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By Lucy Notarantonio
Senior Reporter
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Male fertility is often linked to the health of the testicles, but scientists have discovered another part of the reproductive system may play an equally important role in determining how long men remain fertile as they age.
In a new study published via Protein & Cell, researchers identified a key genetic pathway that helps keep the epididymis—a long, coiled tube where sperm mature and gain the ability to fertilize an egg—healthy over time.
Their findings suggest that when this pathway begins to break down with age, it may contribute to declining fertility.
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One of the study authors, Si Wang, a professor and principal investigator at Xuanwu Hospital Capital Medical University, Beijing, told Newsweek: "Our current data demonstrate that restoring this pathway partially ameliorates epididymal aging-related phenotypes. However, we have not evaluated any alterations in reproductive life span."
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The team also found early evidence that a stem-cell-based treatment could help reverse some of these age-related changes, raising the possibility of new therapies designed to preserve male reproductive health later in life.
Why the Epididymis Matters
While the testicles produce sperm, the epididymis is where sperm undergo their final development. Inside the tube are specialized cells known as "principal cells," which create the ideal environment for sperm to mature and function properly.
Researchers found that these principal cells appear to be particularly vulnerable to aging. Using a technique that examines gene activity in individual cells, they discovered that the cells became increasingly unstable and inflamed as animals grew older.
The Genetic Pathway Linked to Fertility
The study focused on a protein called FOXO1, which has previously been associated with healthy aging and longevity.
Scientists found that levels of FOXO1 drop significantly in aging principal cells. Under normal conditions, FOXO1 switches on another gene called LHX1, which helps protect cells from age-related damage.
When this protective FOXO1-LHX1 pathway breaks down, cells enter a state known as cellular senescence—a process often described as biological aging at the cellular level. Rather than functioning normally, these worn-out cells release inflammatory substances that can damage surrounding tissue and contribute to scarring.
According to the researchers, this deterioration can disrupt the environment sperm need to mature, potentially affecting fertility.
A Potential Way to Reverse the Damage
The team tested a treatment using specialized stem-cell-derived cells and tiny particles they release called exosomes. Exosomes act like biological messengers, carrying signals between cells.
In both mice and primates, the treatment restored FOXO1 levels and reduced the number of aging, damaged cells. It also improved tissue health and increased sperm motility—the ability of sperm to swim effectively, which is crucial for fertilization.
Dr. David Shusterman, a board-certified urologist who was not involved in the study, told Newsweek: "Men should understand that this is early-stage research.
"It does not mean that there is currently a stem-cell or exosome treatment proven to reverse reproductive aging in humans."
A Stanford University study of nearly 170 million U.S. birth records found that the average age of new fathers rose by 3.5 years between 1972 and 2015, reaching 30.9 years old.
Researchers reported that around 9 percent of babies were born to fathers aged 40 or older, highlighting growing interest in how male reproductive health changes with age.
If the human trials are a success, Shusterman, the founder of UroLongevity in New York City, said: "It could eventually lead to treatments designed to preserve the epididymal environment, reduce age-related inflammation and fibrosis, and maintain sperm quality later in life.
"It may also lead to new biomarkers that identify reproductive aging before a standard semen analysis shows a major decline."
He added it may be relevant as more men delay fatherhood.
"We may eventually move from evaluating fertility only after a couple has difficulty conceiving to proactively assessing reproductive aging years earlier," he said.
Update 07/27/26 04:23 a.m. ET: this story has been updated to add comments from Si Wang.
Reference
Huifen Lu, Linguo Cai, DongLiang Lv, Guoqiang Sun, Jinghui Lei, Taixin Ning, Zijuan Xin, Haoyan Huang, Ying Jing, Daoyuan Huang, Shuhui Sun, Shuai Ma, Weiqi Zhang, Fei Gao, Rui Chen, Yingying Qin, Weihong Song, Andy Peng Xiang, Juan Carlos Izpisua Belmonte, Guang-Hui Liu, Jing Qu, Si Wang, Restoring the FOXO1 geroprotective pathway via seno-resistant mesenchymal progenitor cells alleviates primate epididymal aging, Protein & Cell, 2026;, pwag020, https://doi.org/10.1093/procel/pwag020
Contact Newsweek editors on this story: Kara Dolman and Emma Lee-Sang
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