Exploring the causal association between epigenetic clocks and menopause age: insights from a bidirectional Mendelian randomization study

Front Endocrinol (Lausanne). 2024 Aug 23:15:1429514. doi: 10.3389/fendo.2024.1429514. eCollection 2024.

Abstract

Background: Evidence suggests a connection between DNA methylation (DNAm) aging and reproductive aging. However, the causal relationship between DNAm and age at menopause remains uncertain.

Methods: Employing established DNAm epigenetic clocks, such as DNAm Hannum age acceleration (Hannum), Intrinsic epigenetic age acceleration (IEAA), DNAm-estimated granulocyte proportions (Gran), DNAm GrimAge acceleration (GrimAgeAccel), DNAm PhenoAge acceleration (PhenoAgeAccel), and DNAm-estimated plasminogen activator inhibitor-1 levels (DNAmPAIadjAge), a bidirectional Mendelian randomization (MR) study was carried out to explore the potential causality between DNAm and menopausal age. The primary analytical method used was the inverse variance weighted (IVW) estimation model, supplemented by various other estimation techniques.

Results: DNAm aging acceleration or deceleration, as indicated by Hannum, IEAA, Gran, GrimAgeAccel, PhenoAgeAccel, and DNAmPAIadjAge, did not exhibit a statistically significant causal effect on menopausal age according to forward MR analysis. However, there was a suggestive positive causal association between age at menopause and Gran (Beta = 0.0010; 95% confidence interval (CI): 0.0004, 0.0020) in reverse MR analysis.

Conclusion: The observed increase in granulocyte DNAm levels in relation to menopausal age could potentially serve as a valuable indicator for evaluating the physiological status at the onset of menopause.

Keywords: DNA methylation; Mendelian randomization; causal association; epigenetic clocks; menopause.

MeSH terms

  • Adult
  • Age Factors
  • Aging / genetics
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Mendelian Randomization Analysis*
  • Menopause* / genetics
  • Middle Aged

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by grant 82100040, 82302277 from National Natural Science Foundation of China, grant 2022RC1232 from the Science and Technology Innovation Program of Hunan Province, grant 23A0662, 23B0872, 22A0658 from Scientific Research Foundation of Hunan Provincial Education Department, and grant 2022CYY012, 2022CYY029 from ESI Special Project of Changsha Medical University.