ORCID

0009-0005-0729-7980 (Alsamaraee), 0000-0003-2854-7510 (Nyalwidhe), 0000-0002-9014-132X (Brachova), 0000-0003-4067-4387 (Alvarez)

Document Type

Article

Publication Date

2026

DOI

10.1093/reprod/xaag019

Publication Title

Reproduction

Volume

Advance online publication

Pages

37 pp.

Abstract

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, several mitochondrial genes involved in the respiratory chain were affected. We highlight Ndufs4, a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a short isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased 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.

Rights

© The Authors 2026. 

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Original Publication Citation

Alsamaraee, A. T., Correll, V. L., Nyalwidhe, J. O., Brachova, P., & Alvarez, N. S. (2026). Dysregulation of alternative splicing patterns in the ovaries of reproductively aged mice. Reproduction. Advance online publication. https://doi.org/10.1093/reprod/xaag019

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