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      The biological age of the heart is consistently younger than chronological age

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          Abstract

          Chronological age represents the main factor in donor selection criteria for organ transplantation, however aging is very heterogeneous. Defining the biological aging of individual organs may contribute to supporting this process. In this study we examined the biological age of the heart [right (RA)/left atrium (LA)] and peripheral blood leucocytes in the same subject, and compared these to assess whether blood mirrors cardiac biological aging. Biological aging was studied in 35 donors (0.4–72 years) by exploring mitotic and non-mitotic pathways, using telomere length (TL) and age-dependent methylation changes in certain CpG loci (DNAmAge). Heart non-mitotic DNAmAge was strongly younger than that of both blood (− 10 years, p < 0.0001) and chronological age (− 12 years, p < 0.0001). Instead, heart and blood mitotic age (TL) were similar, and there was no difference in DNAmAge and TL between RA and LA. DNAmAge negatively correlated with TL in heart and blood ( p ≤ 0.01). Finally, blood and heart TL ( p < 0.01) and DNAmAge ( p < 0.0001) were correlated. Therefore, blood can be a proxy indicator of heart biological age. While future investigation on post-transplant graft performance in relation to biological aging is still needed, our study could contribute to opening up novel basic and clinical research platforms in the field of organ transplantation.

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          Biological Age Predictors

          The search for reliable indicators of biological age, rather than chronological age, has been ongoing for over three decades, and until recently, largely without success. Advances in the fields of molecular biology have increased the variety of potential candidate biomarkers that may be considered as biological age predictors. In this review, we summarize current state-of-the-art findings considering six potential types of biological age predictors: epigenetic clocks, telomere length, transcriptomic predictors, proteomic predictors, metabolomics-based predictors, and composite biomarker predictors. Promising developments consider multiple combinations of these various types of predictors, which may shed light on the aging process and provide further understanding of what contributes to healthy aging. Thus far, the most promising, new biological age predictor is the epigenetic clock; however its true value as a biomarker of aging requires longitudinal confirmation.
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            Aging of blood can be tracked by DNA methylation changes at just three CpG sites

            Background Human aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age. Results We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure and severe telomere attrition - are predicted to be prematurely aged. Conclusions Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.
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              Adult cardiac stem cells are multipotent and support myocardial regeneration.

              The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing approximately 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.
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                Author and article information

                Contributors
                sofia.pavanello@unipd.it
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                1 July 2020
                1 July 2020
                2020
                : 10
                : 10752
                Affiliations
                [1 ]ISNI 0000 0004 1760 2630, GRID grid.411474.3, Unit of Occupational Medicine, Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, , University Hospital of Padova, ; Via Giustiniani, 2, 35128 Padua, Italy
                [2 ]GRID grid.26618.3b, Lifelab Program, , Consorzio Per La Ricerca Sanitaria-CORIS, ; Veneto Region, Via Giustiniani 2, 35128 Padua, Italy
                [3 ]ISNI 0000 0004 1760 2630, GRID grid.411474.3, Cardiac Surgery Unit, Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, , University Hospital of Padova, ; Via Giustiniani, 2, 35128 Padua, Italy
                Article
                67622
                10.1038/s41598-020-67622-1
                7329913
                32612244
                7ddeedc3-11e9-4159-908c-bb3094ca3d53
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 April 2020
                : 11 June 2020
                Categories
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                © The Author(s) 2020

                Uncategorized
                biomarkers,senescence,epigenetics
                Uncategorized
                biomarkers, senescence, epigenetics

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