Vasomotor Symptoms and Accelerated Epigenetic Aging in the Women’s Health Initiative (WHI)

PURPOSE: The hallmark menopausal symptom, vasomotor symptoms (VMS), has been linked to adverse health indicators. However, the relationship between VMS and biological aging has not been tested. We examined associations between menopausal VMS and biological aging as assessed by 2 DNA methylation-based epigenetic aging indicators previously linked to poor health outcomes. METHODS: Participants were members of the Women's Health Initiative Observational Study integrative genomics substudy (N = 1206) who had both ovaries and were not taking hormone therapy. Relationships between VMS at enrollment (presence, severity) or VMS timing groups (no VMS: not at menopause onset nor at study enrollment; early VMS: at menopause onset but not at enrollment; persistent VMS: at menopause onset and study enrollment; and late VMS: at enrollment but not at menopause onset) and epigenetic clock(definition) indicators predictive of physical aging and early death (DNAm PhenoAge, DNAm GrimAge) were tested in linear regression models adjusting for age, race/ethnicity, hysterectomy, education, body mass index, smoking, and, in additional models, sleep disturbance. RESULTS: Women were on average 65 years of age at enrollment. Severe hot flashes at enrollment were associated with higher DNAm PhenoAge [relative to no hot flashes: B (SE) = 2.79 (1.27), P = 0.028, multivariable]. Further, late-occurring VMS were associated with both higher DNAm PhenoAge [B (SE) = 2.15 (0.84), P = 0.011] and DNAm GrimAge [B (SE) = 1.09 (0.42), P = 0.010, multivariable] relative to no VMS. MAIN CONCLUSIONS: Among postmenopausal women, severe or late-occurring VMS were associated with accelerated epigenetic age, controlling for chronological age. Postmenopausal women with severe or late-occurring VMS may have greater underlying epigenetic aging.