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Conserved shifts in sperm small non-coding RNA profiles during mouse and human aging.

Junchao Shi1,2,3, Xudong Zhang1,2, Chen Cai1

  • 1Molecular Medicine Program, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.

The EMBO Journal
|January 20, 2026
PubMed
Summary

Sperm aging involves significant shifts in small RNA profiles, including a conserved length change in ribosomal RNA-derived small RNAs (rsRNAs) in sperm heads. This discovery offers new biomarkers for male reproductive health and aging.

Keywords:
Aging ClockEpigenetic InheritancePaternal Age EffectSperm EpigeneticsSperm RNA Code

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Area of Science:

  • Reproductive Biology
  • Molecular Biology
  • Genomics

Background:

  • Sperm aging affects male fertility and offspring health, but molecular aging mechanisms in sperm are poorly understood.
  • Identifying reliable biomarkers for sperm aging is crucial for reproductive decision-making.

Purpose of the Study:

  • To profile small non-coding RNAs (sncRNAs) in aging mouse and human sperm to identify molecular determinants of sperm fitness.
  • To investigate the impact of aged sperm sncRNAs on embryonic development.

Main Methods:

  • Utilized PANDORA-seq to profile sperm sncRNAs, overcoming RNA modification biases.
  • Analyzed sncRNA profiles across the lifespan in mouse and human sperm.
  • Investigated the functional impact of aged sperm sncRNAs by transfecting them into mouse embryonic stem cells.

Main Results:

  • Identified an "aging cliff" in mouse sperm RNA profiles, characterized by significant shifts in tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs).
  • Observed a conserved age-dependent length shift in sperm head rsRNAs (longer rsRNAs increase, shorter ones decrease) in both mice and humans.
  • Demonstrated that aged sperm sncRNAs can induce transcriptomic changes in embryonic stem cells, affecting metabolism and neurodegeneration pathways.

Conclusions:

  • Sperm sncRNA profiles undergo significant age-related changes, including a conserved rsRNA length shift in sperm heads.
  • These findings provide novel insights into the molecular dynamics of sperm aging and its impact on offspring.
  • The identified rsRNA length shift represents a potential biomarker for male reproductive aging.