bims-ovagas 2026-07-26 papers

bims-ovagas

Biomed News

on Ovarian aging and cGAS

Issue of 2026–07–26
six papers selected by
Haiyuan Mu, University of California Berkeley

Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.
The Drosophila ovary produces two waves of adult follicles and a novel pupal wave that turns over.
Probing the Ovarian Microenvironment: Methods for Isolation, 2D Culture, and Organoid Culture of Mouse Ovarian Somatic Cells.
Molecular genetics of meiotic initiation in mammals.
Integrated Single-cell Proteomic and Transcriptomic Landscape of Mouse Folliculogenesis.
Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.

Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600323123

Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.

Xifan Wang, Jiping Yang, Chen Jin, Xizhe Wang, Daniela Contreras, Melody Devos, Maggie M Kane, Michael G Rosenfeld, Yousin Suh.

  Reproductive aging in mice leads to estropause, characterized by estrous cycle irregularity and eventual cessation, yet its underlying mechanism remains unclear. Here, we present a comprehensive single-cell atlas of mouse ovaries across precisely defined reproductive stages-from young (regular cycling) through the estropausal transition (regular vs. irregular cycling) to post-estropause (acyclic)-and of ovary-specific senescent cells defined by high senescence-associated β-galactosidase activity. We mapped transcriptomic dynamics of ovarian aging and characterized the molecular features of ovarian senescent cells. Our analyses revealed that during the estropausal transition, irregularly cycling ovaries exhibited accelerated aging and cellular senescence features compared with regularly cycling counterparts, including increased transcriptional noise, altered conserved aging pathways such as oxidative phosphorylation and proteostasis, hormone dysregulation in granulosa cells, and elevated expression of the senescence marker Cdkn1a and senescence-associated secretory phenotype factors. This atlas delineates the cellular and molecular hallmarks of mouse ovarian aging and ovary-specific senescent cells, providing a resource for understanding the mechanisms underlying the estropausal transition.

Keywords:  aging; cellular senescence; estropausal transition; ovary; single-cell RNA-seq

DOI:  https://doi.org/10.1073/pnas.2600323123
Development. 2026 Jul 23. pii: dev.205668. [Epub ahead of print]

The Drosophila ovary produces two waves of adult follicles and a novel pupal wave that turns over.

Wayne Yunpeng Fu, Allan C Spradling.

  Ovarian follicles in most species are assumed to develop using a single pathway. However, in Drosophila pupae, lineage tracing 2,937 single-cell clones identified three follicle "waves" that follow distinct programs arrayed anterior to posterior in the germarium and developing ovarioles. 40 primordial germ cells (PGCs) become anterior germline stem cells (GSCs) that produce "wave 2" follicles throughout adulthood. 100 PGCs posterior to wave 2 develop into "wave 1.5" follicles that form the earliest laid eggs. Different follicle stem cells (FSCs) sequentially occupy the same two niches timed to provide both waves with specific follicle cells, consistent with programmed differences between waves 2 and 1.5. "Wave 1" PGCs located even further posterior proliferate, form cysts, interact with swarm cells, degenerate, break from the ovary 22-26 hours after puparium formation, and release lipid-enriched vacuoles. Some testis germ cells behave similarly. We speculate that wave 1 germ cells contribute directly or indirectly to the pharate adult ecdysone pulse that mediates adult development and sex-specific neural remodeling. Why Drosophila follicle waves generally resemble those clarified recently in mouse preadult ovaries merits additional study.

Keywords:  Drosophila melanogaster ; Follicle stem cell; Germ cell; Germline stem cell; Ovarian follicle wave; Pupal ovary

DOI:  https://doi.org/10.1242/dev.205668
J Vis Exp. 2026 Jul 03.

Probing the Ovarian Microenvironment: Methods for Isolation, 2D Culture, and Organoid Culture of Mouse Ovarian Somatic Cells.

Shweta S Dipali, Aubrey Converse, Madison Q Gowett, Emily J Zaniker-Gomez, Madeline J Perry, Francesca E Duncan.

The ovary consists of heterogeneous populations of somatic cells, both within the follicle and the surrounding stroma, which are critical to support ovarian function and for the generation of high-quality gametes. We report methods for isolating somatic cells from mouse ovaries, including endothelial, epithelial, steroidogenic, stromal, and immune cells. When these primary ovarian somatic cells are plated and cultured in a traditional 2D culture system, the cellular heterogeneity, organization, as well as cell-cell and cell-matrix interactions typically found in the ovary are lost. Thus, we also describe how to generate mouse ovarian somatic organoids using a scaffold-free approach. These organoids self-assemble, maintain diverse cell populations, and produce extracellular matrix and secreted factors, including cytokines. Organoids can be utilized for co-culture experiments and can be maintained in culture for at least 3 weeks with high viability. Overall, these models enable interrogation of ovarian physiology and pathology from the somatic cell perspective.

DOI: https://doi.org/10.3791/71001
Biol Reprod. 2026 Jul 21. pii: ioag155. [Epub ahead of print]

Molecular genetics of meiotic initiation in mammals.

Shelbie M Wenner, Omodasola M Ola, Natalie G Pfaltzgraff, Esther G Ushuhuda, Maria M Mikedis.

  Mammalian fertility is dependent upon meiosis, a specialized cell division by which diploid progenitors undergo one round of DNA replication followed by two rounds of chromosomal segregation to produce haploid gametes. The germ line in the testis and ovary undergoes several rounds of mitotic divisions before ultimately transitioning to the meiotic cell cycle. This transition is achieved by replacing the mitotic cell cycle program with the meiotic one. Here, we discuss the molecular players that regulate the transition from mitosis to meiosis. In spermatogenesis, MEIOC, YTHDC2, and RBM46 form an RNA-binding complex that post-transcriptionally represses the mitotic cell cycle program, while in oogenesis, MEIOC inhibits mitotic cycling prior to meiotic initiation. STRA8 and MEIOSIN act as a transcription factor complex to drive meiotic initiation by upregulating genes involved in cell cycle progression and the unique chromosomal events of meiosis in oogenesis and spermatogenesis. These complexes are activated by upstream molecular players, including transcription factors, epigenetic regulators of chromatin structure, and extrinsic signaling factors, that form an intricate and reinforced molecular network to precisely regulate the transition from the mitotic to meiotic cell cycle. Here, we integrate current knowledge of the regulation of meiotic initiation in mammals and highlight key gaps in this regulatory program that remain to be explored.

Keywords:  BMP; KIT ligand; WNT; cell cycle; gene expression; meiosis; oogenesis; post-transcriptional regulation; retinoic acid; spermatogenesis

DOI:  https://doi.org/10.1093/biolre/ioag155
Genomics Proteomics Bioinformatics. 2026 Jul 23. pii: qzag068. [Epub ahead of print]

Integrated Single-cell Proteomic and Transcriptomic Landscape of Mouse Folliculogenesis.

Hongchao Li, Xinshuai Zhang, Huimin Kang, Yun Yang, Xinyu Xiao, Yan Wang, Bin Fu, Jie Chen, Xinwen Dong, Yuanjun Zhai, Jing Yang, Jianming Ying, Fuchu He, Yang Li, Xiaowen Wang.

  Folliculogenesis is a complex process essential to female fertility, characterized by multifaceted communication between oocytes and granulosa cells (GCs). While transcriptional regulation during folliculogenesis has been extensively studied, the proteomic landscape remains largely unexplored. Here, we profiled both the proteomic and transcriptomic landscapes of single oocytes and their surrounding mini-bulk GCs across four consecutive stages, from secondary to preovulatory follicles. Integrated dual-omics analysis provided a high-resolution characterization of cell type-specific transcriptional and proteomic changes. Proteomic profiling revealed coordinated metabolic programs, in which oocytes shift toward lipid storage while GCs enhance energy production and steroidogenic metabolism to support oocyte maturation. These metabolic changes in oocytes were accompanied by dynamic remodeling of mitochondrial organization. In addition, we identified novel transcription factors involved in regulating folliculogenesis, as well as a SATB1-centered regulatory network that may reflect preparatory chromatin remodeling preceding zygotic genome activation. Furthermore, GDF9-BMPR2 signaling progressively increased from the secondary stage to the preovulatory stage, indicating strengthened intercellular communication between oocytes and GCs. Together, these findings provide mechanistic insights into oocyte development and follicle growth, with potential implications for novel fertility treatments and diagnostic strategies.

Keywords:  Folliculogenesis; Intercellular communication; Single-cell proteome; Single-cell transcriptome; Transcription factor regulatory network

DOI:  https://doi.org/10.1093/gpbjnl/qzag068
Nat Aging. 2026 Jul 24.

Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.

Mariah F Calubag, Ismail Ademi, Cara L Green, Dulmalika N H Manchanayake, Hashan S M Jayarathne, Ryan N Marshall, Sandra M Le, Penelope Lialios, Lucia E Breuer, Shoshana Yakar, Reji Babygirija, Michelle M Sonsalla, Isaac Grunow, Chung-Yang Yeh, Yang Liu, Bailey A Knopf, Sarah Yandell, Charles I Opara, William A Ricke, Teresa T Liu, Mark P Keller, Alan D Attie, Marianna Sadagurski, Dudley W Lamming.

Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

DOI: https://doi.org/10.1038/s43587-026-01169-0