News | New Clue to Risks of Advanced Paternal Age: Key Changes Occur in Sperm RNA, Not DNA
As men delay fatherhood, growing evidence links advanced paternal age with increased risks such as obesity and stillbirth in offspring, but the biological mechanisms have remained unclear. A new study led by University of Utah Health identifies a previously overlooked factor: RNA molecules in sperm that change with age.
Published recently in The EMBO Journal, the study found systematic age-related changes in sperm RNA in both mice and humans, with a marked, rapid shift in middle age. These molecules, called “old RNA” by the researchers, appear able to reshape cellular metabolism, offering a possible molecular explanation for health risks associated with later fatherhood.
“It is like discovering a molecular clock that keeps time in both mice and humans,” said co-corresponding author Qi Chen, associate professor of urology and human genetics at University of Utah Health. “Gradual changes in RNA length may accumulate quietly before triggering a cliff-like shift in middle age.”
Past research on paternal age and offspring health has focused mainly on sperm DNA fragmentation and mutations. Yet sperm also carries many RNA molecules involved in regulating early embryonic development. Chen’s team previously showed that environmental factors such as paternal diet can alter sperm RNA and affect the next generation, but conventional sequencing has struggled to detect the most important RNA types.
The researchers therefore developed PANDORA-seq, an advanced RNA sequencing method that systematically detects previously “invisible” sperm RNA. In mouse sperm, they found a dramatic change in RNA composition between about 50 and 70 weeks of age—an “aging cliff.” They also observed a slower, continuous trend: some sperm RNA fragments became longer with age, while shorter fragments declined.
“This seemed counterintuitive,” Chen said. “We already knew that sperm DNA becomes more fragmented with age and expected the same of RNA. Instead, certain sperm RNAs become longer.”
Importantly, these RNA changes were more than molecular markers. When researchers introduced a set of “old RNAs” into mouse embryonic stem cells, which biologically resemble early embryos, gene expression changed significantly, especially in pathways related to metabolism and neurodegenerative disease. This suggests sperm RNA may shape long-term health risks in offspring by influencing early embryonic metabolic programming.
The key signal appeared only when RNA from isolated sperm heads was analyzed. The sperm head delivers genetic material and RNA to the egg, while noisier RNA from the tail obscured the pattern. Co-corresponding author Tong Zhou, associate professor at the University of Nevada, Reno School of Medicine, said separating and sequencing sperm heads enabled this distinctive change in RNA length to be detected for the first time.
Using University of Utah Health clinical and research resources, the team then validated the findings in human sperm samples and confirmed an RNA aging pattern highly consistent with that in mice. Kenneth Aston, director of the University of Utah Andrology and IVF Laboratories, called this cross-species validation an important breakthrough.
The discovery may also have clinical potential. James M. Hotaling, chief innovation officer at University of Utah Health, said PANDORA-seq offers a new tool for future male fertility assessment: “These findings could support better-informed reproductive decisions for older men and ultimately improve reproductive outcomes.”
The team will next identify the enzymes driving these RNA changes. Chen said that if the key enzymes can be defined, they may become intervention targets and offer a new biological route to improving sperm quality in older men.
Story source:
Collected online
Published 2026-01-21
This article was prepared with AI assistance and reviewed by our editorial team before publication.
This content is for informational purposes only and does not constitute medical advice. Please consult a licensed physician. Content guidelines & editorial policy
News | New clue to risks of older fatherhood: key changes occur in sperm RNA, not DNA
News | New Clue to Risks of Advanced Paternal Age: Key Changes Occur in Sperm RNA, Not DNA
As men delay fatherhood, growing evidence links advanced paternal age with increased risks such as obesity and stillbirth in offspring, but the biological mechanisms have remained unclear. A new study led by University of Utah Health identifies a previously overlooked factor: RNA molecules in sperm that change with age.
Published recently in The EMBO Journal, the study found systematic age-related changes in sperm RNA in both mice and humans, with a marked, rapid shift in middle age. These molecules, called “old RNA” by the researchers, appear able to reshape cellular metabolism, offering a possible molecular explanation for health risks associated with later fatherhood.
“It is like discovering a molecular clock that keeps time in both mice and humans,” said co-corresponding author Qi Chen, associate professor of urology and human genetics at University of Utah Health. “Gradual changes in RNA length may accumulate quietly before triggering a cliff-like shift in middle age.”
Past research on paternal age and offspring health has focused mainly on sperm DNA fragmentation and mutations. Yet sperm also carries many RNA molecules involved in regulating early embryonic development. Chen’s team previously showed that environmental factors such as paternal diet can alter sperm RNA and affect the next generation, but conventional sequencing has struggled to detect the most important RNA types.
The researchers therefore developed PANDORA-seq, an advanced RNA sequencing method that systematically detects previously “invisible” sperm RNA. In mouse sperm, they found a dramatic change in RNA composition between about 50 and 70 weeks of age—an “aging cliff.” They also observed a slower, continuous trend: some sperm RNA fragments became longer with age, while shorter fragments declined.
“This seemed counterintuitive,” Chen said. “We already knew that sperm DNA becomes more fragmented with age and expected the same of RNA. Instead, certain sperm RNAs become longer.”
Importantly, these RNA changes were more than molecular markers. When researchers introduced a set of “old RNAs” into mouse embryonic stem cells, which biologically resemble early embryos, gene expression changed significantly, especially in pathways related to metabolism and neurodegenerative disease. This suggests sperm RNA may shape long-term health risks in offspring by influencing early embryonic metabolic programming.
The key signal appeared only when RNA from isolated sperm heads was analyzed. The sperm head delivers genetic material and RNA to the egg, while noisier RNA from the tail obscured the pattern. Co-corresponding author Tong Zhou, associate professor at the University of Nevada, Reno School of Medicine, said separating and sequencing sperm heads enabled this distinctive change in RNA length to be detected for the first time.
Using University of Utah Health clinical and research resources, the team then validated the findings in human sperm samples and confirmed an RNA aging pattern highly consistent with that in mice. Kenneth Aston, director of the University of Utah Andrology and IVF Laboratories, called this cross-species validation an important breakthrough.
The discovery may also have clinical potential. James M. Hotaling, chief innovation officer at University of Utah Health, said PANDORA-seq offers a new tool for future male fertility assessment: “These findings could support better-informed reproductive decisions for older men and ultimately improve reproductive outcomes.”
The team will next identify the enzymes driving these RNA changes. Chen said that if the key enzymes can be defined, they may become intervention targets and offer a new biological route to improving sperm quality in older men.
Story source:
Collected online