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      Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels

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          Abstract

          Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=−0.41, p=5.5×10 −8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels.

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          DNA methylation age of blood predicts all-cause mortality in later life

          Riccardo E Marioni, Sonia Shah, Allan McRae … (2015)
          Background DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age. Results Here we test whether differences between people’s chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (Δage) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between Δage and mortality. A 5-year higher Δage is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher Δage. A pedigree-based heritability analysis of Δage was conducted in a separate cohort. The heritability of Δage was 0.43. Conclusions DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0584-6) contains supplementary material, which is available to authorized users.
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            Obesity accelerates epigenetic aging of human liver.

            S Horvath, W Erhart, M Brosch … (2014)
            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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              Decline in genomic DNA methylation through aging in a cohort of elderly subjects.

              Valentina Bollati, Joel Schwartz, Robert B. Wright … (2009)
              Loss of genomic DNA methylation has been found in a variety of common human age-related diseases. Whether DNA methylation decreases over time as individuals age is unresolved. We measured DNA methylation in 1097 blood DNA samples from 718 elderly subjects between 55 and 92 years of age (1-3 samples/subjects), who have been repeatedly evaluated over an 8-year time span in the Boston area Normative Aging Study. DNA methylation was measured using quantitative PCR-Pyrosequencing analysis in Alu and LINE-1 repetitive elements, heavily methylated sequences with high representation throughout the human genome. Age at the visit was negatively associated with Alu element methylation (beta=-0.12 %5mC/year, p=0.0005). A weaker association was observed with LINE-1 elements (beta=-0.06 %5mC/year, p=0.049). We observed a significant decrease in average Alu methylation over time, with a -0.2 %5mC change (p=0.012) compared to blood samples collected up to 8 years earlier. The longitudinal decline in Alu methylation was linear and highly correlated with time since the first measurement (beta=-0.089 %5mC/year, p<0.0001). In contrast, average LINE-1 methylation did not vary over time [p=0.51]. Our results demonstrate a progressive loss of DNA methylation in repetitive elements dispersed throughout the genome.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Aging (Albany NY)
                Journal ID (iso-abbrev): Aging (Albany NY)
                Journal ID (publisher-id): Aging
                Journal ID (publisher-id): ImpactJ
                Title: Aging (Albany NY)
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1945-4589
                Publication date Collection: August 2016
                Publication date (Electronic): 27 July 2016
                Volume: 8
                Issue: 7
                Pages: 1485-1504
                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 CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA
                4 Department of Anatomy and Medical Imaging, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand
                5 Centre for Brain Research, Faculty of Medical and Health Science (FMHS), University of Auckland, Auckland, New Zealand
                6 Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
                7 Pathology and Laboratory Medicine, and Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA
                8 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
                9 UCLA Brain Research Institute, Los Angeles, CA 90095, USA
                Author notes
                Correspondence to: Steve Horvath, PhD; shorvath@ 123456mednet.ucla.edu
                Article
                Publisher ID: 101005
                DOI: 10.18632/aging.101005
                PMC ID: 4993344
                PubMed ID: 27479945
                SO-VID: 27880206-2c94-498d-8db5-a54dc62cd271
                Copyright © Copyright: © 2016 Horvath et al.
                License:

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

                History
                Date received : 5 May 2016
                Date accepted : 12 July 2016
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Cell biology
                Keywords: huntington's disease,epigenetic clock,dna methylation,epigenetics,biomarker of aging,brain
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: huntington's disease, epigenetic clock, dna methylation, epigenetics, biomarker of aging, brain

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