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<p>Sperm aging impacts male fertility and offspring health, highlighting the need for reliable aging biomarkers to guide reproductive decisions. However, the molecular determinants of sperm fitness during aging remain ill-defined. Here, we profiled sperm small non-coding RNAs (sncRNAs) using PANDORA-seq, which overcomes RNA modification–induced detection bias to capture previously undetectable sncRNA species associated with mouse and human spermatozoa throughout the lifespan. We identified an “aging cliff” in mouse sperm RNA profiles—a sharp age-specific transition marked by significant shifts in genomic and mitochondrial tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs). Notably, rsRNAs in mouse&#xa0;sperm heads exhibited a transformative length shift, with longer rsRNAs increasing and shorter ones decreasing with age, suggesting altered biogenesis or processing with age. Remarkably, this sperm head-specific shift in rsRNA length was consistently observed in two independent human aging cohorts. Moreover, transfecting a combination of tsRNAs and rsRNAs resembling the RNA species in aged sperm was able to induce transcriptomic changes in mouse embryonic stem cells, impacting metabolism and neurodegeneration pathways, mirroring the phenotypes observed in offspring fathered by aged sperm. These findings provide novel insights into longitudinal dynamics of sncRNAs during sperm aging, highlighting an rsRNA length shift conserved in mice and humans.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月20日

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  • Junchao Shi,
  • Xudong Zhang,
  • Chen Cai,
  • Shichao Liu,
  • Jiancheng Yu,
  • Emma R James,
  • Lihua Liu,
  • Benjamin R Emery,
  • Megan R McMurray Bires,
  • Elizabeth Torres-Arce,
  • Hukam C Rawal,
  • Joemy Ramsay,
  • Jason Kunisaki,
  • Changcheng Zhou,
  • David S Milstone,
  • Mary Elizabeth Patti,
  • Xiaoxu Yang,
  • Tim G Jenkins,
  • Aaron Quinlan,
  • Bradley R Cairns,
  • Paul Schimmel,
  • James M Hotaling,
  • Kenneth I Aston,
  • Tong Zhou,
  • Qi Chen

摘要

Sperm aging impacts male fertility and offspring health, highlighting the need for reliable aging biomarkers to guide reproductive decisions. However, the molecular determinants of sperm fitness during aging remain ill-defined. Here, we profiled sperm small non-coding RNAs (sncRNAs) using PANDORA-seq, which overcomes RNA modification–induced detection bias to capture previously undetectable sncRNA species associated with mouse and human spermatozoa throughout the lifespan. We identified an “aging cliff” in mouse sperm RNA profiles—a sharp age-specific transition marked by significant shifts in genomic and mitochondrial tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs). Notably, rsRNAs in mouse sperm heads exhibited a transformative length shift, with longer rsRNAs increasing and shorter ones decreasing with age, suggesting altered biogenesis or processing with age. Remarkably, this sperm head-specific shift in rsRNA length was consistently observed in two independent human aging cohorts. Moreover, transfecting a combination of tsRNAs and rsRNAs resembling the RNA species in aged sperm was able to induce transcriptomic changes in mouse embryonic stem cells, impacting metabolism and neurodegeneration pathways, mirroring the phenotypes observed in offspring fathered by aged sperm. These findings provide novel insights into longitudinal dynamics of sncRNAs during sperm aging, highlighting an rsRNA length shift conserved in mice and humans.