Medicine Research Center, , National Yang-Ming University, ; Taipei, Taiwan
                Article
                131
                10.1186/s12979-018-0131-x
                6223078
                30455721
                be0c5613-6e00-4b38-a45f-fa5844b8d14a
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 July 2018
                : 21 September 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;
                Award ID: 104-2314-B-418-017
                Award ID: 105-2314-B-418-002
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Immunology
                immunosenescence,aging,cvd,inflammation,esrd
                Immunology
                immunosenescence, aging, cvd, inflammation, esrd

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