Advanced paternal age has been linked to greater offspring health risks like obesity and stillbirth, yet the mechanisms driving this increased risk remain unclear. While studies have examined age-related DNA changes in sperm, RNAs carried by sperm have received less focus until now. New research from University of Utah Health has found that the RNA contents of sperm go through similar shifts over time in both mice and humans. In addition, “old RNA” seems to change cells’ metabolism—potentially contributing to the health risks of having kids later in life.
Central to the study is PANDORA-seq, an advanced RNA sequencing method created to reveal previously undetectable sperm RNA populations. Standard techniques lacked the sensitivity to capture these molecules. Applying PANDORA-seq to mouse sperm exposed an “aging cliff”—a dramatic RNA content transition between 50 and 70 weeks of age. The method also detected a molecular clock effect, where longer RNA fragments increased and shorter ones decreased over time. Human sperm showed the same pattern.
Qi Chen, senior author of the study published in The EMBO Journal, observed, “It's like finding a molecular clock that ticks with age in both mice and humans, suggesting a fundamental, conserved molecular signature of sperm aging.” He further notes, “Maybe this progressive length shift accumulates quietly, until it triggers the ‘cliff’ change at mid-life.”
This result runs contrary to expectations based on DNA. “At first glance, this finding seems counterintuitive,” Chen says. “For decades, we have known that as sperm age, their DNA becomes more fragmented and broken. One might expect RNA to follow this pattern. Instead, we found the opposite: specific sperm RNAs actually become longer with age.”
PANDORA-seq succeeded by targeting RNA from sperm heads, the part transferred to the egg. According to co-author Tong Zhou “This rsRNA length shift was a unique signal, specific to the sperm heads. It was obscured by the 'noisier' profile of the whole sperm.” Earlier whole-sperm sequencing had hidden this detail.
Experiments injecting “old RNA” into mouse embryonic stem cells produced gene expression changes linked to metabolism and neurodegeneration. These alterations suggest a way aged RNA might influence the next generation’s health.
“This discovery, made possible by PANDORA-seq, could lay the groundwork for future diagnostics to help guide informed reproductive decisions and improve fertility outcomes,” explains co-author James M. Hotaling.
Publication details: Shi, J., Zhang, X., Cai, C. et al. Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging. EMBO J (2026). https://doi.org/10.1038/s44318-025-00687-8
Central to the study is PANDORA-seq, an advanced RNA sequencing method created to reveal previously undetectable sperm RNA populations. Standard techniques lacked the sensitivity to capture these molecules. Applying PANDORA-seq to mouse sperm exposed an “aging cliff”—a dramatic RNA content transition between 50 and 70 weeks of age. The method also detected a molecular clock effect, where longer RNA fragments increased and shorter ones decreased over time. Human sperm showed the same pattern.
Qi Chen, senior author of the study published in The EMBO Journal, observed, “It's like finding a molecular clock that ticks with age in both mice and humans, suggesting a fundamental, conserved molecular signature of sperm aging.” He further notes, “Maybe this progressive length shift accumulates quietly, until it triggers the ‘cliff’ change at mid-life.”
This result runs contrary to expectations based on DNA. “At first glance, this finding seems counterintuitive,” Chen says. “For decades, we have known that as sperm age, their DNA becomes more fragmented and broken. One might expect RNA to follow this pattern. Instead, we found the opposite: specific sperm RNAs actually become longer with age.”
PANDORA-seq succeeded by targeting RNA from sperm heads, the part transferred to the egg. According to co-author Tong Zhou “This rsRNA length shift was a unique signal, specific to the sperm heads. It was obscured by the 'noisier' profile of the whole sperm.” Earlier whole-sperm sequencing had hidden this detail.
Experiments injecting “old RNA” into mouse embryonic stem cells produced gene expression changes linked to metabolism and neurodegeneration. These alterations suggest a way aged RNA might influence the next generation’s health.
“This discovery, made possible by PANDORA-seq, could lay the groundwork for future diagnostics to help guide informed reproductive decisions and improve fertility outcomes,” explains co-author James M. Hotaling.
Publication details: Shi, J., Zhang, X., Cai, C. et al. Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging. EMBO J (2026). https://doi.org/10.1038/s44318-025-00687-8