Prediction of aging pace and health risks by granulosa cell deoxyribonucleic acid methylation

OBJECTIVE: To investigate the correlation between the pace of aging in granulosa cells, as measured by the DunedinPACE clock, and ovarian reserve; and examine the relationship between ovarian reserve and the predicted risk of cardiovascular (CVD) and metabolic diseases through methylation risk scores (MRS). Epigenetic biomarkers have been used to characterize biological age and predict future health outcomes. DESIGN: Cross-sectional study. SUBJECTS: Seventy women undergoing either in vitro fertilization or elective oocyte cryopreservation. EXPOSURE: Ovarian reserve was assessed using antimüllerian hormone (AMH) and antral follicle count (AFC). MAIN OUTCOME MEASURES: Participants had a mean age of 36.8 years and a mean body mass index of 26.8 kg/m². The cohort was racially and ethnically diverse: 54.3% non-Hispanic White, 20.0% Asian, and 18.6% non-Hispanic Black. Nineteen (27.1%) underwent elective oocyte cryopreservation, and 51 (72.9%) underwent in vitro fertilization. After adjustment for age and body mass index, DunedinPACE was inversely associated with AMH (β = 0.025) and AFC (β = -0.008). Similarly, both CVD MRS (AMH: β = -0.030; AFC: β = -0.011), and metabolic syndrome (MetS) MRS (AMH: β = -0.084; AFC: β = -0.027) were inversely associated with ovarian reserve markers. DunedinPACE, CVD MRS, and MetS MRS also showed significant negative associations with follicle count ≥14 mm at trigger and the number of oocytes retrieved, although the association between MetS MRS and oocyte retrieval was not statistically significant after adjustment. CONCLUSION: Deoxyribonucleic acid methylation patterns derived from follicular fluid may offer insight into biological aging and cardiometabolic risk. Our findings demonstrate that lower ovarian reserve is significantly associated with accelerated pace of aging and higher MRS for cardiovascular and metabolic disease. Although further validation is needed, these associations raise the possibility that women with lower ovarian reserve may benefit from earlier identification and preventive health interventions targeting long-term disease risk.