Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans.

Background: Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited. Methods: Mendelian randomization (MR) was applied to investigate the associations between the ages of menarche or first childbirth and age-related outcomes and diseases. Ingenuity Pathway Analysis was employed to explore gene-related aspects associated with significant single-nucleotide polymorphisms (SNPs) detected in MR analysis. The associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes were validated in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Results: Using MR, we demonstrated that later ages of menarche or first childbirth were genetically associated with longer parental lifespan, decreased frailty index, slower epigenetic aging, later menopause, and reduced facial aging. Moreover, later menarche or first childbirth was also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease, type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease. We identified 158 significant SNPs that influenced age-related outcomes, some of which were involved in known longevity pathways, including insulin-like growth factor 1, growth hormone, AMP-activated protein kinase, and mTOR signaling. Our study also identified higher body mass index as a mediating factor in causing the increased risk of certain diseases, such as type 2 diabetes and heart failure, in women with early menarche or early pregnancy. We validated the associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Our results demonstrated that menarche before the age of 11 and childbirth before 21 significantly accelerated the risk of several diseases and almost doubled the risk for diabetes, heart failure, and quadrupled the risk of obesity, supporting the antagonistic pleiotropy theory. Conclusions: Our study highlights the complex relationship between genetic legacies and modern diseases, emphasizing the need for gender-sensitive healthcare strategies that consider the unique connections between female reproductive health and aging. Funding: Hevolution Foundation (PK). National Institute of Health grant R01AG068288 and R01AG045835 (PK). Larry L. Hillblom Foundation (PK), Larry L. Hillblom Foundation (PS), Glenn Foundation (VN).