In August, 2023, AthenaDAO announced their commitment to combat ovarian aging, by dedicating $120,000 to Dr. Mario Cordero at Pablo de Olavide University. Not only was the preliminary science promising, but Dr. Cordero's own journey through fertility struggles, combined with his genuine desire to connect with the community he aimed to serve demonstrated a clear alignment in values. Since then, Dr. Cordero has been hard at work generating data, and we’re happy to let you know that things have gone well!
In order to continue this important work, Dr. Cordero, together with AthenaDAO, is looking to the community for support in raising $75k to fund the next milestones. Before we look too far ahead, we thought we’d walk you through the most recent results.
Fertility 101
Fertility often influences major life decisions and future planning. Estimates suggest that one in six people experience fertility issues during their lifetime - a challenge that people usually bear privately behind closed doors, feeling isolated and confused. With no clear biomarkers to indicate how many eggs a woman has or how much time she has left to conceive, decisions about family planning can feel like a race against an invisible clock. This isn’t just about reproduction—it’s about choice. The ability to make informed decisions about when to start a family, or whether to start one at all, is crucial for many women. Even beyond fertility, ovarian aging also impacts the onset of menopause, a life-altering transition that many women may be unprepared for.
What is Ovarian Aging?
Ovarian aging is the gradual decline of the processes that maintain fertility over time. As women age, their ovarian reserve—the number of viable eggs—naturally diminishes. But this decline isn’t the same for everyone. Some women experience a faster depletion, known as diminished ovarian reserve (DOR), where fertility declines earlier than expected. This can lead to fewer reproductive options for those affected.
At birth, women have around 1-2 million eggs, but by the time they reach menopause (around age 51), only about 1,000 remain. The most significant drop in egg quality and quantity occurs between the ages of 35 and 40, contributing to reduced fertility, a higher risk of miscarriage, and an increased chance of genetic issues in embryos. Globally, millions of women are affected by this decline, with many experiencing these challenges well before the average age due to conditions like DOR.
Factors that can cause ovarian aging to occur prematurely include genetics, autoimmune disorders, certain medical treatments (like chemotherapy), and environmental exposures. These influences can fast-track the decline, often leading to fertility challenges in women as early as their late 20s or early 30s.
Understanding ovarian aging is vital for women who want to take control of their fertility and make informed choices about their future. It’s also crucial for the doctors and specialists who support them in navigating these deeply personal decisions. By recognizing the signs early and raising awareness, we can help women explore their options sooner and find ways to preserve their fertility for when they’re ready.
Tracking Ovarian Health
One key biomarker often used to track ovarian health is Anti-Müllerian Hormone (AMH), a hormone produced by cells in the ovary. As the ovarian reserves drop, so do the AMH levels, providing insights into how quickly time is catching up with a woman’s reproductive ability. But AMH isn’t the only clue! Another key hormone, Follicle-Stimulating Hormone (FSH), rises as the ovaries become less responsive to its signals, consequently, prompting the brain to pump out more FSH in an attempt to maintain fertility. This ultimately leads to a cycle of increasing FSH levels, indicating a declining ovarian reserve and reduced fertility, which results in fewer healthy follicles developing into viable eggs. In addition, these hormonal changes don’t happen in isolation. The ovaries themselves also undergo structural changes, leading to fewer healthy follicles developing into viable eggs. Together, these biomarkers form a roadmap of ovarian aging, one that researchers like Dr. Mario Cordero are actively working to understand, in an effort to uncover novel treatments.
Until now, the process of ovarian aging has seemed like a predestined path, unable to be disrupted. However, what if there were ways to change direction? What if we could slow down this process? During research funded by the AthenaDAO community, Dr. Mario Cordero uncovered a surprising biological pathway, which may hold the key to new treatments. The pathway, known for its role in immune response, is called the cGAS-STING pathway.
The Role of the cGAS-STING Pathway in Ovarian Aging
Emerging research shows that the cGAS-STING pathway might be a major cause of inflammation and tissue damage in aging ovaries. In both humans and animal models, higher levels of STING have been found in the ovaries, especially in a specific cell type called granulosa cells. These cells are crucial because they help eggs (oocytes) grow and mature, which is key to fertility. When this pathway is overactive in aging ovaries, it leads to increased production of certain inflammatory substances (such as IL-6 and Type I interferons). These substances cause inflammation and gradually reduce the ovaries' ability to function properly. When STING remains active for too long in ovarian cells, it can lead to several problems: the cells may age faster, their energy production can be disrupted, and their DNA can become damaged.
All of these issues can speed up the loss of eggs and simultaneously lower the quality of the remaining ones.
Results from Dr. Cordero’s research so far
This research was designed to look at how the cGAS-STING pathway might be linked to aging in the ovaries and how it affects fertility. The researchers also studied how this process might be involved when chemotherapy damages the ovaries. The project was divided into three main parts, called work packages (WP).
WP1: Studying How the cGAS-STING Pathway Affects Aging in Ovaries
In the first part (WP1), the scientists looked at how the cGAS-STING pathway changes as women get older. The first experiments were designed to check whether or not cGAS-STING was involved at all with ovarian aging. If not, then it wouldn’t make sense to pursue further experiments. If yes, then full steam ahead!
They found that the STING protein is more active in older ovaries, which may contribute to the ovaries aging. This was seen in both human and mouse ovaries. They discovered that cells in the ovaries, especially in granulosa cells, are where this process happens most. Both mouse and human samples were tested because mice are often used as model organisms. However, if there was a big difference between the mouse and human data, then it would not be possible to continue using mice to study these effects, and another model organism would need to be chosen.
Since the data showed that mice can be used as a tool to study these effects, Dr. Cordero’s lab continued with their plan, and used a STING knockout model to see what would happen to the ovarian reserves if the STING protein was no longer present. Knockout mice are used to study what happens in an organism when a particular gene is absent.
Dr. Cordero found that mice lacking the STING protein had more eggs and better fertility as they aged. The figure below shows mouse ovaries from ‘normal’ and ‘knockout’ mice, and the white arrows point to more follicles developing in the knockout mouse compared to the normal, wild-type mouse.
Finally, the researchers also found that women with diminished ovarian reserve had higher STING activity in their ovarian cells, as shown by higher levels of STING protein levels in samples from a healthy female compared to samples from a female with DOR.
Together, the results from WP1 suggest that blocking the cGAS-STING pathway might help women keep their fertility longer as they get older.
WP2: Looking at Chemotherapy’s Effect on Ovaries
In the second part (WP2), the researchers wanted to see if the cGAS-STING pathway also plays a role in how chemotherapy damages the ovaries. Early findings showed that chemotherapy increases STING activity in patients.
In experiments with mice, they found that mice without the STING protein were protected from the harmful effects of chemotherapy on their ovaries. This means that blocking the cGAS-STING pathway could help protect women’s ovaries during chemotherapy, potentially saving their fertility while receiving life-saving treatment.
WP3: Creating Therapies to Block the cGAS-STING Pathway
The third part (WP3) was about developing new drugs to block the cGAS-STING pathway. The scientists tested several small molecules and found one, called "A2," that works well at reducing the harmful effects of the cGAS-STING pathway, such as inflammation and cell death. This drug could be helpful in protecting or improving fertility in women as they age or undergo chemotherapy.
It's time to fundraise for the next milestones!
True to the belief in equitable and accessible scientific research, AthenaDAO will be tokenizing the Cordero IP-NFT into Intellectual Property Tokens (IPTs) with the support of Molecule. These tokens enable the distribution of IP rights to holders to both raise funds for continued scientific research and empower the community to govern the resulting IP.
Due to the successful completion of the work packages in the first milestone of the project, Dr. Mario Cordero is looking to raise $75,000 USD to continue the work in milestone 2. With these funds, he is hoping to achieve two clear goals:
- Continue the development of in vitro testing of these newly discovered inhibitors (A2) from WP3
- Test to see what happens when the cGAS-STING pathway is inhibited with Dr. Cordero’s newly developed compounds in animal models with reduced ovarian reserve
Why choose the IPT model?
By giving community members the power to co-develop research projects via IPTs, AthenaDAO is harnessing the potential of decentralized science. As the project moves forward, important decisions—such as which delivery vehicles to test, the best disease indications for clinical trials, and how to raise additional funds—will be guided by the collective expertise of the community. With the power of IP tokenization, the wisdom of the crowd will play a critical role in shaping the future of fertility research.
AthenaDAO will be sharing more details on the crowdsale soon - subscribe to their newsletter, join the community on telegram, or follow on X so you can be the first to know.
Supporting research that matters
At its core, this research is about empowering women with new options for their reproductive health. By tackling ovarian aging at a deeper level, we’re moving closer to a future where the limits of biology can be redefined. We’ve been honored to support Dr. Cordero’s partnership with AthenaDAO, and hope that you’ll join us on this journey.
References:
- Jirge, P. (2016) ‘Poor ovarian reserve’, Journal of Human Reproductive Sciences, 9(2), p. 63. doi:10.4103/0974-1208.183514.
- Moolhuijsen, L.M. and Visser, J.A. (2020) ‘Anti-müllerian hormone and Ovarian Reserve: Update on assessing ovarian function’, The Journal of Clinical Endocrinology & Metabolism, 105(11), pp. 3361–3373. doi:10.1210/clinem/dgaa513.
- Oh, S.R., Choe, S.Y. and Cho, Y.J. (2019) ‘Clinical application of serum anti-Müllerian hormone in women’, Clinical and Experimental Reproductive Medicine, 46(2), pp. 50–59. doi:10.5653/cerm.2019.46.2.50.
- Decout, A. et al. (2021) ‘The CGAS–sting pathway as a therapeutic target in inflammatory diseases’, Nature Reviews Immunology, 21(9), pp. 548–569. doi:10.1038/s41577-021-00524-z.
