Genes consist of exon sequences and intron sequences that, once transcribed into RNA, are spliced together to form the final RNA molecule. Exons are usually included and introns usually excluded, but many genes can encode for multiple different RNA molecules via alternative splicing arrangements. The regulation of RNA splicing is complex, and like all complex aspects of our biochemistry it becomes dysfunctional with advancing age. The proportions of normal versus alternative splicing are altered, and outright incorrect RNA molecules can be formed as well.
It remains an open question as to the degree to which RNA splicing dysfunction is an important contribution to degenerative aging. Clearly it can cause harm, but as is the case for much of aging, it is hard to assess whether this harm is meaningful in comparison to other causes of damage, dysfunction, and cell stress. Today’s open access paper is one example of a range of evidence that supports a greater rather than lesser role for RNA splicing dysfunction in aging. While focused on one tissue only, if harms can be shown in one location in the body it is reasonable to think they are occurring elsewhere as well.
A related open question is whether it is worth attempting to find ways to directly correct the operation of RNA splicing in aged cells versus attempting to identify and fix the underlying causes of RNA splicing dysfunction. One might expect RNA splicing dysfunction to be downstream of epigenetic changes characteristic of aging, as epigenetic change can cause a reduction in the production of critical molecular machinery or imbalances in the relative numbers of specific molecules needed for RNA splicing. There is the hope that success in developing therapies based on partial reprogramming will address RNA splicing dysfunctions and many other issues by resetting epigenetic marks into a more youthful state. But this remains to be seen, and a number of groups are pursing other approaches that may improve the operation of RNA splicing to some degree.
Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice
Female reproductive aging is characterized by progressive deterioration of ovarian function, yet the molecular mechanisms driving these changes remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice after controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries.
Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, mitochondrial genes were disproportionately affected. We highlight Ndufs4, a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a truncated isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased reactive oxygen species (ROS) production.
Our data suggest a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the model of the splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline.
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