Research has increasingly shown that as fathers grow older, the risk of health problems in their children rises, including higher chances of obesity and stillbirth. Although this association has been documented for years, the biological reasons behind it have remained largely unresolved. Most studies have concentrated on age-related damage to DNA within sperm, assuming this to be the primary driver of risk. Yet sperm cells contain far more than genetic code alone, and scientists are now turning their attention to other molecular components that may influence development in the next generation.
Among these components are RNAs, a diverse group of molecules that help regulate how genes function. New research from the University of Utah Health has revealed that the RNA carried by sperm changes steadily as males age, both in mice and in humans. Rather than shifting gradually in a smooth, linear fashion, these changes appear to build up quietly before reaching a dramatic turning point around midlife. This pattern suggests that sperm carry an internal biological timer, one that records the passage of time at the molecular level.
Qi Chen, MD, PhD, associate professor of urology and human genetics and a senior author of the study, describes this phenomenon as a conserved molecular clock shared across species. According to Chen, subtle changes in RNA accumulate over many years until they eventually trigger a sudden transition, comparable to stepping off a cliff. This discovery implies that sperm ageing is not merely a slow decline but involves a critical threshold beyond which molecular characteristics shift rapidly. The findings were reported in The EMBO Journal.
Previous research from Chen’s laboratory had already demonstrated that sperm RNA can be influenced by a father’s environment, including dietary factors, and that these changes can affect offspring’s health. However, many of the most influential RNA molecules are difficult to detect using conventional sequencing methods. To address this challenge, the research team developed a specialised technique known as PANDORA-seq, which allows scientists to detect RNA species that were previously invisible. Using this approach in mice, they identified a striking change in sperm RNA composition between 50 and 70 weeks of age, alongside a steady increase in the length of specific RNA fragments over time.
This finding was unexpected, as ageing sperm DNA is known to become increasingly fragmented and damaged. Researchers had assumed RNA would follow a similar pattern of breakdown. Instead, they observed the opposite trend: certain RNA molecules actually became longer with age. When these “old” RNAs were introduced into mouse embryonic stem cells, the cells showed altered gene expression linked to metabolism and neurodegeneration. These changes hint at a potential mechanism through which ageing sperm RNA could influence early development and long-term health outcomes in offspring.
Importantly, the researchers found that these RNA patterns were only clearly visible when analysing RNA from the sperm head alone, the part of the cell that delivers its contents to the egg. RNA from the sperm tail obscured the signal, masking the ageing pattern until now. Using clinical and research resources, the team confirmed that the same RNA shifts seen in mice also occur in humans. Future work will focus on identifying the enzymes responsible for driving these changes, with the hope that they could one day become targets for interventions aimed at improving sperm quality in ageing males.
More information: Junchao Shi et al, Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging, The EMBO Journal. DOI: 10.1038/s44318-025-00687-8
Journal information: The EMBO Journal Provided by University of Utah Health
