Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in  APOL2

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Abstract

To investigate the potential role of alcohol use disorder (AUD) in aging processes, we employed Levine’s epigenetic clock (DNAm PhenoAge) to estimate DNA methylation age in 331 individuals with AUD and 201 healthy controls (HC). We evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. To characterize potential underlying genetic variation contributing to EAA in AUD, we performed genome-wide association studies (GWAS) on EAA, including pathway analyses. We followed up on relevant top findings with in silico expression quantitative trait loci (eQTL) analyses for biological function using the BRAINEAC database. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition ( p = 1.85 × 10 ⁻⁵). This association remained significant after adjusting for race, body mass index, and smoking status (1.38 years, p = 0.02). Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days (all ps < 0.05). The genome-wide meta-analysis of EAA in AUD revealed a significant single nucleotide polymorphism (SNP), rs916264 ( p = 5.43 × 10 ⁻⁸), in apolipoprotein L2 ( APOL2) at the genome-wide level. The minor allele A of rs916264 was associated with EAA and with increased mRNA expression in hippocampus ( p = 0.0015). Our data demonstrate EAA in AUD and suggest that disease severity further accelerates epigenetic aging. EAA was associated with genetic variation in APOL2, suggesting potential novel biological mechanisms for age acceleration in AUD.

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An epigenetic biomarker of aging for lifespan and healthspan

Morgan E Levine, Ake T. Lu, Austin Quach … (2018)

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

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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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Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Steve Horvath, Junko Oshima, George M Martin … (2018)

DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

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Author and article information

Contributors

Falk W. Lohoff: falk.lohoff@nih.gov

Journal

Journal ID (nlm-ta): Neuropsychopharmacology

Journal ID (iso-abbrev): Neuropsychopharmacology

Title: Neuropsychopharmacology

Publisher: Springer International Publishing (Cham )

ISSN (Print): 0893-133X

ISSN (Electronic): 1740-634X

Publication date (Electronic): 29 August 2019

Publication date PMC-release: 29 August 2019

Publication date (Print): January 2020

Volume: 45

Issue: 2

Pages: 327-336

Affiliations

[1 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, , National Institutes of Health, ; Bethesda, MD USA

[2 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Department of Psychiatry and Psychotherapy, , Charite – Universitaetsmedizin Berlin, ; Berlin, Germany

[3 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, , National Institutes of Health, ; Bethesda, MD USA

[4 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Human Genetics, David Geffen School of Medicine, , University of California Los Angeles, ; Los Angeles, CA USA

[5 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Biostatistics, Fielding School of Public Health, , University of California Los Angeles, ; Los Angeles, CA USA

[6 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, The Royal’s Institute of Mental Health Research, , University of Ottawa, ; Ottawa, ON Canada

Author information

Christine Muench http://orcid.org/0000-0001-5103-9229

Article

Publisher ID: 500

DOI: 10.1038/s41386-019-0500-y

PMC ID: 6901591

PubMed ID: 31466081

SO-VID: 8034ab96-d85e-41c3-97fa-ff5104cc9aea

License:

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