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      Accelerated epigenetic aging in Down syndrome

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          Abstract

          Down Syndrome (DS) entails an increased risk of many chronic diseases that are typically associated with older age. The clinical manifestations of accelerated aging suggest that trisomy 21 increases the biological age of tissues, but molecular evidence for this hypothesis has been sparse. Here, we utilize a quantitative molecular marker of aging (known as the epigenetic clock) to demonstrate that trisomy 21 significantly increases the age of blood and brain tissue (on average by 6.6 years, = 7.0 × 10 −14).

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          Most cited references26

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          DNA methylation age of human tissues and cell types

          Background It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. Results I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. Conclusions I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.
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            Genome-wide methylation profiles reveal quantitative views of human aging rates.

            The ability to measure human aging from molecular profiles has practical implications in many fields, including disease prevention and treatment, forensics, and extension of life. Although chronological age has been linked to changes in DNA methylation, the methylome has not yet been used to measure and compare human aging rates. Here, we build a quantitative model of aging using measurements at more than 450,000 CpG markers from the whole blood of 656 human individuals, aged 19 to 101. This model measures the rate at which an individual's methylome ages, which we show is impacted by gender and genetic variants. We also show that differences in aging rates help explain epigenetic drift and are reflected in the transcriptome. Moreover, we show how our aging model is upheld in other human tissues and reveals an advanced aging rate in tumor tissue. Our model highlights specific components of the aging process and provides a quantitative readout for studying the role of methylation in age-related disease. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Obesity accelerates epigenetic aging of human liver.

              Because of the dearth of biomarkers of aging, it has been difficult to test the hypothesis that obesity increases tissue age. Here we use a novel epigenetic biomarker of aging (referred to as an "epigenetic clock") to study the relationship between high body mass index (BMI) and the DNA methylation ages of human blood, liver, muscle, and adipose tissue. A significant correlation between BMI and epigenetic age acceleration could only be observed for liver (r = 0.42, P = 6.8 × 10(-4) in dataset 1 and r = 0.42, P = 1.2 × 10(-4) in dataset 2). On average, epigenetic age increased by 3.3 y for each 10 BMI units. The detected age acceleration in liver is not associated with the Nonalcoholic Fatty Liver Disease Activity Score or any of its component traits after adjustment for BMI. The 279 genes that are underexpressed in older liver samples are highly enriched (1.2 × 10(-9)) with nuclear mitochondrial genes that play a role in oxidative phosphorylation and electron transport. The epigenetic age acceleration, which is not reversible in the short term after rapid weight loss induced by bariatric surgery, may play a role in liver-related comorbidities of obesity, such as insulin resistance and liver cancer.
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                Author and article information

                Journal
                Aging Cell
                Aging Cell
                acel
                Aging Cell
                BlackWell Publishing Ltd (Oxford, UK )
                1474-9718
                1474-9726
                June 2015
                09 February 2015
                : 14
                : 3
                : 491-495
                Affiliations
                [1 ]Human Genetics, David Geffen School of Medicine, University of California Los Angeles Los Angeles, CA, 90095, USA
                [2 ]Biostatistics, Fielding School of Public Health, University of California Los Angeles Los Angeles, CA, 90095, USA
                [3 ]Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna Bologna, 40126, Italy
                [4 ]Interdepartmental Center ‘L. Galvani’, University of Bologna Bologna, 40126, Italy
                [5 ]CNR, Applied Biomedical Research Center, S. Orsola-Malpighi Polyclinic Bologna, 40138, Italy
                [6 ]Personal Genomics S.r.l. Verona, 37134, Italy
                [7 ]Center of Research and Biomedical Technology, Istituto Auxologico Italiano IRCCS Via Zucchi 18, Cusano Milanino, 20095, Milan, Italy
                [8 ]Department of Biological, Geological and Environmental Sciences, University of Bologna Bologna, 40126, Italy
                [9 ]Department of Neurology and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA, 90095, USA
                [10 ]IRCCS, Institute of Neurological Sciences of Bologna 40139, Bologna, Italy
                Author notes
                Correspondence, Steve Horvath, Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. Tel.: 310 825 9299; fax: 310-794-5446; e-mail : shorvath@ 123456mednet.ucla.edu
                [*]

                These authors contributed equally.

                Article
                10.1111/acel.12325
                4406678
                25678027
                c0cdc4fa-2a68-4ee3-bea7-ac53a7814c45
                © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                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
                : 05 January 2014
                Categories
                Original Articles

                Cell biology
                biomarker of aging,dna methylation,down syndrome,epigenetics
                Cell biology
                biomarker of aging, dna methylation, down syndrome, epigenetics

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