Menopause accelerates biological aging

Morgan E. Levine, Ake T. Lu, Brian H. Chen, Dena G. Hernandez, Andrew B. Singleton, Luigi Ferrucci, Stefania Bandinelli, Elias Salfati, Jo Ann E Manson, Austin Quach, Cynthia D J Kusters, Diana Kuhi, Andrew Wong, Andrew E. Teschendorff, Martin Widschwendter, Beate R. Ritz, Devin Absher, Themistocles L. Assimes, Steve Horvath

Research output: Contribution to journalArticlepeer-review

158 Scopus citations


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 womenwho underwentmenopausal 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 studieswill be needed to dissect cause-and-effect relationships further.

Original languageEnglish (US)
Pages (from-to)9327-9332
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
StatePublished - Aug 16 2016
Externally publishedYes


  • Aging
  • DNA methylation
  • Epigenetic clock
  • Menopause
  • WHI

ASJC Scopus subject areas

  • General


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