Can Spermidine Save Female Fertility? How This Antioxidant Compound Mitigates Reproductive Stem Cell Aging

Female fertility declines irreversibly with increasing age, as a woman’s most successful reproductive years are thought to be in her mid-to-late-20s. Yet many women are now waiting longer and longer to become pregnant, leading patients and doctors alike to search for ways to delay this age-related decline in fertility.

Researchers out of Shanghai, China, may have found one such way to preserve female fertility, with the antioxidant compound spermidine. Published in the June 2021 issue of Cell & Bioscience, Yuan and colleagues look at the effects of spermidine on autophagy — our body’s internal recycling program that removes damaged or dysfunctional cells, cell parts, and proteins — in specific cells of the female reproductive system. 

With these findings, spermidine may soon be a leading contender for protecting and prolonging fertility with advancing maternal age. This research provides hope for many women who want to have children in their 40s, 50s, and beyond — perhaps even catching up with the current oldest mother in the world, who gave birth at an astonishing 74 years. 

Is Infertility Imminent With Increasing Age?

Beginning in a woman’s mid-30s, both the number of viable egg cells and the chances of becoming pregnant naturally decrease year after year. Aging oocytes, which is the term for immature egg cells before they fully mature into eggs that can be fertilized, have significantly impaired follicular development, ovulation rates, and maturation, leading to low fertility. 

Oocytes were previously thought to be non-self-renewing cells in humans — meaning, the number of oocytes at birth would be the most a female ever has. However, a unique type of cell called female germline stem cells (FGSCs), also known as oogonial stem cells or egg precursor cells, have been found to contain the ability to renew and mature into different cell types, including oocytes. 

This has led to recent research — albeit controversial — arguing that, because females from other species, ranging from fruit flies to rodents to primates, can use their pool of FGSCs as a source of new oocytes, humans may be able to, as well. If the ability to isolate and promote the growth and development of FGSCs in humans is confirmed, it will provide a groundbreaking way to treat female infertility in women of older age.

But, researchers aren’t quite sure yet how these cells can be utilized to preserve or restore female fertility. Plus, FGSCs are susceptible to the typical insults and injuries that other cells experience with age, including damage from oxidative stress — the buildup of inflammatory compounds called reactive oxygen species (ROS). An accumulation of ROS, combined with increased apoptosis (programmed cell death), can reduce the number of functional FGSCs in the ovaries. 

Saving Female Fertility With Spermidine

One such way to mitigate FGSC aging may be with spermidine, which is found in a variety of foods, including wheat germ, aged cheese, mushrooms, and rice bran. One of spermidine’s best-known functions is its ability to boost autophagy. With advancing age, both our spermidine levels and autophagic abilities decline progressively. This leads to a buildup of dysfunctional or toxic cells and proteins, increasing the risk of chronic diseases and other age-related bodily changes —  including infertility.

Because ovarian aging is affected by oxidative stress, Yuan and colleagues tested if spermidine could protect against this cellular damage to preserve female fertility. The research team isolated FGSCs from mice and characterized how the cells responded to spermidine over 24 hours. Compared to untreated cells, the spermidine-treated FGSCs experienced a significant increase in both number and viability. These beneficial results are likely due to spermidine’s autophagic abilities, which act as a protective mechanism for cell survival. 

The researchers verified spermidine’s effects on autophagy by measuring the activity of several proteins and genes known to be involved with these cellular recycling processes — all of which were increased after adding spermidine to the FGSC cultures. Plus, the spermidine-treated cells had boosted activity of genes related to cellular and ovarian follicle development, cell growth regulation, and inhibition of apoptosis — a kamikaze-like programmed cell crash — consistent with the previous experiment that showed spermidine to increase the growth and viability of FGSCs. 

Yuan and colleagues reflect on the significance of these results, stating, “The viability of FGSCs plays a critical role in maintenance of normal oogenesis [the process of mature female sex cells, or ova, developing from germ cells], which is important for determining a young state of the body. Therefore, maintaining the vitality of germline stem cells can not only increase fertility, but also play an important role in delaying the aging process.” 

Lastly, the research team looked at how FGSCs react in the face of oxidative stress, which was induced by adding the compound hydrogen peroxide to the cell cultures — and how spermidine works to mitigate this damage. Spermidine was added to the FGSC cultures either 24 hours before hydrogen peroxide was included, or immediately after the oxidative stress was induced. While both groups did show reduced markers of cellular senescence — the irreversible growth arrest of cells that contributes to aging — the cells that received spermidine before the oxidative damage was done showed the greatest ability to resist oxidative stress and fight senescence. 

The Controversial Future of Female Germline Stem Cells

As spermidine is a natural autophagy inducer with no known side effects — and has also been shown to improve cognition and cardiovascular health and possibly even extend lifespan — many researchers are hopeful that this compound will also be a therapeutic option for preserving female fertility with age.

However, as this study was done in the lab, and used mouse cells instead of human cells, we can’t say for sure if spermidine will benefit adult female fertility. Plus, as the debate over the existence of human ovarian FGSCs is still ongoing, there is likely still a long way to go before this research could be meaningfully applied to human infertility treatment. 

But, the researchers on this study are optimistic, and suggest that spermidine’s ability to promote autophagy and mitigate oxidative stress could be used as an anti-aging treatment, regardless of its application to fertility. 

Yuan and colleagues conclude, “Our research on [spermidine] improving aging of FGSCs caused by [hydrogen peroxide] will provide a good direction for searching for clinical therapeutic drugs to maintain intracellular homeostasis in the future. Because of the unique characteristics of [spermidine] (naturally non-toxic, drug efficacy with tissue specificity, and a dietary nutrient), it is likely to be used as an anti-aging drug in the future.”

References:

Hanna CB, Hennebold JD. Ovarian germline stem cells: an unlimited source of oocytes?. Fertil Steril. 2014;101(1):20-30. doi:10.1016/j.fertnstert.2013.11.009

Martin JJ, Woods DC, Tilly JL. Implications and Current Limitations of Oogenesis from Female Germline or Oogonial Stem Cells in Adult Mammalian Ovaries. Cells. 2019;8(2):93. Published 2019 Jan 28. doi:10.3390/cells8020093

Yuan X, Tian GG, Pei X, Hu X, Wu J. 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 Biosci. 2021;11(1):107. Published 2021 Jun 7. doi:10.1186/s13578-021-00614-4