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.

Institute of Animal Science Prague Czech Republic

Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

University of Teramo Teramo Italy

University of Zurich Zurich Switzerland

Zobrazit více v PubMed

Baumann, C. , Zhang X., Kandasamy M. K., et al. 2023. “Acute Irradiation Induces a Senescence‐Like Chromatin Structure in Mammalian Oocytes.” Communications Biology 6: 1–16. PubMed PMC

Check, J. H. , Jamison T., Check D., Choe J. K., Brasile D., and Cohen R.. 2011. “Live Delivery and Implantation Rates of Donor Oocyte Recipients in Their Late Forties Are Similar to Younger Recipients.” Journal of Reproductive Medicine 56: 149–152. PubMed

Chen, Y. , Liang R., Li Y., et al. 2024. “Chromatin Accessibility: Biological Functions, Molecular Mechanisms and Therapeutic Application.” Signal Transduction and Targeted Therapy 9: 340. PubMed PMC

Chiang, T. , Duncan F. E., Schindler K., Schultz R. M., and Lampson M. A.. 2010. “Evidence That Weakened Centromere Cohesion Is a Leading Cause of Age‐Related Aneuploidy in Oocytes.” Current Biology 20: 1522–1528. PubMed PMC

Clain, E. , Jahandideh S., Imudia A. N., Sarkar P., Devine K., and Roeca C.. 2022. “Recipient Age Is Not Associated With Outcomes in Donor Egg IVF Cycles.” Fertility and Sterility 118: e260–e261.

Dion, V. , Kalck V., Seeber A., Schleker T., and Gasser S. M.. 2013. “Cohesin and the Nucleolus Constrain the Mobility of Spontaneous Repair Foci.” EMBO Reports 14: 984–991. PubMed PMC

Duncan, F. E. , Jasti S., Paulson A., Kelsh J. M., Fegley B., and Gerton J. L.. 2017. “Age‐Associated Dysregulation of Protein Metabolism in the Mammalian Oocyte.” Aging Cell 16: 1381–1393. PubMed PMC

Fulka, H. , Ogura A., Loi P., and Fulka J. J.. 2019. “Dissecting the Role of the Germinal Vesicle Nuclear Envelope and Soluble Content in the Process of Somatic Cell Remodelling and Reprogramming.” Journal of Reproduction and Development 65: 433–441. PubMed PMC

Fulka, J. , Moor R. M., and Loi P.. 2003. “Enucleolation of Porcine Oocytes.” Theriogenology 59: 1879–1885. PubMed

Greda, P. , Karasiewicz J., and Modlinski J. A.. 2006. “Mouse Zygotes as Recipients in Embryo Cloning.” Reproduction 132: 741–748. PubMed

Gręda, P. , Modliński J. A., and Piliszek A.. 2015. “Developmental Potential of Selectively Enucleated Mouse Zygotes Reconstituted With Embryonic Cell, Embryonic Stem Cell and Somatic Cell Nuclei.” 33: 323–336.

Hodges, C. A. , and Hunt P. A.. 2002. “Simultaneous Analysis of Chromosomes and Chromosome‐Associated Proteins in Mammalian Oocytes and Embryos.” Chromosoma 111: 165–169. PubMed

Holinka, C. F. , and Finch C. E.. 1981. “Efficiency of Mating in C57BL/6J Female Mice as a Function of Age and Previous Parity.” Experimental Gerontology 16: 393–398. PubMed

Lowe, D. G. 2004. “Distinctive Image Features From Scale‐Invariant Keypoints.” International Journal of Computer Vision 60: 91–110.

Manosalva, I. , and González A.. 2010. “Aging Changes the Chromatin Configuration and Histone Methylation of Mouse Oocytes at Germinal Vesicle Stage.” Theriogenology 74: 1539–1547. PubMed

Mayer, A. , Baran V., Sakakibara Y., et al. 2016. “DNA Damage Response During Mouse Oocyte Maturation.” Cell Cycle 15: 546–558. PubMed PMC

Ogushi, S. , Yamagata K., Obuse C., et al. 2017. “Reconstitution of the Oocyte Nucleolus in Mice Through a Single Nucleolar Protein, NPM2.” Journal of Cell Science 130: 2416–2429. PubMed PMC

Paulson, R. J. , Hatch I. E., Lobo R. A., and Sauer M. V.. 1997. “Cumulative Conception and Live Birth Rates After Oocyte Donation: Implications Regarding Endometrial Receptivity.” Human Reproduction 12: 835–839. PubMed

Price, B. D. , and D'Andrea A. D.. 2013. “Chromatin Remodeling at DNA Double‐Strand Breaks.” Cell 152: 1344–1354. PubMed PMC

Sharma, N. , Coticchio G., Borini A., Tachibana K., Nasmyth K. A., and Schuh M.. 2024. “Changes in DNA Repair Compartments and Cohesin Loss Promote DNA Damage Accumulation in Aged Oocytes.” Current Biology 34: 5131–5148.e6. PubMed

Short, R. E. , Staigmiller R. B., Bellows R. A., and Greer R. C.. 1993. “Breeding Heifers at One Year of Age: Biological and Economic Considerations.” In Factors Affecting Calf Crop. CRC Press.

Stone, B. J. 2020. “Nonsurgical Embryo Transfer Protocol for Use With the NSET Device.” Methods in Molecular Biology 2066: 107–111. PubMed

Sun, F. , Ali N. N., Londoño‐Vásquez D., et al. 2024. “Increased DNA Damage in Full‐Grown Oocytes Is Correlated With Diminished Autophagy Activation.” Nature Communications 15: 9463. PubMed PMC

Tachibana‐Konwalski, K. , Godwin J., van der Weyden L., et al. 2010. “Rec8‐Containing Cohesin Maintains Bivalents Without Turnover During the Growing Phase of Mouse Oocytes.” Genes & Development 24: 2505–2516. PubMed PMC

Takeo, T. , and Nakagata N.. 2011. “Reduced Glutathione Enhances Fertility of Frozen/Thawed C57BL/6 Mouse Sperm After Exposure to Methyl‐Beta‐Cyclodextrin.” Biology of Reproduction 85: 1066–1072. PubMed

Thévenaz, P. , Ruttimann U. E., and Unser M.. 1998. “A Pyramid Approach to Subpixel Registration Based on Intensity.” IEEE Transactions on Image Processing 7: 27–41. PubMed