bims-ovagas Biomed News
on Ovarian aging and cGAS
Issue of 2026–06–28
twelve papers selected by
Haiyuan Mu, University of California Berkeley
  1. Mice lacking NF-ĸB1 undergo premature ovarian aging.
  2. Mechanisms and Evolutionary Advantages of Unlimited Reproductive Lifespans in Naked Mole-Rat Queens.
  3. Ultrastructural, Histological, and Immunofluorescence Evaluation of Autophagy in Murine Embryonic, Postnatal, and Prepubertal Ovaries.
  4. The role of anti-Müllerian hormone as a therapeutic agent to preserve the ovarian follicle pool during chemotherapy.
  5. Germline cysts require Ecdysone Receptor for proper timing of encapsulation in the Drosophila ovary.
  6. Future Therapies for Autoimmune Premature Ovarian Insufficiency.
  7. From Cytoskeletal Remodeling to Oocyte Quality: The Emerging Role of Mechanics.
  8. Immunotherapy for Fertility in Autoimmune Premature Ovarian Insufficiency.
  9. IL17 signaling promotes oocyte developmental competence acquisition during maturation.
  10. Making themselves scarce: immune cells in the ovary.
  11. Identification of the homozygous truncating mutation in CNTD1 as a novel genetic cause of diminished ovarian reserve.
  12. PCOS Is Now PMOS-Will a New Name Translate to Improved Clinical Care?
  1. Reprod Biol Endocrinol. 2026 Jun 25.
    Mice lacking NF-ĸB1 undergo premature ovarian aging.
    Carolina Lliberos, Seng H Liew, Yasmin Lewis, Nadeen Zerafa, Darcy Ellis, Ashley Mansell, Steve Gerondakis, Karla Hutt.
      Female fertility declines dramatically with age, primarily due to the loss of oocyte number and quality. This physiological event leads to ovarian dysfunction and infertility, irregular cycles and ultimately menopause. Despite its significance, the factors that underlie the natural process of age-related follicle loss, or those that promote premature ovarian aging, remain unknown. Here we show that low levels of chronic inflammation in mice lacking the nuclear factor kappa B transcription factor NF-ĸB1 (Nfkb1-/-) coincide with accelerated depletion of the ovarian reserve, characteristic of premature ovarian aging. While Nfkb1-/- mice enter adult life with normal numbers of primordial follicles, as females age, the primordial follicle pool is depleted more rapidly than in age-matched wild-type controls. Similarly, mice hemizygous for Nfkb1 (Nfkb1±) also exhibit an early loss of the ovarian reserve and a decrease in the number of corpora lutea, consistent with reduced ovulation. Loss of NF-ĸB1 was accompanied by elevated serum cytokine and intra-ovarian inflammatory levels. Overt ovarian fibrosis was not observed in aging Nfkb1-/- mice, indicating that fibrosis may not the mechanism underlying premature follicle depletion. Collectively, these data suggest that loss of NF-ĸB1 and chronic low-grade inflammation may accelerate the age-associated depletion of follicles, leading to early loss of fertility and premature menopause.
    Keywords:  Aging; Follicle; Inflammation; NF-ĸB; Ovary; Premature aging
    DOI:  https://doi.org/10.1186/s12958-026-01574-5
  2. Annu Rev Genet. 2026 Jun 25.
    Mechanisms and Evolutionary Advantages of Unlimited Reproductive Lifespans in Naked Mole-Rat Queens.
    Andrew C Pearson, Odei Barreñada, Miguel A Brieño-Enríquez.
      The naked mole-rat (Heterocephalus glaber) defies mammalian norms with lifelong fertility and postnatal oogenesis. Unlike most mammals, which experience reproductive senescence due to depletion of a finite ovarian follicle pool, naked mole-rat queens maintain fertility for their entire 30+-year lifespan through multiple mechanisms, including postnatal oogenesis, an exceptionally large ovarian reserve, and maintenance of primordial germ cells into adulthood. This review explores the unique reproductive biology of naked mole-rats within the context of their eusocial lifestyle, examining how social suppression of reproduction in subordinates, the role of very-high-molecular-weight hyaluronan (vHMW-HA) in cancer resistance and tissue maintenance, and the maintenance of germline stem cell populations contribute to their extraordinary reproductive longevity. We discuss the evolutionary advantages of eusociality, mechanisms of reproductive suppression and activation, and the potential of naked mole-rats as a research model for understanding ovarian aging and developing fertility-preserving therapies in humans.
    DOI:  https://doi.org/10.1146/annurev-genet-011626-014848
  3. Anat Histol Embryol. 2026 Jul;55(4): e70116
    Ultrastructural, Histological, and Immunofluorescence Evaluation of Autophagy in Murine Embryonic, Postnatal, and Prepubertal Ovaries.
    Fakhroddin Mesbah, Tahereh Talaei-Khozani, Hossein Bordbar, Mojde Pajokh.
      The ovary of mammals is a unique organ that is characterized by morphological tissue rearrangements, which include the development and death of germ cells, alongside the development and atresia of follicles. Additionally, the initiation of meiosis in germ cells, the development of follicles, and the onset of puberty likely involve cellular mechanisms such as autophagy. Despite some knowledge has been gained, there remains a gap in understanding the precise role of autophagy in these processes, particularly with the emergence of a specific variant termed mitophagy in reproductive sciences. In addition to its role in regulating energy metabolism and maintaining cellular homeostasis, autophagy can either facilitate cell survival or induce cell death. Considering the critical time points during female gonad development where autophagy may be involved in various cellular processes, we assessed the ultrastructural and histological characteristics of autophagy. This evaluation included Beclin-1 immunodetection as an autophagy marker in the embryonic ovary of female mice at 13.5 days post coitum, as well as in ovaries collected from newborns at 1 postnatal day and prepubertal at 21 postnatal days. The study revealed ultrastructural features of autophagy and mitophagy in embryonic and neonatal germ cells, as well as in follicular development and atresia in the ovaries of prepubertal mice. This process was confirmed by the detection of Beclin-1 protein expression. Moreover, our findings indicate a heightened level of Beclin-1 immunodetection in the oocytes of preantral and antral atretic follicles, which was correlated with the progress of atresia.
    Keywords:  Beclin‐1; autophagy; histology; mouse ovary; ultrastructure
    DOI:  https://doi.org/10.1111/ahe.70116
  4. J Assist Reprod Genet. 2026 Jun 20.
    The role of anti-Müllerian hormone as a therapeutic agent to preserve the ovarian follicle pool during chemotherapy.
    Irene Peregrin-Alvarez, Roni Zemet, Terri Lynn Woodard, Leah Michelle Schenk, Laurie Jane McKenzie, Jaou-Chen Huang, Momal Sharif, Laura Detti.
       PURPOSE: Cancer treatments can deplete the ovarian follicle reserve, causing infertility and early menopause, with subsequent decline in cardiovascular, cognitive, and overall women's health. Medical measures to prevent this chemotherapy-induced ovarian damage are currently not available. Anti-Müllerian hormone (AMH) is an inhibitory glycoprotein that plays a central role in regulating ovarian follicle development across the female lifespan, and in vitro, ex vivo, and gene therapy studies have demonstrated that AMH can protect the ovarian follicle pool during chemotherapy treatments.
    METHODS: Narrative review of available literature.
    RESULTS: Experimental work has shown how AMH modulates folliculogenesis, notably through its signaling pathway that activates SMAD proteins, ultimately modulating the PI3K/AKT/FOXO3a pathway to help maintain primordial follicle dormancy and prevent premature depletion of the ovarian pool.
    CONCLUSIONS: This review summarizes current understanding of AMH biosynthesis, AMH receptor 2 (AMHR2) signaling, and their genetic regulation, and examines emerging translational research on the use of recombinant AMH to protect the ovarian follicle reserve in models of accelerated ovarian damage, specifically chemotherapy-induced gonadotoxicity. Finally, this review highlights the potential of AMH-based therapies to preserve fertility and delay follicular depletion in conditions such as endometriosis, chronic inflammation, and natural aging. It distinguishes established findings from emerging hypotheses and outlines key challenges for translating these strategies into early-phase clinical trials.
    Keywords:  Anti-Müllerian hormone; Follicle development; Müllerian-inhibiting substance; Ovarian reserve; Recombinant AMH
    DOI:  https://doi.org/10.1007/s10815-026-03941-y
  5. Dev Biol. 2026 Jun 20. pii: S0012-1606(26)00133-8. [Epub ahead of print]
    Germline cysts require Ecdysone Receptor for proper timing of encapsulation in the Drosophila ovary.
    Lindsay A Swain, Daniel N Phipps, Susannah Catherine G Webster, Lauren E Jung, Elizabeth T Ables.
      Oocytes are packaged into ovarian follicles, each containing a maturing germ cell surrounded by a layer of somatic cells. This conserved arrangement is essential for proper oocyte development and reproductive success. Continuous coordination and bi-directional signaling from somatic cells to germ cells are necessary for proper oocyte packaging. In Drosophila, although germ cell packaging has been presumed to be controlled by somatic follicle cells enveloping passive germ cells, recent studies suggest that germ cells themselves produce motor forces that drive somatic encapsulation. Here, in support of this hypothesis, we present data suggesting that cyst encapsulation requires Ecdysone Receptor (EcR), a steroid hormone receptor known to control multiple aspects of oogenesis. Using tools to deplete EcR or block EcR signaling specifically in the germline, we show that germline-autonomous EcR is necessary for the timing of cyst encapsulation. When EcR signaling is inactivated, germ cell encapsulation is slowed, resulting in abnormal oocyte positioning and decreased fecundity. EcR facilitates germ cell cyst encapsulation by promoting proliferation and intercalation of overlying somatic cells. We conclude that EcR likely promotes cyst packaging by specifically inducing EGFR signaling in posterior escort and follicle cells. Overall, these data demonstrate that EcR is necessary in the germline to promote timely ovarian follicle assembly and development.
    Keywords:  ecdysone; egg chamber; follicle; oogenesis; steroid hormone
    DOI:  https://doi.org/10.1016/j.ydbio.2026.06.008
  6. NEJM Evid. 2026 Jul;5(7): EVIDe2600164
    Future Therapies for Autoimmune Premature Ovarian Insufficiency.
    Claire L Wood, Simon H Pearce.
      
    DOI:  https://doi.org/10.1056/EVIDe2600164
  7. Adv Sci (Weinh). 2026 Jun 26. e76323
    From Cytoskeletal Remodeling to Oocyte Quality: The Emerging Role of Mechanics.
    Anastasia Shihabi, Rose Bulteau, Lucie Barbier, Marie-Emilie Terret.
      Oocyte quality is essential for successful fertilization and embryonic development. At the end of mammalian oogenesis, oocytes undergo two highly asymmetric meiotic divisions that preserve maternal reserves while generating a haploid gamete. These divisions rely on dynamic cytoplasmic and cortical actomyosin networks. The mechanical properties of the oocyte, shaped by the remodeling of these networks, are critical regulators of oocyte morphogenesis, controlling cytoplasmic organization, spindle positioning, chromosome segregation, and cytokinesis. Meiotic errors, which increase with maternal age, compromise fertility and embryonic development. In parallel, the growing use of assisted reproductive technologies, including oocyte freezing for fertility preservation, has intensified the need for reliable markers of oocyte quality. Beyond conventional morphological assessment, oocyte mechanical properties have recently emerged as promising indicators of developmental competence, as naturally occurring mechanical defects can impair oocyte quality. This review discusses the molecular and cellular pathways regulating oocyte mechanics in relation to actomyosin reorganization, their roles during oocyte divisions, their alteration in pathological contexts, and their potential clinical applications as markers in reproductive medicine.
    Keywords:  actomyosin networks; assisted reproductive technologies (ART); female fertility; meiotic maturation; oocyte mechanical properties; oocyte quality
    DOI:  https://doi.org/10.1002/advs.76323
  8. NEJM Evid. 2026 Jul;5(7): EVIDoa2500303
    Immunotherapy for Fertility in Autoimmune Premature Ovarian Insufficiency.
    Angelica Lindén Hirschberg, Sigridur Björnsdottir, Iva Gunnarsson, Fotios Sergouniotis, Kjell Wånggren, Carolina Sousa Silva, Elinor Vogt, Marianne Øksnes, Eystein S Husebye, Sophie Bensing, Olle Kämpe.
       BACKGROUND: Women with autoimmune diseases have an increased risk of premature ovarian insufficiency (POI), leading to early menopause and infertility. We hypothesized that B-cell depletion with rituximab could reverse autoimmune activity, enhance ovarian responsiveness to gonadotropins, and transiently restore fertility in autoimmune POI.
    METHODS: In this proof-of-concept study, we enrolled women between the ages of 18 and 35 years with autoimmune POI. Each participant underwent controlled ovarian hyperstimulation before and 4 to 6 months after treatment with rituximab (two 1-g infusions, administered 2 weeks apart). Participants were followed for 12 months after rituximab infusion. The primary outcomes of interest were the number of antral follicles and the size of the largest follicle in response to ovarian stimulation. In the case of successful oocyte retrieval, oocytes were cryopreserved or fertilized. For safety, embryo transfer was deferred until at least 12 months after rituximab administration.
    RESULTS: We enrolled 12 women, with a mean (standard deviation) age of 30.8 (2.8) years. Two women withdrew consent prior to initiating the study. Prior to rituximab, none of the participants responded to ovarian hyperstimulation with follicular development. Following rituximab, after undergoing another ovarian hyperstimulation, follicular development occurred in six women that led to oocyte retrieval (responders). In three of these cases, oocytes were fertilized and embryos preserved; all three women subsequently delivered healthy children. One serious adverse event occurred during the trial, related to ovarian hyperstimulation.
    CONCLUSIONS: In this small proof-of-concept study with no control group, of 10 women with premature ovarian insufficiency who received rituximab followed by ovarian stimulation, six underwent oocyte retrieval. A randomized controlled trial is needed to further evaluate this treatment strategy. (Funded by the Swedish Research Council and others; EudraCT number, 2017-004532-10; ClinicalTrials.gov number, NCT05586737.).
    DOI:  https://doi.org/10.1056/EVIDoa2500303
  9. Cell Mol Biol Lett. 2026 Jun 22.
    IL17 signaling promotes oocyte developmental competence acquisition during maturation.
    Huaxing Zhao, Xiaohua He, Junsong Shi, Xiao Wu, Yalin Liang, Xingwang Wang, Zheng Ao, Xianjun Zhang, Yuxing Zhang, Yanan Li, Yiqian Zhang, Yazheng Dong, Jingfeng Peng, Yunfei Hou, Rong Zhou, Fang Zeng, Linjun Hong, Ting Gu, Huaqiang Yang, Jie Yang, Zheng Xu, Sixiu Huang, Gengyuan Cai, Zicong Li, Zhenfang Wu.
       BACKGROUND: Defects in the acquisition of oocyte developmental competence during the maturation process causes subfertility or infertility in animals and humans. Understanding the regulatory mechanisms of oocyte maturation is essential for reproductive biology and medicine. Follicular fluid (FF) is an important microenvironment governing oocyte maturation.
    METHODS: A tandem mass tags (TMT)-based comparative FF proteomic analysis was employed to identify FF proteins that are potentially crucial for oocyte maturation. A very large number of pig and mouse oocytes (approximately 20,000) and embryos (over 13,000, including somatic cell nuclear transfer, parthenogenetic activation, and in vitro fertilization embryos) were used to investigate the effects of identified FF proteins on in vitro oocyte maturation and subsequent in vitro and in vivo embryo development. RNA sequencing, quantitative PCR, enzyme-linked immunosorbent assays, and immunofluorescence were used to study the expression patterns and action mechanisms of identified FF proteins in oocytes. In addition, intra-oocyte levels of glutathione and reactive oxygen species were measured to assess redox homeostasis.
    RESULTS: Interleukin 17D (IL17D) was identified as an important FF protein and it is significantly upregulated in porcine FF during oocyte maturation. IL17D promotes oocyte maturation by enhancing bidirectional communication between oocytes and cumulus cells, via upregulating CX43 expression and transzonal projections, which helps to maintain oocyte redox homeostasis and nuclear-cytoplasmic synchrony. IL17D treatment of oocytes enhances subsequent in vitro and in vivo full-term embryo development by modulating lipid metabolism and histone modification reprogramming. IL17D exerts its function via activating IL17 signaling through binding to CD93. Two other IL17 family members, IL17A and IL17F, also enhance oocyte maturation quality. IL17D displays a conserved expression pattern and function in pig and mouse oocytes.
    CONCLUSIONS: This study reveals the critical roles of IL17D in regulating oocyte developmental competence acquisition during maturation by activating IL17 signaling. The findings provide valuable insights into the molecular mechanisms underlining oocyte developmental potential acquisition and may help to develop methods for efficient production of oocytes for assisted reproduction.
    Keywords:  Cell communication; Follicular fluid; IL17 signaling; IL17D; Oocyte; Proteome
    DOI:  https://doi.org/10.1186/s11658-026-00971-3
  10. J Ovarian Res. 2026 Jun 26.
    Making themselves scarce: immune cells in the ovary.
    Bettina Toth, Elisabeth Reiser, Samuel M Vorbach, Monika Frank, Lea Huber, Thomas Seppi, Elisabeth Pechriggl, Bettina Böttcher, Katharina Feil, Marko Konschake, Ute Ganswindt, Michael Niederwanger.
       RESEARCH QUESTION: In human and animal reproduction, the majority of the ovary's reproductive potential is lost before puberty. In order to survive, oocytes must interact with stromal cells. However, the specific distribution and role of ovarian immune cells compared to lymphatic organs is still indistinct.
    DESIGN: Immune cell composition in the ovary, spleen, and lymph nodes was analyzed in six-week-old female C57BL/6 mice using flow cytometry. The following populations were examined: macrophages, dendritic cells, natural killer cells, NKT cells, B cells, T cells, CD4 + T cells and CD8 + T cells.
    RESULTS: Only 3% of the cells that make up the ovary are immune cells. Ovarian immune cells consisted of natural killer cells (24%), T cells including CD4+- and CD8 + T cells (21%), macrophages (17%), dendritic cells (7%), NKT- and B cells (each 11%). In contrast, spleen and lymph nodes were dominated by B and T cells (spleen: 56% and 32%; lymph nodes: 33% and 62%).
    CONCLUSIONS: Ovarian immune cells are scarce in healthy young mice. Apart from a relatively large T-cell population, the ovarian immune compartment is dominated by innate immune cells, particularly macrophages and natural killer cells, which is in line with the multifarious role of macrophages in multiple aspects of ovarian physiology. In contrast, adaptive immune cells such as B and T lymphocytes are primarily enriched in secondary lymphoid organs, including the spleen and lymph nodes.
    Keywords:  Aging; Immune cells; Ovary
    DOI:  https://doi.org/10.1186/s13048-026-02177-9
  11. Genes Dis. 2026 Sep;13(5): 101900
    Identification of the homozygous truncating mutation in CNTD1 as a novel genetic cause of diminished ovarian reserve.
    Liwei Sun, Yi Chen, Keya Tong, Weiwei Liu, Bei Liu, Yifan Wang, Guoning Huang, Jingyu Li.
      Diminished ovarian reserve (DOR) is one of the leading causes of infertility, which accounts for approximately 10% of women seeking fertility treatment. However, their genetic etiology and pathogenesis are largely unknown. Recently, cyclin N-terminal domain containing 1 (CNTD1) was reported to be critical for meiosis in female mice. However, no CNTD1 mutation has been reported to be associated with reproductive diseases in humans. Here, we firstly identified CNTD1 mutation in a DOR patient. The homozygous CNTD1 splicing mutation (NM_173478.3: c.823-2A > G) was identified in a DOR patient by whole-exome sequencing. The pathogenic effect of the identified CNTD1 splicing mutation was investigated by sequencing the transcript from the patient's primary leukocytes and minigene assay. A CRISPR/Cas9-mediated Cntd1 knockout mouse line was generated to investigate its role in ovarian function. The pathogenic mechanism of the identified CNTD1 mutation was further verified by functional studies. As a result, minigene assay and direct transcript sequencing from the patient revealed that this splicing mutation induced aberrant exon skipping. The homozygous truncating mutation in CNTD1 result in the production of a C-terminally truncated protein that cannot interact with its essential meiosis partner of proline-rich protein 19 (PRR19). Cntd1 knockout mice were characterized by dramatically reduced size of ovaries and prematurely depleted follicular pools, which indicated its role in female fertility. In conclusion, this study is the first to identify CNTD1 as a novel genetic cause for DOR patients and suggests the essential role of CNTD1 in human reproduction.
    Keywords:  CNTD1; Diminished ovarian reserve; Novel genetic cause; Splicing mutation; Whole-exome sequencing
    DOI:  https://doi.org/10.1016/j.gendis.2025.101900
  12. JAMA. 2026 Jun 26.
    PCOS Is Now PMOS-Will a New Name Translate to Improved Clinical Care?
    Kate Schweitzer.
      
    DOI:  https://doi.org/10.1001/jama.2026.10402
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