It is well established that the age of the male parent can impact a range of health issues in offspring. Separately, of late researchers have noted that aging produces changes in RNA processing that depend on RNA length. Longer RNA transcripts exhibit greater changes in abundance, for example, which could be characterized as a systemic downregulation biased towards longer RNAs. The work on RNA in aged sperm noted here falls into this line of research, as the data indicates subtly detrimental changes that depend on RNA length. This is again indicative of age-related changes in RNA processing machinery.
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 transfer RNA (tRNA)-derived small RNAs (tsRNAs) and ribosomal RNA (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.
