title: Menopause accelerates biological aging.
abstract: Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Center for Neurobehavioral Genetics, University of California, Los Angeles, CA 90095;
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Levine
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Ake T
authors.initials: AT
authors.lastname: Lu
authors.affiliation: Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Brian H
authors.initials: BH
authors.lastname: Chen
authors.affiliation: Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.affiliation: Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Geriatric Unit, Azienda Sanitaria di Firenze, 50100; Florence, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Elias
authors.initials: E
authors.lastname: Salfati
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Austin
authors.initials: A
authors.lastname: Quach
authors.affiliation: Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA 90095;
authors.forename: Cynthia D J
authors.initials: CD
authors.lastname: Kusters
authors.affiliation: Medical Research Council Unit for Lifelong Health and Ageing, University College London, London WC1B 5JU, United Kingdom;
authors.forename: Diana
authors.initials: D
authors.lastname: Kuh
authors.affiliation: Medical Research Council Unit for Lifelong Health and Ageing, University College London, London WC1B 5JU, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.affiliation: Department of Women's Cancer, University College London, London WC1 6BT, United Kingdom; University College London Cancer Institute, University College London, London WC1 6BT, United Kingdom; Statistical Genomics Group, University College London Cancer Institute, University College London, London WC1E 6DD, United Kingdom; Chinese Academy of Sciences Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Society Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai Institute for Biology, Shanghai 200031, China;
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.affiliation: Department of Women's Cancer, University College London, London WC1 6BT, United Kingdom;
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.affiliation: Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA 90095;
authors.forename: Beate R
authors.initials: BR
authors.lastname: Ritz
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806;
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA 90095 shorvath@mednet.ucla.edu.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
mesh_terms: D000328:Adult; D000375:Aging / Q000502:physiology*; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D057182:Mendelian Randomization Analysis; D008593:Menopause / Q000502:physiology*; D008875:Middle Aged; D010052:Ovariectomy; D020641:Polymorphism, Single Nucleotide
keywords: DNA methylation; WHI; aging; epigenetic clock; menopause