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      DNA methylation profile is a quantitative measure of biological aging in children

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          Abstract

          DNA methylation changes within the genome can be used to predict human age. However, the existing biological age prediction models based on DNA methylation are predominantly adult-oriented. We established a methylation-based age prediction model for children (9-212 months old) using data from 716 blood samples in 11 DNA methylation datasets. Our elastic net model includes 111 CpG sites, mostly in genes associated with development and aging. The model performed well and exhibited high precision, yielding a 98% correlation between the DNA methylation age and the chronological age, with an error of only 6.7 months. When we used the model to assess age acceleration in children based on their methylation data, we observed the following: first, the aging rate appears to be fastest in mid-childhood, and this acceleration is more pronounced in autistic children; second, lead exposure early in life increases the aging rate in boys, but not in girls; third, short-term recombinant human growth hormone treatment has little effect on the aging rate of children. Our child-specific methylation-based age prediction model can effectively detect epigenetic changes and health imbalances early in life. This may thus be a useful model for future studies of epigenetic interventions for age-related diseases.

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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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            Epigenetic Predictor of Age

            From the moment of conception, we begin to age. A decay of cellular structures, gene regulation, and DNA sequence ages cells and organisms. DNA methylation patterns change with increasing age and contribute to age related disease. Here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. Furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. The methylation of three sites—in the promoters of the EDARADD, TOM1L1, and NPTX2 genes—is linear with age over a range of five decades. Using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years. In forensic science, such a model could estimate the age of a person, based on a biological sample alone. Furthermore, a measurement of relevant sites in the genome could be a tool in routine medical screening to predict the risk of age-related diseases and to tailor interventions based on the epigenetic bio-age instead of the chronological age.
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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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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                30 November 2019
                22 November 2019
                : 11
                : 22
                : 10031-10051
                Affiliations
                [1 ]Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
                [2 ]Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
                [3 ]Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Guangzhou, Guangdong, China
                [4 ]Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, Guangdong, China
                [5 ]Department of Cardiovascular Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
                [6 ]The Guangdong Early Childhood Development Applied Engineering and Technology Research Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong, China
                Author notes
                [*]

                Equal contribution

                Correspondence to: Huiying Liang; email: lianghuiying@hotmail.com
                Correspondence to: Yanyan Song; email: yansong84@126.com
                Article
                102399 102399
                10.18632/aging.102399
                6914436
                31756171
                5dc7c49d-3c74-4a6e-8889-48bdbdf581ad
                Copyright © 2019 Wu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 April 2019
                : 26 October 2019
                Categories
                Research Paper

                Cell biology
                children,biological age,prediction,methylation,age-related diseases
                Cell biology
                children, biological age, prediction, methylation, age-related diseases

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