A new study highlights the importance of the relationship between spermidine, autophagy, and antioxidant protection in maintaining fertility. Reductions in female fertility are often associated with poor oocyte (egg) quality, which can be the result of an inability to manage oxidative stress (Yuan et al., 2021). In one of the first studies to look at the role of spermidine in female fertility, researchers from Ningxia Medical University and Shanghai Jiao Tong University used hydrogen peroxide to induce oxidative stress in female germline stem cells (“FGSCs”), the precursors to mature egg cells. They then studied whether spermidine could protect FGSCs against this induced oxidative stress, and the related mechanisms of action.

In summary, spermidine increased expression of autophagy markers and increased both the number and viability of female germline stem cells. Spermidine further reduced oxidative stress induced aging markers in the cell.

Connecting the Dots: The Importance of Autophagy for Reproduction

Autophagy is thought to impact resource allocation between somatic cells and germline cells during sexual reproduction (Gao et al., 2020). It is required for oogenesis, or the process by which a primary egg cell becomes a mature egg:

“In mammals, autophagy is indispensable for spermatogenesis and oogenesis, and it participates in early embryonic development and maternal-fetus crosstalk to ensure the development of embryos or fetuses. Thus, autophagy provides the molecular basis for resource allocation among parents and their offspring, providing an important way to benefit the next generation”(Gao et al., 2020, p. 18).

Peri-ovulatory Ovarian ODC Deficiency and Reproductive Aging

Other researchers have highlighted the role the polyamine pathway may play in ovarian function. Humans can generate polyamines endogenously via conversion of the amino acid ornithine to putrescine, spermidine, and spermidine. The rate limiting enzyme in the polyamine biosynthesis pathway is Ornithine Decarboxylase (“ODC”). According to Liu (2016), there is an upregulation of ODC expression and putrescine production triggered by luteinizing hormone during oocyte maturation. Liu and colleagues have further demonstrated that old mice who are deficient in this polyamine generating pathway have impaired fertility (Tao & Liu, 2013), and further that putrescine supplementation in vivo corrects this impairment (Liu et al., 2017).

More human research is needed to fully understand why ovarian function fails with age, and how we can delay this process. However, using polyamines to protect against oxidative stress is a promising approach to improve oocyte quality and prolong fertility (Yuan et al., 2021).

References:

Gao, H., Khawar, M. B., & Li, W. (2020). Essential role of autophagy in resource allocation during sexual reproduction. Autophagy, 16(1), 18-27.

Liu, X. J. (2016). Targeting oocyte maturation to improve fertility in older women. Cell and tissue research, 363(1), 57-68.

Liu, D., Mo, G., Tao, Y., Wang, H., & Liu, X. J. (2017). Putrescine supplementation during in vitro maturation of aged mouse oocytes improves the quality of blastocysts. Reproduction, Fertility and Development, 29(7), 1392-1400.

Tao, Y., Tartia, A., Lawson, M., Zelinski, M. B., Wu, W., Liu, J. Y., ... & Liu, X. J. (2019). Can peri-ovulatory putrescine supplementation improve egg quality in older infertile women?. Journal of assisted reproduction and genetics, 36(3), 395-402.

Tao, Y., & Liu, X. J. (2013). Deficiency of ovarian ornithine decarboxylase contributes to aging‐related egg aneuploidy in mice. Aging Cell, 12(1), 42-49.

Yuan, X., Tian, G. G., Pei, X., Hu, X., & Wu, J. (2021). Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression. Cell & bioscience, 11(1), 1-14.