Reproduction, DNA methylation and biological age

Hum Reprod. 2019 Oct 2;34(10):1965-1973. doi: 10.1093/humrep/dez149.


Study question: Are reproductive characteristics associated with genome-wide DNA methylation and epigenetic age?

Summary answer: Our data suggest that increasing parity is associated with differences in blood DNA methylation and small increases in epigenetic age.

What is known already: A study of 397 young Filipino women (ages 20-22) observed increasing epigenetic age with an increasing number of pregnancies.

Study design, size, duration: We used data from 2356 non-Hispanic white women (ages 35-74) enrolled in the Sister Study cohort.

Participants/materials, setting, methods: Data on reproductive history were ascertained via questionnaire. Of the 2356 women, 1897 (81%) reported at least one live birth. Among parous women, 487 (26%) women reported ever experiencing a pregnancy complication. Three epigenetic clocks (i.e. Hannum, Horvath and Levine) and genome-wide methylation were measured in DNA from whole blood using Illumina's HumanMethylation450 BeadChip. We estimated association β-values and 95% CIs using linear regression.

Main results and the role of chance: All three epigenetic clocks showed weak associations between number of births and epigenetic age (per live birth; Hannum: β = 0.16, 95% CI = 0.02, 0.29, P = 0.03; Horvath: β = 0.12, 95% CI = -0.04, 0.27, P = 0.14; Levine: β = 0.27, 95% CI = 0.08, 0.45, P = 0.01); however, additional adjustment for current BMI attenuated the associations. Among parous women, a history of abnormal glucose tolerance during pregnancy was associated with increased epigenetic age by the Hannum clock (β = 0.96; 95% CI = 0.10, 1.81; P = 0.03) and Levine clocks (β = 1.69; 95% CI = 0.54, 2.84; P < 0.01). In epigenome-wide analysis, increasing parity was associated with methylation differences at 17 CpG sites (Bonferroni corrected P≤ 1.0 × 10-7).

Limitations, reasons for caution: We relied on retrospective recall to ascertain reproductive history and pregnancy complications.

Wider implications of the findings: Our findings suggest that parity is associated with small increases in epigenetic age and with DNA methylation at multiple sites in the genome.

Study funding/competing interest(s): This research was supported by the Intramural Research program of the NIH, National Institute of Environmental Health Sciences (Z01-ES049033, Z01-ES049032 and Z01-ES044055). None of the authors have a conflict of interest.

Trial registration number: Not applicable.

Keywords: DNA methylation; biological age; epigenetic clock; parity; pregnancy complications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aging / genetics*
  • Body Mass Index
  • DNA Methylation / physiology*
  • Epigenesis, Genetic / physiology*
  • Female
  • Humans
  • Live Birth
  • Middle Aged
  • Parity / genetics*
  • Pregnancy
  • Pregnancy Complications / epidemiology*
  • Pregnancy Complications / genetics
  • Prospective Studies
  • Puerto Rico / epidemiology
  • Retrospective Studies
  • Surveys and Questionnaires / statistics & numerical data
  • United States / epidemiology