Oocyte Age-Dependent DNA Damage Can Be Reverted by the DNA Repair Competent Karyoplasm of Young Oocytes

Mammalian fully grown oocytes are believed to exhibit a weakened DNA damage response, leading to the accumulation of substantial levels of DNA damage and increased frequency of aneuploidies in an age-dependent manner. These hallmarks of reproductive ageing are generally presumed to be irreversible by rendering the oocyte chromosome complement incompatible with development. To test whether this is indeed true, we performed a series of germinal vesicle (GV) transfers between oocytes from females of late breeding/post-breeding age and oocytes from young animals. Our results show that age-associated DNA damage can be effectively suppressed: introducing the GVs of advanced-maternal-age (AMA) oocytes into DNA repair-competent cytoplasts generated by selective enucleation (SE) of young oocytes effectively suppresses the signs of age-dependent DNA damage. This is accompanied by a partial recovery of the chromatin dynamics and, surprisingly, a higher fidelity of chromosome segregation. By dissecting the GV fractions, we show that the ability to sense and repair DNA is linked to the free, non-chromatin-bound nuclear factors but not the oocyte nucleolus. Finally, we show that the overall improved state of the reconstructed oocytes is accompanied by enhanced full-term development. Therefore, contrary to popular belief, our results show that the age-associated decline in oocyte quality can be effectively mitigated, opening new possibilities for cell-based oocyte therapy.