Women are born with a finite supply of eggs that cannot be replenished. As women age, the quantity and quality of these eggs significantly decline. This process – known as ovarian aging – is influenced by various molecular and cellular mechanisms [1]. Today, many women delay motherhood due to changing lifestyles, which often leads to fertility-based challenges related to ovarian aging.
Cellular Reprogramming: A Hope for Ovarian Rejuvenation
Cellular reprogramming allows for the conversion of specialized somatic cells into pluripotent cells through the expression of the reprogramming factors; however, this process can also reverse cellular phenotypes associated with aging [2][3]. The expression of reprogramming factors in aged cells for short periods can restore youthful epigenetic modifications, inhibit the senescence-associated secretory pathway (SASP), and reduce the number of senescent cells [4]. This approach – known as “partial reprogramming” – can promote significant rejuvenation effects [5] and has been shown to benefit a number of tissues [6][7]; we hypothesize that partial reprogramming could have similar effects on ovarian tissues, opening new possibilities for treating age-related infertility.
Our Research on Ovarian Rejuvenation
Recently, Drs. Felipe Vilella and Ana Monteagudo received a competitive grant from the Carlos III Health Institute to support their research on ovarian rejuvenation through partial cellular reprogramming. The goal of the project is to understand the mechanisms of ovarian aging and develop future therapies for infertility. They plan to conduct a study using ovaries from women of different ages to decipher the molecular mechanisms underlying ovarian aging and subsequently evaluate a novel strategy to mitigate the effects of ovarian aging, which could lead to the development of new therapies to improve fertility using a woman’s own eggs. The clinical application of this approach would involve a less invasive and less costly procedure with huge potential for integration into national health systems.
References:
1. Wasserzug-Pash, P., Rothman, R., Reich, E., Zecharyahu, L., Schonberger, O., Weiss, Y., Srebnik, N., Cohen-Hadad, Y., Weintraub, A., Ben-Ami, I., Holzer, H., & Klutstein, M. (2022). Loss of heterochromatin and retrotransposon silencing as determinants in oocyte aging. Aging cell, 21(3), e13568. https://doi.org/10.1111/acel.13568
2. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676. https://doi.org/10.1016/j.cell.2006.07.024
3. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872. https://doi.org/10.1016/j.cell.2007.11.019
4. Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., Araoka, T., Vazquez-Ferrer, E., Donoso, D., Roman, J. L., Xu, J., Rodriguez Esteban, C., Nuñez, G., Nuñez Delicado, E., Campistol, J. M., Guillen, I., … Izpisua Belmonte, J. C. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719–1733.e12. https://doi.org/10.1016/j.cell.2016.11.052
5. Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., Araoka, T., Vazquez-Ferrer, E., Donoso, D., Roman, J. L., Xu, J., Rodriguez Esteban, C., Nuñez, G., Nuñez Delicado, E., Campistol, J. M., Guillen, I., … Izpisua Belmonte, J. C. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719–1733.e12. https://doi.org/10.1016/j.cell.2016.11.052
6. Hishida, T., Yamamoto, M., Hishida-Nozaki, Y., Shao, C., Huang, L., Wang, C., Shojima, K., Xue, Y., Hang, Y., Shokhirev, M., Memczak, S., Sahu, S. K., Hatanaka, F., Ros, R. R., Maxwell, M. B., Chavez, J., Shao, Y., Liao, H. K., Martinez-Redondo, P., Guillen-Guillen, I., … Izpisua Belmonte, J. C. (2022). In vivo partial cellular reprogramming enhances liver plasticity and regeneration. Cell reports, 39(4), 110730. https://doi.org/10.1016/j.celrep.2022.110730
7. Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D. L., Zeng, Q., Yu, D., Bonkowski, M. S., Yang, J. H., Zhou, S., Hoffmann, E. M., Karg, M. M., Schultz, M. B., Kane, A. E., Davidsohn, N., Korobkina, E., Chwalek, K., Rajman, L. A., … Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature, 588(7836), 124–129. https://doi.org/10.1038/s41586-020-2975-4