As ovaries age, their supporting tissue becomes stiffer, and slowing that process may be key to extending fertility.
The space between cells isn't just an empty void: it's more like a jelly bath, rich with proteins and other molecules that support the cells suspended within.
It's also the medium through which important chemical and mechanical signals are transmitted between cells.
Scientists call it the extracellular matrix.
The consistency of this matrix is not the same throughout the ovary.
The primordial follicles are structures within the ovary that hold small primary oocytes, as they wait for their turn to become fully-fledged eggs.
These follicles lack any blood supply, and their only contact with other cells is via the extracellular matrix.
To protect these follicles until they're needed, the extracellular matrix is kept stiff and tightly controlled.
Meanwhile, around follicles that are ready for their big moment, the extracellular matrix is softened, so the cells involved can receive the nutrients they need, and to give them room to grow.
There are many different experiences that can impact the aging of the ovary, with oxidative stress and chronic inflammation being some of the prime candidates.
Studies have shown that, several decades into life, the ovaries begin to show wear and tear from these cumulative experiences: fibrosis – a buildup of scar tissue, and stiffening of the ovarian matrix as collagen accumulates.
That stiffening has a detrimental effect on egg development, and could be part of why menopause kicks in when it does.
Now, a team led by scientists from Huazhong University of Science and Technology in China has demonstrated a way to keep the ovarian matrix more flexible – in mice, at least.
This discovery could lead to treatments that potentially postpone menopause, extending people's reproductive years. It involves a secreted signaling protein called interleukin 11 (IL-11).
"The increase in ovarian matrix stiffness is critically dependent on IL-11," the study's authors explain in their paper, published in Nature Aging.
"Notably, blocking the IL-11 pathway can reduce the ovarian matrix stiffness and improve ovarian function in aging individuals, as well as in the presence of various pathological mediators, indicating that this common cellular program can be triggered in response to ovarian injury from diverse causes."
First, they explored what signs of ovarian aging might look like in humans.
They collected samples of healthy ovaries from volunteers who were having their uterus or ovaries removed due to cervical or endometrial cancer, grouped into reproductively young (18–28 years), middle‑aged (35–42 years) and older (47–52 years).
These ovaries did not contain the cancer, which was located elsewhere in the reproductive tract.
They also collected ovarian tissue samples from volunteers aged 30–40 whose ovaries were dysfunctional due to chemotherapy-induced premature ovarian insufficiency (POI), polyendocrine metabolic ovarian syndrome (PMOS), and ovarian endometriosis.
This revealed that some markers of ovarian aging – as well as conditions that may impact the reproductive function of the ovaries, such as chemotherapy-induced POI, PMOS, and ovarian endometriosis – are associated with an increase in the stiffness of the ovarian matrix.
"Hallmarks of ovarian aging drive fibrotic remodeling and matrix stiffening through intertwined pathways, which in turn accelerates ovarian aging, creating a vicious cycle," the authors note, referencing past studies in mice.
The team used RNA sequencing and proteomics on human ovarian samples to identify molecules that might be responsible for activating the fibroblasts that stiffen the ovary, which led them to IL‑11 and Il11ra1 – a gene that encodes an IL-11 receptor component.
Remarkably, IL-11 expression in the ovary increased with age not only in mice, but also in rats and, importantly, in humans.
"We found that aging, chemotherapy, PCOS, and endometriosis all lead to the secretion of IL-11 in the ovaries, causing an increase in matrix stiffness," they report.
The researchers then inhibited IL-11 signaling in mice, first by deleting the gene and then with a more treatment-like approach – using RNA-loaded nanoparticles designed to reduce the protein.
Ovarian stiffness and collagen buildup in the mice were reduced, and they produced more pups per pregnancy.
We're still a long way off seeing this research translated into a treatment that could help humans improve their chances of having children. But clinical trials for anti-IL-11 treatments for other health conditions are already underway.
"Perhaps anti-IL-11 therapy may be trialed to prevent chemotherapy-induced premature ovarian insufficiency and/or to treat polycystic ovary syndrome," writes biomedical researcher Stuart Cook, who was not involved in the study, in an accompanying News & Views article for Nature.
Related: Ovaries Appear to Develop an Incredible Second Role After Menopause
For the tens of millions worldwide impacted by infertility, it's tentatively hopeful news.
"Blocking IL-11 signaling in both physiological ovarian aging model and various pathological ovarian dysfunction models holds significant therapeutic potential for improving ovarian function," the study authors write.
The research was published in Nature Aging.
This article was fact-checked by Carly Cassella and edited by Rebecca Dyer. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.