Softer ovaries extend the fertility window in rats, IL-11 blockade reduces stiffness, doubles conception
As women age, their ovaries become progressively stiffer. With that stiffness comes a decline in follicle development, hormone production, and ultimately fertility, a process that, for most women, culminates in menopause around age 50. A team from Tongji Medical College at Huazhong University of Science and Technology in Wuhan, China, has now identified a key molecular driver of that stiffening process, and shown that blocking it can dramatically reverse the fertility decline in aged rodents.
The study, published July 2 in Nature Aging, reports that silencing the gene for interleukin-11 (IL-11), a pro-fibrotic signaling protein, reduces ovarian matrix stiffness by 36% in mice. In rats, the treatment doubled conception rates and increased average litter size fivefold, from approximately 1 pup to approximately 5.
The mechanism: from fibrosis to fertility
The team, led by Jinjin Zhang, Shixuan Wang, Jun Dai, Yan Li, and Wenwen Wang, began with a cross-species observation: IL-11 levels increase with age in the ovaries of mice, rats, and humans. Examining human ovarian tissue samples across age groups (young, ages 18–28; middle, ages 35–42; older, ages 47–52), they found that ovarian stiffness measured by atomic force microscopy increased with age in parallel with IL-11 expression.
The causal chain, the team showed, runs through ovarian fibroblasts. IL-11 activates these cells into myofibroblasts via the ERK1/2 signaling pathway, causing them to secrete excessive extracellular matrix, particularly collagen I and collagen III. The accumulating collagen stiffens the ovarian stroma, which in turn impairs follicle development, reduces estradiol and progesterone secretion, disrupts estrous cycles, and lowers ovulation rates.
Blocking IL-11, either through genetic knockout of its receptor (Il11ra1⁻/⁻) or through siRNA nanoparticles delivered intravenously, broke this chain. With less IL-11 signaling, fewer fibroblasts became activated, less collagen was deposited, and the ovaries remained softer.
The numbers
In 36-week-old mice (roughly equivalent to human late 30s to early 40s), four weeks of twice-weekly intravenous siRNA against IL-11:
- Reduced ovarian matrix stiffness by approximately 36%
- Increased the conception rate from 25% to 50%
- Increased average litter size from approximately 3 pups to approximately 5
In 40-week-old rats, the results were even more striking:
- Conception rate rose from 20% (1 in 5) to 50% (5 in 10)
- Average litter size rose from approximately 1 to approximately 5, a fivefold increase
The team confirmed the effect was ovary-intrinsic by locally injecting an AAV-delivered short hairpin RNA against the IL-11 receptor into the ovarian bursa, producing similar results without systemic exposure, suggesting the mechanism operates locally within the ovary, not through broader systemic changes.
IL-11 as a specific target
IL-11 sits downstream of TGFβ1, a well-known master regulator of fibrosis. But TGFβ1 controls such a broad range of cellular processes that blocking it systemically causes serious side effects. IL-11, as a more specific downstream effector of fibrotic signaling in fibroblasts, presents a more druggable target, one that is already being pursued clinically for fibrotic diseases of the heart and lung through anti-IL-11 biologics in clinical trials.
Human ovarian tissue data in the study confirmed that IL-11 expression rises with age in women. Shear-wave elastography measurements showed, for example, that an ovary from a 41-year-old woman had a stiffness of approximately 30 kPa compared with approximately 16 kPa for a 31-year-old.
Caveats
The study is entirely preclinical. No human trials of IL-11 blockade for ovarian aging have been conducted, and significant safety questions remain. IL-11 is expressed in many human tissues, lung, heart, liver, bone, and systemic blockade could cause unintended effects. The siRNA approach used here requires intravenous administration, making chronic therapy less practical than a small-molecule or biologic approach.
The human ovarian tissue data, while valuable, came from women with a history of gynecological cancer whose ovaries were reported as “unaffected”, a population that may not fully represent healthy reproductive aging.
Francesca Duncan of Northwestern University, commenting on the study for New Scientist, noted that the intervention could potentially lead to similar outcomes in premenopausal women, but cautioned that the human data came from a specific clinical population. Barbara Vanderhyden of the University of Ottawa highlighted broader implications: prolonging ovarian function could delay menopause-related health impacts beyond fertility, including osteoporosis and heart disease.
For now, the work establishes a clear molecular target and a proof of principle: that pharmacological softening of the ovary is a viable strategy for delaying reproductive aging.
Sources:
1. Wu, M., Zhu, Q., Xiong, J. et al. “Modulating IL-11-dependent matrix stiffness to delay ovarian aging.” Nature Aging (2026). DOI: 10.1038/s43587-026-01159-2
2. Cook, S.A. “Targeting interleukin-11 to slow ovarian aging.” Nature Aging News & Views (2026). DOI: 10.1038/s43587-026-01137-8
3. Thompson, T. “Our fertility window could be extended by making ovaries softer.” New Scientist, July 8, 2026. https://www.newscientist.com/article/2533507-our-fertility-window-could-be-extended-by-making-ovaries-softer/