Association of female reproductive traits with altered aging trajectories: Insights from genetic and observational analyses

Women's reproductive health plays a pivotal role in both longevity and the aging process. We conduct Mendelian randomization (MR) and observational analyses to investigate these relationships. Univariate MR analyses reveal that older age at first birth, later menarche, higher estradiol, and sex hormone-binding globulin (SHBG) increase longevity, while pre-eclampsia liability decreases longevity. Older ages at first birth and at first sexual intercourse are associated with lower DNAmGrimAgeAccel, but these associations disappear after mutual adjustment. Mediation analyses identify cardiometabolic diseases, lung diseases, and mental disorders as key mediators. In corroborating the MR results, observational analyses show that early reproductive behaviors, such as age at first sex, are associated with accelerated biological aging. Additionally, we observe significant non-linear associations between hormone levels, age at menopause, and aging outcomes. This study highlights the impact of reproductive health on aging and suggests potential strategies for promoting healthy aging in women.