bims-ovagas Biomed News
on Ovarian aging and cGAS
Issue of 2026–05–31
eleven papers selected by
Haiyuan Mu, University of California Berkeley
  1. Establishment of an Autoimmune Premature Ovarian Insufficiency Mouse Model with Proteomic Analyses: An Exploratory Study.
  2. Beyond reproduction: The ovary as a systemic regulator of female health and aging.
  3. Camsap3-mediated microtubules maintain transzonal projections essential for soma-germ communication during ovarian follicle maturation in mice.
  4. Single-nucleus profiling reveals age-associated remodeling opposed by parity in the postmenopausal human ovary.
  5. A cohesion optimum underlies chromosome segregation fidelity in oocytes.
  6. From germline immortality to somatic rejuvenation: Unlocking the ovarian blueprint for longevity.
  7. PIWIL3-piRNA pathway controls rabbit oogenesis and embryogenesis via broad regulation of the transcriptome and proteome.
  8. Multi-omics pleiotropic association analyses reveal functionally relevant genes and druggable pathways for ovarian aging.
  9. Dynamic regulation of H3K9 dimethylation drives mouse minor zygotic genome activation.
  10. Quantifying Mechanical Properties of Fresh Ovarian Tissue with Optical Brillouin Microscopy.
  11. R-loop homeostasis at transposable elements safeguards transcriptional silencing in replication-quiescent oocytes.
  1. Int J Mol Sci. 2026 May 11. pii: 4270. [Epub ahead of print]27(10):
    Establishment of an Autoimmune Premature Ovarian Insufficiency Mouse Model with Proteomic Analyses: An Exploratory Study.
    Ying Tian, Jiaqi Zhou, Xinyi Pei, Feiran Liu, Feiyang Diao.
      Premature ovarian insufficiency (POI) impairs fertility and health in reproductive-age women, with autoimmune factors contributing to 4-30% of cases. To investigate immune dysregulation in POI, we developed two mouse models using pZP3 induction: regular immune (RE-POI) and enhanced immune (EN-POI) cycles. The EN-POI model exhibited stable, irreversible ovarian dysfunction, including disrupted estrous cycles, hormonal changes (elevated FSH, decreased AMH, and estradiol), follicular depletion, and infertility. Immune profiling demonstrated consistent T-lymphocyte imbalance across both RE-POI and EN-POI model groups, characterized by expanded splenic CD4+ T cells, diminished regulatory T cells, elevated systemic inflammatory cytokines, and ovarian fibrosis. Proteomic comparison between the control and EN-POI groups identified 198 differentially expressed proteins, mainly enriched in immune and inflammatory pathways. Based on these differential proteins, subsequent network analysis further identified six key hub proteins, namely Mmp9, Isg15, Ikbke, Siglec1, Pf4, and Cdkn1b. This study establishes a stable autoimmune POI model, elucidates T-cell imbalance with cytokine storm and fibrosis, and identifies key molecules linking immune abnormalities to ovarian failure, offering new insights into POI research.
    Keywords:  autoimmunity; immune imbalance; mouse model; premature ovarian failure; proteomics
    DOI:  https://doi.org/10.3390/ijms27104270
  2. PLoS Biol. 2026 May;24(5): e3003800
    Beyond reproduction: The ovary as a systemic regulator of female health and aging.
    Jennifer L Garrison.
      Classifying ovaries solely as reproductive organs has obscured their role as systemic regulators of female physiology. This Perspective makes the case that ovarian aging is a primary determinant of healthspan and belongs at the center of geroscience.
    DOI:  https://doi.org/10.1371/journal.pbio.3003800
  3. iScience. 2026 Jun 19. 29(6): 115911
    Camsap3-mediated microtubules maintain transzonal projections essential for soma-germ communication during ovarian follicle maturation in mice.
    Akihiro Aikawa, Takao Tsurumaki, Erina Kuranaga, Junya Ito, Mika Toya, Masamitsu Sato.
      Oocytes are surrounded by layers of maternal somatic granulosa cells (GCs) in ovarian follicles. GCs extend actin-containing transzonal projections (TZPs) to oocytes across the zona pellucida to establish communication. Microtubules have rarely been observed in TZPs, and their significance in TZP organization and follicular maturation remains unknown. Here, using super-resolution microscopy, we visualized microtubules alongside F-actin in most TZPs. Knockout (KO) mice of the microtubule minus-end binding protein Camsap3 (calmodulin-regulated spectrin-associated protein 3) exhibited infertility without ovulation despite normal estrous cycles. Ovaries of Camsap3-KO mice contained fewer developing follicles, particularly of antral and Graafian stages. In earlier stages of Camsap3-KO follicles, TZP numbers were reduced compared to wild-type follicles, and microtubules in TZPs were disorganized, leading to decreased contact between GCs and oocytes. TZP morphology in wild-type transforms during follicle development, and Camsap3-mediated microtubules govern the number and morphology of TZPs, contributing to successful follicle development for fertile oocyte production.
    Keywords:  cell biology; reproductive medicine
    DOI:  https://doi.org/10.1016/j.isci.2026.115911
  4. bioRxiv. 2026 May 14. pii: 2026.05.11.724381. [Epub ahead of print]
    Single-nucleus profiling reveals age-associated remodeling opposed by parity in the postmenopausal human ovary.
    Josef Byrne, Nicolas Martin, Bikem Soygur, Mark A Watson, Kevin Schneider, Birgit Schilling, Simon Melov.
      The postmenopausal ovary is commonly viewed as a passive organ, and its biology and cell composition remain incompletely characterized. Here, we generated a single-nucleus atlas of the aging postmenopausal human ovary comprising 439,011 nuclei across 64 ovarian samples from 28 donors. We resolved 37 fine cell states, revealing extensive stromal, vascular, and immune heterogeneity in the postmenopausal ovary. Aging was associated with stromal stress-state expansion, vascular and immune depletion, and enrichment of steroidogenic programs consistent with ovarian androgenization. Several major age-associated compositional shifts were supported in an independent GTEx ovary bulk RNA-seq cohort. Notably, the number of live births broadly opposed age-associated transcriptional and compositional remodeling. Together, our findings show that the postmenopausal ovary remains an actively remodeled aging tissue and that reproductive history leaves durable molecular and cellular imprints on ovarian aging.
    DOI:  https://doi.org/10.64898/2026.05.11.724381
  5. bioRxiv. 2026 May 11. pii: 2026.05.08.723885. [Epub ahead of print]
    A cohesion optimum underlies chromosome segregation fidelity in oocytes.
    Yan Yun, Kanako Ikami, Duy Do, Ziyang Guo, Jiyeon Leem, Hilina Bekele, Binyam Mogessie, Neil Hunter.
      Chromosome segregation is compromised in eggs from women of both early and advanced reproductive ages. Deteriorating cohesion causes premature separation of sister-chromatids in eggs from older females. We show that the converse is true for oocytes of adolescents, with excessive cohesion impeding segregation. Oocytes from juvenile mice show severe chromosome lagging in anaphase I, leading to nondisjunction or, in extreme cases, failure of the first meiotic division. These defects are suppressed by experimentally weakening cohesion or enhancing its resolution during anaphase I. By contrast, lagging and nondisjunction are rare in the oocytes of young adults because cohesion is inherently weaker. Thus, relative cohesion strength underlies both the frequency and type of segregation errors observed in eggs throughout the female reproductive lifespan.
    One-Sentence Summary: In eggs, errors in chromosome segregation arise from age-dependent imbalances in how tightly chromosomes are held together.
    DOI:  https://doi.org/10.64898/2026.05.08.723885
  6. PLoS Biol. 2026 May;24(5): e3003804
    From germline immortality to somatic rejuvenation: Unlocking the ovarian blueprint for longevity.
    Priscila Chiavellini, Vittorio Sebastiano.
      Aging is typically framed as a one-way, irreversible accumulation of molecular damage in cells and tissues, leading to progressive functional decline. Yet mammalian reproduction, and particularly female reproduction, reveals a striking exception to this rule. Despite residing within an aging organism and within a fast-aging ovarian tissue environment, oocytes give rise to embryos that begin life with restored developmental potential and youthful molecular organization. By reframing ovarian biology as a model for rejuvenation rather than solely as a site of reproductive decline, this Essay proposes that the ovary offers a powerful blueprint for advancing the biology of aging and longevity.
    DOI:  https://doi.org/10.1371/journal.pbio.3003804
  7. Nat Commun. 2026 May 26.
    PIWIL3-piRNA pathway controls rabbit oogenesis and embryogenesis via broad regulation of the transcriptome and proteome.
    Yuanyuan Gong, Shuo Shi, Ling Li, Yuqiang Qian, Ting Lu, Zhaoran Zhang, Lichun Jiang, Guohui Liu, Meihua Cui, Shangang Li, Zhanjun Li, Haifan Lin.
      Female infertility often arises from oogenic defects, yet the underlying molecular mechanisms remain elusive. The Piwi-piRNA pathway is crucial for gametogenesis, but its role in mammalian female fertility remains unclear, partly due to reliance on mouse models lacking PIWIL3. PIWIL3 exits in most other placental mammals and is highly expressed in human oocytes, but its function remains largely unexplored. Here, we show that rabbit PIWIL3 closely resembles its human counterpart and is the predominant PIWI protein in oocytes. Using CRISPR-Cas9 knockout, we demonstrate that PIWIL3 is essential for female fertility in rabbits, its loss leads to severe defects in oogenesis. Embryos lacking maternal PIWIL3 arrest by the 8-cell stage. Mechanistically, PIWIL3 binds ~18-nucleotide piRNAs, supports piRNA biogenesis, and regulates transcriptomic, proteomic, and transposable element dynamics during oocyte maturation and early embryogenesis. These findings establish PIWIL3 as an essential regulator of female fertility in non-rodent mammals, potentially including humans.
    DOI:  https://doi.org/10.1038/s41467-026-73503-4
  8. Genome Biol. 2026 May 28.
    Multi-omics pleiotropic association analyses reveal functionally relevant genes and druggable pathways for ovarian aging.
    Xuan Lian, Shuang Song, Chen Lou, Ming Zhu, Yan Li, Wenjian Li, Xintong Jiang, Guiquan Wang, Haiyan Yang, Lin Wang, Liying He, Yunlong Ma, Xi Dong, Yijie Chen, Hsun-Ming Chang, Wencheng Zhu, Jia Wang, Yang Yu, Yang Wu, Yue Zhao, Liangshan Mu.
       BACKGROUND: Ovarian aging, marked by the gradual decline in both the number and quality of oocytes, significantly impacts women's reproductive lifespan and overall health. However, the biological mechanisms driving ovarian aging remain poorly understood and current treatment strategies are limited.
    RESULTS: We perform an integrative analysis using multi-omics summary data and genome-wide association studies for ovarian aging to identify molecular traits linked to ovarian aging. By applying Mendelian randomization and cross-omics association approaches, we prioritize key proteins, gene expressions, splicing events, and metabolites. Our analysis identifies conservation of key genes across species and cell types, with the mismatch repair gene MSH6 (MutS Homolog 6) emerging as a consistently prioritized candidate. Experimental validation shows that targeting DNA repair through PD-L1 (Programmed Death-Ligand 1) blockade may offer a potential therapeutic strategy to delay ovarian aging.
    CONCLUSIONS: This study uncovers the multi-layered genetic and molecular architecture underlying ovarian aging. The identified molecular traits provide promising candidates for functional studies and suggest new avenues for developing therapies aimed at preserving ovarian function and preventing age-related decline.
    Keywords:  DNA repair; MSH6; Mendelian randomization; Multi-omics; Ovarian aging; PD-L1
    DOI:  https://doi.org/10.1186/s13059-026-04118-7
  9. Nat Struct Mol Biol. 2026 May 26.
    Dynamic regulation of H3K9 dimethylation drives mouse minor zygotic genome activation.
    Ryo Maeda, Shunsuke Kuroki, Hiromi Shimojo, Masahiro Nagano, Masahiro Matsuwaka, Hiroshi Sasaki, Azusa Inoue, Makoto Tachibana.
      Minor zygotic genome activation (ZGA) is crucial for early development and totipotency acquisition; however, the regulatory mechanisms controlling minor ZGA gene expression remain elusive. Here, we show that mouse minor ZGA is driven by spatiotemporally dynamic regulation of H3K9 dimethylation (H3K9me2). H3K9me2 levels at the minor ZGA gene loci are reduced at the early two-cell stage and are reestablished by the morula stage. Maternal depletion of the H3K9 demethylases KDM3A and KDM3B leads to increased H3K9me2 levels and impaired minor ZGA at the early two-cell, followed by arrest at the two-cell to four-cell stage. In mouse embryonic stem cells, H3K9 at the minor ZGA loci is dimethylated. Combined loss of the H3K9 methyltransferases G9a and SETDB1 results in the synergistic derepression of minor ZGA genes. Mechanistically, SETDB1 targets the transcriptional factor Dux, while G9a broadly represses minor ZGA genes through H3K9me2 deposition linked to lamina-associated heterochromatin formation. Therefore, H3K9me2 dynamics are unveiled as an important regulator of minor ZGA, highlighting the indispensable role of epigenetic control in early embryogenesis.
    DOI:  https://doi.org/10.1038/s41594-026-01811-w
  10. Methods Mol Biol. 2026 May 26.
    Quantifying Mechanical Properties of Fresh Ovarian Tissue with Optical Brillouin Microscopy.
    Shahrin Jahan Jaima, Mankirat Singh, Saumya Nigam, Zexu Jiao, Ping Wang, Jitao Zhang.
      Mechanical properties play a critical role in regulating ovarian function, yet their spatial variation within intact tissue remains poorly understood due to the limitations of conventional mechanical testing techniques. Confocal Brillouin microscopy offers a non-contact and label-free approach for mapping mechanical properties of the intact ovarian tissue without perturbing tissue structure. In fresh ovarian tissue, Brillouin images reveal spatial heterogeneity in mechanical properties across follicles, surrounding stroma, and fluid-filled regions, suggesting underlying differences in cellular organization and extracellular matrix composition. These measurements capture both inter- and intra-follicular variations, providing insight into regional differences in mechanical properties within and between follicles. This chapter outlines the principles of Brillouin microscopy and its application to fresh ovarian tissue, highlighting its capability to resolve microscale mechanical variations in situ. This method provides a foundation for understanding the role of mechanical properties in ovarian function, with potential applications in disease models and reproductive health research.
    Keywords:  Brillouin microscopy; Folliculogenesis; Mechanobiology; Ovary; Reproductive health; Tissue biomechanics
    DOI:  https://doi.org/10.1007/7651_2026_710
  11. Nat Commun. 2026 May 29.
    R-loop homeostasis at transposable elements safeguards transcriptional silencing in replication-quiescent oocytes.
    Shao-Yuan Liu, Xin-Yi Tian, Hong-Fen Fu, Yong Zhou, Yi-Sha Cai, Jun Wen, Ze-Lin Wang, Yun-Wen Wu, Qiong-Wen Lu, Xiu-Quan Liao, Qian-Qian Sha.
      R-loops, though implicated in genome stability, have poorly defined transcriptional roles due to confounding replication processes in proliferating cells. Here, by leveraging replication-free oocytes and RTACC-seq, a tailored high-specificity R-loop mapping approach for low-input samples, we identify dynamic R-loop enrichment at both gene promoters and distal transposable elements. We find that transposable element-associated R-loops accumulate in transcriptionally active stage oocytes and resolve in fully grown oocytes, coinciding with chromatin condensation and transcriptional silencing. R-loops exert opposing, location-dependent regulatory functions, with reduced transcription rate at promoters and enhanced rates at transposable elements, raising the possibility of enhancer-like activity at a subset of hybrid-associated transposable element loci. In mice, oocyte-specific deletion of Rnaseh1, a gene that encodes an RNA:DNA hybrid-specific endonuclease, leads to persistent R-loops, chromatin decondensation, and impaired transcriptional silencing in fully grown oocytes, culminating in premature ovarian failure and female subfertility. These findings characterize the mechanistic basis of R-loops as mediators of chromatin remodeling, transcriptional regulation, and germ cell developmental competence.
    DOI:  https://doi.org/10.1038/s41467-026-73781-y
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