Menopause timing, epigenetic aging and blood-cell traits

Abstract Menopause timing links reproductive lifespan with later-life health, motivating investigation of its molecular and hematological correlates. We combined Generation Scotland analyses of women sampled at or after reported menopause (n = 1,444) and initially menstruating women followed for GP-ascertained menopause onset (n = 1,725; 251 events) with bidirectional and multivariable Mendelian randomization. Higher age-adjusted GrimAge V1, GrimAge V2 and DunedinPACE corresponded to 0.34–0.40 years earlier menopause per SD in the retrospective cohort at nominal P < 0.05. Prospective associations were nonsignificant, and cohort and primary bidirectional aging-related genetic associations did not survive multiple-testing correction. Genetically predicted later menopause was associated with higher neutrophil percentage and count and lower lymphocyte percentage in women; these associations and female–male contrasts survived correction. CRP conditional on menopause timing was associated with higher GrimAge and PhenoAge acceleration and shorter leukocyte telomere(definition) length after correction. None of 36 estimated inflammatory indirect effects reached P < 0.05. These findings highlight blood-cell composition as a prominent correlate of reproductive timing and identify selected methylation-aging signatures for further study. Together, they position reproductive–hematological relationships as a specific avenue for understanding the connection between menopause and systemic aging.