Ovary as a Biomarker of Health and Longevity: Insights from Genetics

Reproductive fitness and its influence on overall health has been a topic of significant study and interest. Multiple studies have found that age at last reproduction associates with overall health. Women who conceive later in life are significantly more likely to outlive their peers who are unable to conceive. The mechanisms behind these observations are not well understood. Earlier age at menopause associates with shorter life span, increased risk for diabetes mellitus, and increased risk of heart disease, and represents a surrogate marker for the age at last reproduction. Recent applications of genome-wide association studies as well as whole-exome sequencing to familial primary ovarian insufficiency (POI) and menopause have identified new genomic regions that link reproductive aging and adverse health outcomes. The preponderance of DNA damage response genes in menopause and POI represents a relatively new paradigm in this area, and links overall aging and reproduction at the molecular level. Identification of the subset of individuals who are at risk for adverse health outcomes remains a significant and high priority research challenge. The combination of epidemiologic studies in women with diminished ovarian reserves, ovarian insufficiency, and early menopause, as well as appropriate animal studies, will be necessary to dissect genotype-phenotype correlations not only in the cause of ovarian dysfunction but also in the cause of adverse health outcomes.