As the ovaries grow older, the tissue that supports them gradually becomes stiffer, and researchers believe that slowing this change could help preserve fertility for longer.
The area surrounding cells is far from empty. Instead, it resembles a gel-like environment filled with proteins and other molecules that provide structural support and nourishment to the cells.
How the Extracellular Environment Enables Cell Signaling
This extracellular environment also serves as a pathway for vital chemical and mechanical signals that enable cells to communicate with one another.
Scientists refer to this supportive network as the extracellular matrix.
Within the ovary, the extracellular matrix does not have a uniform texture or stiffness. Instead, its properties vary across different regions.
Primordial follicles are ovarian structures containing immature eggs that remain dormant until development begins.
The Unique Microenvironment of Ovarian Follicles
These follicles have no direct blood supply and interact with surrounding tissues only through the extracellular matrix.
To preserve them in this resting state, the extracellular matrix remains firm and carefully regulated, providing a protective environment.
In contrast, the extracellular matrix surrounding developing follicles becomes more flexible. This allows nutrients to reach the growing cells and creates the space needed for the follicles to expand and mature.
A variety of factors contribute to ovarian aging, with oxidative stress and chronic inflammation considered among the most significant.
Research has shown that, over the course of several decades, the ovaries accumulate damage from these ongoing stresses. This damage is characterized by fibrosis—the formation of excess scar tissue—and increased stiffness of the ovarian extracellular matrix due to collagen buildup.
As the ovarian matrix becomes stiffer, it creates a less favorable environment for egg development, which may help explain the onset of menopause.
Building on this understanding, researchers at Huazhong University of Science and Technology in China have identified a method to preserve the flexibility of the ovarian matrix in mice.
IL-11 as a Potential Target for Extending Ovarian Lifespan
Their findings suggest a potential strategy for delaying menopause and extending reproductive lifespan. The approach targets interleukin-11 (IL-11), a signaling protein that regulates changes in the ovarian matrix.
“The researchers report that the rise in ovarian matrix stiffness is largely driven by IL-11,” according to their study published in Nature Aging.
Blocking IL-11 signaling may reduce ovarian stiffness and restore function in aging and disease.
To begin their investigation, the team examined the biological characteristics of ovarian aging in humans.
They analyzed healthy ovarian tissue from cancer surgery patients across three age groups: young (18–28), middle-aged (35–42), and older (47–52).
Importantly, the ovarian samples themselves were free of cancer, as the malignancy was located in other parts of the reproductive tract.
They also analyzed ovarian tissue from 30–40-year-old volunteers with impaired ovarian function due to conditions including chemotherapy-induced POI, PMOS, and endometriosis.
The Impact of Aging and Disease on Ovarian Tissue Architecture
The findings linked ovarian aging and disorders like chemotherapy-induced POI, PMOS, and endometriosis to increased ovarian matrix stiffness.
The authors explain that ovarian aging features promote fibrotic changes and matrix stiffening through interconnected mechanisms. This increased stiffness then further contributes to ovarian aging, forming a self-reinforcing cycle, as previously observed in mouse studies.
The researchers used RNA sequencing and proteomic analyses of human ovarian tissue to identify molecules that activate fibroblasts involved in ovarian stiffening. This investigation pointed to IL-11 and Il11ra1, a gene that encodes a component of the IL-11 receptor, as key candidates.
Notably, ovarian IL-11 levels increased with age across multiple species, including mice, rats, and, most significantly, humans.
Ovarian Stressors Trigger IL-11 Production and Tissue Stiffening
Aging, chemotherapy, PCOS, and endometriosis increase ovarian IL-11 production, driving extracellular matrix stiffness.
The team blocked IL-11 signaling in mice by removing the gene or using RNA nanoparticles to reduce IL-11 production.
IL-11 inhibition reduced ovarian stiffness and collagen buildup and improved reproductive outcomes, including larger litters.
Although translating these findings into a human fertility treatment will require substantial further research, anti-IL-11 therapies are already being evaluated in clinical trials for other medical conditions.
Stuart Cook, a biomedical researcher not involved in the study, suggested in a Nature News & Views article that anti-IL-11 therapy could be explored to prevent chemotherapy-induced premature ovarian insufficiency or treat polycystic ovary syndrome.
Read the original article on: sciencealert
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