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      Aging of blood can be tracked by DNA methylation changes at just three CpG sites

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          Abstract

          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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          Most cited references 43

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          High density DNA methylation array with single CpG site resolution.

          We have developed a new generation of genome-wide DNA methylation BeadChip which allows high-throughput methylation profiling of the human genome. The new high density BeadChip can assay over 480K CpG sites and analyze twelve samples in parallel. The innovative content includes coverage of 99% of RefSeq genes with multiple probes per gene, 96% of CpG islands from the UCSC database, CpG island shores and additional content selected from whole-genome bisulfite sequencing data and input from DNA methylation experts. The well-characterized Infinium® Assay is used for analysis of CpG methylation using bisulfite-converted genomic DNA. We applied this technology to analyze DNA methylation in normal and tumor DNA samples and compared results with whole-genome bisulfite sequencing (WGBS) data obtained for the same samples. Highly comparable DNA methylation profiles were generated by the array and sequencing methods (average R2 of 0.95). The ability to determine genome-wide methylation patterns will rapidly advance methylation research. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Telomeres and human disease: ageing, cancer and beyond.

             Maria Blasco (2005)
            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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              Obesity, cigarette smoking, and telomere length in women.

              Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.
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                Author and article information

                Contributors
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central
                1465-6906
                1465-6914
                2014
                3 February 2014
                : 15
                : 2
                : R24
                Affiliations
                [1 ]Helmholtz-Institute for Biomedical Engineering; Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany
                [2 ]Institute for Biomedical Engineering - Cell Biology, RWTH Aachen University Medical School, Aachen, Germany
                [3 ]Institute for Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, Essen, Germany
                [4 ]Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany
                [5 ]Department of Obstetrics and Gynecology, RWTH Aachen University Medical School, Aachen, Germany
                [6 ]Department of Cardiology, West-German Heart Center Essen, University Duisburg-Essen, Essen, Germany
                [7 ]Institute of Human Genetics, University of Bonn, Bonn, Germany
                [8 ]Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
                [9 ]Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany
                Article
                gb-2014-15-2-r24
                10.1186/gb-2014-15-2-r24
                4053864
                24490752
                Copyright © 2014 Weidner et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Research

                Genetics

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