Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

• MeSH
• Alleles MeSH
• Genome-Wide Association Study MeSH
• Checkpoint Kinase 1 genetics   MeSH
• Checkpoint Kinase 2 genetics   MeSH
• Diabetes Mellitus, Type 2 MeSH
• Diet MeSH
• Longevity genetics   MeSH
• Adult MeSH
• Fertility genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Bone and Bones metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Menopause genetics   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Ovary metabolism   MeSH
• Menopause, Premature genetics   MeSH
• Primary Ovarian Insufficiency genetics   MeSH
• Fragile X Mental Retardation Protein genetics   MeSH
• Aging genetics   MeSH
• Uterus MeSH
• Healthy Aging genetics   MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Asia, Eastern MeSH
• Europe MeSH