Aging Ovary Research Articles

Single-cell profiling of mouse and primate ovaries identifies high levels of EGFR for stromal cells in ovarian aging

Increased ovarian fibrosis and an expanded stromal cell compartment are the main characteristics of aging ovaries. However, the molecular mechanisms and the key factor of stromal cells underlying ovarian aging remain unclear. Here, we explored single-cell transcriptomic data of ovaries from the adult mouse (4,363 cells), young (1,122 cells), and aged (1,479 cells) non-human primates (NHPs) to identify expression patterns of stromal cells between young and old ovaries. An increased number of stromal cells (p= 0.0386) was observed in aged ovaries of NHPs, with enrichment processes related to the collagen-containing extracellular matrix. In addition, differentially expressed genes of stromal cells between young and old ovaries were regulated by ESR1 (p= 7.94E-08) and AR (p= 1.99E-05). Among them, EGFR was identified as the common target and was highly expressed (p= 7.69E-39) in old ovaries. In human ovaries, the correlated genes of EGFR were associated with the process of the cell-substrate junction. Silencing of EGFR in human ovarian stromal cells led to the reduction of cell-substrate junction via regulating phosphorylation modification of the AKT-mTOR signaling pathway and stromal cell marker genes. Overall, we identified high levels of EGFR for stromal cells in ovarian aging, which provides insight into the cell type-specific molecular mechanisms underlying ovarian aging at single-cell resolution.

Determining the impact of FSH glycosylation variants on the pre-antral follicle transcriptome in the ageing ovary

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Transcriptomic Interaction between Young Fecal Transplantation and Perfluorobutanesulfonate in Aged Zebrafish Gonads.

The transfer of young fecal microbiota has been found to significantly refresh the reproductive endocrine system and effectively ameliorate the toxicity of perfluorobutanesulfonate (PFBS) in aged zebrafish recipients. However, the mechanisms underlying the antagonistic action of young fecal microbiota against the reproductive endocrine toxicity of PFBS remain largely unknown. In this study, the aged zebrafish were transplanted with feces from young donors and then exposed to PFBS for 14 days. After exposure, the shift in the transcriptomic fingerprint of the gonads was profiled by using high-throughput sequencing, aiming to provide mechanistic clues into the interactive mode of action between young fecal transplantation and PFBS's innate toxicity. The results showed that the gene transcription pattern associated with protein and lipid synthesis in the gonads of the aged individuals was quite different from the young counterparts. It was intriguing that the transplantation of young feces established a youth-like transcriptomic phenotype in the elderly recipients, thus attenuating the functional decline and maintaining a healthy aging state of the gonads. A sex specificity response was clearly observed. Compared to the aged females, more metabolic pathways (e.g., glycine, serine, and threonine metabolism; glyoxylate and dicarboxylate metabolism; pyrimidine metabolism) were significantly enriched in aged males receiving young feces transplants. PFBS dramatically altered the transcriptome of aged testes, while a much milder effect was observable in aged ovaries. Accordingly, a suite of biological processes related to germ cell proliferation were disrupted by PFBS in aged males, including the ECM-receptor interaction, retinol metabolism, and folate biosynthesis. In aged ovaries exposed to PFBS, mainly the fatty acid and arginine biosynthesis pathway was significantly affected. However, these transcriptomic disorders caused by PFBS were largely mitigated in aged gonads by transferring young feces. Overall, the present findings highlighted the potential of young fecal transplantation to prevent the functional compromise of gonads resulting from aging and PFBS.

Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism.

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases.

Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice.

Ovarian fibrosis is a pathological condition associated with aging and is responsible for a variety of ovarian dysfunctions. Given the known contributions of tissue fibrosis to tumorigenesis, it is anticipated that ovarian fibrosis may contribute to ovarian cancer risk. We recently reported that diabetic postmenopausal women using metformin had ovarian collagen abundance and organization that were similar to premenopausal ovaries from nondiabetic women. In this study, we investigated the effects of aging and metformin on mouse ovarian fibrosis at a single-cell level. We discovered that metformin treatment prevented age-associated ovarian fibrosis by modulating the proportion of fibroblasts, myofibroblasts, and immune cells. Senescence-associated secretory phenotype (SASP)-producing fibroblasts increased in aged ovaries, and a unique metformin-responsive subpopulation of macrophages emerged in aged mice treated with metformin. The results demonstrate that metformin can modulate specific populations of immune cells and fibroblasts to prevent age-associated ovarian fibrosis and offers a new strategy to prevent ovarian fibrosis.

Young fecal transplantation mitigates the toxicity of perfluorobutanesulfonate and potently refreshes the reproductive endocrine system in aged recipients

The aging process leads to the gradual impairment of physiological functions in the elderly, making them more susceptible to the toxicity of environmental pollutants. In this study, aged zebrafish were first transplanted with the feces from young donors and subsequently exposed to perfluorobutanesulfonate (PFBS), an emerging persistent toxic pollutant. The interaction between young fecal transplant and PFBS inherent toxicity was investigated, focusing on reproductive performance and the underlying endocrine mechanism. The results showed that PFBS single exposure increased the percentage of primary oocytes in aged ovaries, implying a blockage of oogenesis. However, transplantation of young feces completely abolished the effects of PFBS and promoted oocyte growth, as inferred by the obviously lower percentage of primary oocytes, accompanied by a higher percentage of cortical-alveolar oocytes. Measurement of sex hormones found that PFBS significantly increased the blood concentration of estradiol and disrupted the balance of sex hormones in the elderly, which were, however, efficiently ameliorated by young fecal transplantation. Based on gene transcription along the hypothalamic-pituitary-gonadal axis, hierarchical clustering analysis showed similar profiles of the reproductive endocrine system between young zebrafish and their aged counterparts transplanted with young feces, implying that young fecal transplantation might refresh the endocrine system of aged recipients, regardless of PFBS exposure. The increased transcription levels of mRNAs encoding vitellogenin, activinBA, and membrane bound progestin receptors would cooperatively enhance the growth and maturation of oocytes in the ovaries of aged zebrafish receiving young fecal transplantation. Overall, the findings highlighted the potent efficacy of young fecal transplantation to improve the reproductive function of the elderly and to mitigate the endocrine disruption of an environmental pollutant. These findings are expected to broaden our understanding of the efficacy, mechanisms, and application of fecal transplantation.

Ginsenosides improve reproductive capability of aged female Drosophila through mechanism dependent on ecdysteroid receptor (ECR) and steroid signaling pathway.

Aging ovaries caused diminished fertility and depleted steroid hormone level. Ginsenosides, the active ingredient in ginseng, had estrogen-like hormonal effects. Although ginsenosides were well known for their ability to alleviate many age-related degenerative diseases, the effect of ginsenosides on the decline in reproductive capability caused by aging, as well as the mechanism, are unknown. We found that ginsenosides improved the quantity and quality of the offspring, prolonged life and restored muscle ability in aged female Drosophila. In addition, ginsenosides inhibited ovarian atrophy and maintained steroid hormone 20-Hydroxyecdysone (20E) and juvenile-preserving hormone (JH)) levels. Ginsenosides activated ecdysteroid receptor (ECR) and increased the expression of the early transcription genes E74 and Broad (Br), which triggered steroid signaling pathway. Meanwhile, ginsenosides promoted JH biosynthesis by increasing the expression of Hydroxyl-methylglutaryl-CoA reductase (HMGR) and juvenile hormone acid O-methyltransferase (JHAMT). Subsequently, JH was bound to Methoprene Tolerant (Met) and activated the transcription of the responsive gene Kruppel Homolog 1 (Kr-h1), which coordinated with 20E signaling to promote the reproduction of aged female Drosophila. The reproductive capacity and steroid hormone levels were not improved and the steroid signaling pathway was not activated in ginsenoside-treated ECR knockout Drosophila. This suggested that ginsenosides played a role dependent on targeted ECR. Furthermore, 17 kinds of ginsenoside monomers were identified from the total ginsenosides. Among them, Rg1, Re and Rb1 improved the reproductive capacity and steroid hormone levels of aged female Drosophila, which has similar effects to the total ginsenoside. These results indicated that ginsenosides could enhance the reproductive capacity of aged female Drosophila by activating steroid signals dependent on nuclear receptor ECR. In addition, ginsenoside monomers Rg1, Rb1 and Re are the main active components of total ginsenosides to improve reproductive ability. This will provide strong evidence that ginsenosides had the potential to alleviate age-induced reproductive degradation.

Dysfunctional Ovarian Stem Cells Due to Neonatal Endocrine Disruption Result in PCOS and Ovarian Insufficiency in Adult Mice.

Polycystic ovarian syndrome (PCOS) is a common global cause of anovulatory infertility but underlying etiology leading to PCOS still remains elusive. Fetal and perinatal endocrine disruption reportedly affects germ cell nests (GCN) breakdown, meiosis, and primordial follicle (PF) assembly with unassembled oocytes in neonatal ovaries. We recently reported that very small embryonic-like stem cells (VSELs) and ovarian stem cells (OSCs) express ERα, ERβ and FSHR, undergo distinct cyclic changes and neo-oogenesis encompassing GCN formation, meiosis, and primordial follicle (PF) assembly on regular basis in adult mice ovaries and these GCN are arrested in pre-meiotic or early meiotic stage in aged ovaries. Present study was undertaken to evaluate whether neonatal exposure to endocrine disruption (estradiol E2 or diethylstilbestrol DES) affects ovarian stem cells and their differentiation (neo-oogenesis) and PF assembly in adult 100 days old ovaries. Neonatal exposure to E2 resulted in typical features of PCOS including hyperandrogenism, infertility, increased stromal compartment, absent corpus lutea, and cystic follicles whereas DES treated ovaries showed rapid recruitment of follicles in young ovaries and multi-ovular/cystic follicles. Ovary surface epithelial cells smears showed large numbers of growth-arrested GCN in zygotene/pachytene with increased expression of Mlh-1 and Scp-1 suggesting defects at synapsis and recombination stages during prophase-1 of meiosis. Being immortal and expression of ERα and ERβ makes VSELs directly vulnerable to carry developmental endocrine insults to adult life. Dysfunction of VSELs/OSCs possibly results in oocyte defects observedin our study in PCOS/POI besides the widely reported defects in granulosa cells.

Fecal microbiota transplantation from young donor mice improves ovarian function in aged mice

Advanced maternal age is characterized by declines in the quantity and quality of oocytes in the ovaries, and the aging process is accompanied by changes in gut microbiota composition. However, little is known about the relationship between gut microbiota and ovarian aging. By using fecal microbiota transplantation (FMT) to transplant material from young (5-week-old) into aged (42-week-old) mice, we find that the composition of gut microbiota in FMT-treated mice presents a “younger-like phenotype” and an increase of commensal bacteria, such as Bifidobacterium and Ruminococcaceae. Moreover, the FMT-treated mice show increased anti-inflammatory cytokine IL-4 and decreased pro-inflammatory cytokine IFN-γ. Fertility tests for assessing ovarian function reveal that the first litter size of female FMT-treated mice is significantly higher than that of the non-FMT group. Morphology analysis demonstrates a dramatic decrease in follicle atresia and apoptosis as well as an increase in cellular proliferation in the ovaries of the FMT-treated mice. Our results also show that FMT improves the immune microenvironment in aged ovaries, with decreased macrophages and macrophage-derived multinucleated giant cells (MNGCs). These results suggest that FMT from young donors could be a good choice for delaying ovarian aging.

Menstrual blood-derived stem cells and its mitochondrial treatment improve the ovarian condition of aged mice.

Aging causes a decline in ovarian function and may contribute to ovarian failure and infertility. We investigated the effect of menstrual blood-derived mesenchymal stem cells (MenSCs) and their mitochondria on ovarian function in aged mice. We performed two treatment protocols: i) ovaries of recipient aged mice were treated in vivo with MenSCs 3D alginate gel; ii) ovaries were injected with mitochondria suspension and then incubated with mitochondrial 3D gel. Seven days after treatment, ovaries were harvested for histological assessment by HE staining and transcriptomic analysis by RNA-seq. Our data showed that after incubation with stem cell 3D gel, the MenSCs could be detected in the recipient mouse ovary. HE staining showed that the follicular state of aging ovary improved with both treatments. RNA-seq analysis showed that mitochondrial pathway-related genes were upregulated and significantly enriched in the ovaries treated by MenSCs or their mitochondria.Conclusions: Treatment with MenSCs or their mitochondria can enhance the expression of mitochondrial pathway-related genes and promote the recovery of ovarian function in aged mice.

Changes in IL-16 Expression in the Ovary during Aging and Its Potential Consequences to Ovarian Pathology.

Aging in females is not only associated with the changes in hormonal status but is also responsible for dysregulation of immune functions in various organs including ovaries. The goal of this study was to determine whether the expression of interleukin 16 (IL-16), a proinflammatory and chemoattractant cytokine, changes during ovarian aging, to determine factors involved in such changes in IL-16 expression, and to examine if changes in IL-16 expression during aging predisposes the ovary to pathologies. Ovarian tissues from premenopausal women (30-50 years old), women at early menopause (55-59 years old), and late menopause (60-85 years old) were used. In addition, tumor tissues from patients with ovarian high-grade serous carcinoma at early stage (n = 5) were also used as reference tissue for comparing the expression of several selected markers in aging ovaries. The expression of IL-16, frequency of macrophages (a source of IL-16) and expression of microRNA (miR) 125a-5p (a regulator of IL-16 gene) were performed by immunohistochemistry, immunoblotting, and gene expression assays. In addition, we examined changes in nuclear expression of IL-16 expression with regards to exposure to follicle-stimulating hormone (FSH) by in vitro cell culture assays with human ovarian cancer cells. The frequencies of IL-16 expressing cells were significantly higher in ovarian stroma in women at early and late menopause as compared with premenopausal women (P < 0.0001). Similar patterns were also observed for macrophages. Expression of miR-125a-5p decreased significantly (P < 0.001) with the increase in IL-16 expression during aging. Furthermore, expression of nuclear IL-16 increased remarkably upon exposure to FSH. Consequently, ovarian aging is associated with increased expression of IL-16 including its nuclear fraction. Therefore, persistent high levels of FSH in postmenopausal women may be a factor for enhanced expression of IL-16. Effects of increased nuclear fraction of IL-16 need to be examined.

Aged mice ovaries harbor stem cells and germ cell nests but fail to form follicles

BackgroundWe recently published evidence to suggest that two populations of stem cells including very small embryonic-like stem cells (VSELs) and ovarian stem cells (OSCs) in ovary surface epithelium (OSE) undergo proliferation/differentiation, germ cell nests (GCN) formation, meiosis and eventually differentiate into oocytes that assemble as primordial follicles on regular basis during estrus cycle. Despite presence of stem cells, follicles get exhausted with advancing age in mice and result in senescence equivalent to menopause in women. Stem cells in aged ovaries can differentiate into oocytes upon transplantation into young ovaries, however, it is still not well understood why follicles get depleted with advancing age despite the presence of stem cells. The aim of the present study was to study stem cells and GCN in aged ovaries.MethodsOSE cells from aged mice (> 18 months equivalent to > 55 years old women) were enzymatically separated and used to study stem cells. Viable (7-AAD negative) VSELs in the size range of 2–6 µm with a surface phenotype of Lin−CD45−Sca-1+ were enumerated by flow cytometry. Immuno-fluorescence and RT-PCR analysis were done to study stem/progenitor cells (OCT-4, MVH, SCP3) and transcripts specific for VSELs (Oct-4A, Sox-2, Nanog), primordial germ cells (Stella), germ cells (Oct-4, Mvh), early meiosis (Mlh1, Scp1) and ring canals (Tex14).ResultsPutative VSELs and OSCs were detected as darkly stained, spherical cells with high nucleo-cytoplasmic ratio along with germ cells nests (GCN) in Hematoxylin & Eosin stained OSE cells smears. Germ cells in GCN with distinct cytoplasmic continuity expressed OCT-4, MVH and SCP3. Transcripts specific for stem cells, early meiosis and ring canals were detected by RT-PCR studies.ConclusionRather than resulting as a consequence of accelerated loss of primordial follicle and their subsequent depletion, ovarian senescence/menopause occurs as a result of stem cells dysfunction. VSELs and OSCs exist along with increased numbers of GCNs arrested in pre-meiotic or early meiotic stage in aged ovaries and primordial follicle assembly is blocked possibly due to age-related changes in their microenvironment.

Secoisolariciresinol Diglucoside Improves Ovarian Reserve in Aging Mouse by Inhibiting Oxidative Stress.

Ovarian reserve is a key factor in the reproductive function of the ovaries. Ovarian aging is characterized by a gradual decline in the quantity and quality of follicles. The underlying mechanism of ovarian aging is complex and age-related oxidative stress is considered one of the most likely factors. Secoisolariciresinol diglucoside (SDG) has been shown to have good scavenging ability against reactive oxygen species (ROS) which slowly accumulates in ovarian tissues. However, it is unknown whether SDG had beneficial effects on aging ovaries. In this study, we used 37-week-old female C57BL/6J mouse as a natural reproductive aging model to evaluate the role of SDG in ovarian aging. SDG (7 and 70 mg/kg) intragastric administration was performed in the mice daily. After 8 weeks, the effects of SDG on aging ovaries were evaluated by counting the number of follicles and the expression of follicle-stimulating hormone receptors (FSHR) in the ovary. The mechanism of SDG on the aging ovaries was further explored through ovarian metabolomics. It was found that SDG can effectively increase the number of growing follicles and increase the expression of the FSHR protein. The metabolomics results showed that the ovaries in the SDG intervention group achieved better uptake and transport of nutrients, including amino acids and glucose that are necessary for the development of oocytes. At the same time, the ovaries of the SDG intervention group showed that the drug reduced ROS generation. Additionally, we found that ovarian telomere length and ovarian mitochondrial DNA copy number that are highly susceptible to ROS damage and are also related to aging. The results showed that SDG can significantly increase mitochondrial DNA copy number and slow down the process of telomere shortening. These data indicate that SDG improves ovarian reserve by inhibiting oxidative stress.

Ovarian Aging: Role of Pituitary-Ovarian Axis Hormones and ncRNAs in Regulating Ovarian Mitochondrial Activity.

The number of mitochondria in the oocyte along with their functions (e.g., energy production, scavenger activity) decline with age progression. Such multifaceted functions support several processes during oocyte maturation, ranging from energy supply to synthesis of the steroid hormones. Hence, it is hardly surprising that their impairment has been reported in both physiological and premature ovarian aging, wherein they are crucial players in the apoptotic processes that arise in aged ovaries. In any form, ovarian aging implies the progressive damage of the mitochondrial structure and activities as regards to ovarian germ and somatic cells. The imbalance in the circulating hormones and peptides (e.g., gonadotropins, estrogens, AMH, activins, and inhibins), active along the pituitary-ovarian axis, represents the biochemical sign of ovarian aging. Despite the progress accomplished in determining the key role of the mitochondria in preserving ovarian follicular number and health, their modulation by the hormonal signalling pathways involved in ovarian aging has been poorly and randomly explored. Yet characterizing this mechanism is pivotal to molecularly define the implication of mitochondrial dysfunction in physiological and premature ovarian aging, respectively. However, it is fairly difficult considering that the pathways associated with ovarian aging might affect mitochondria directly or by altering the activity, stability and localization of proteins controlling mitochondrial dynamics and functions, either unbalancing other cellular mediators, released by the mitochondria, such as non-coding RNAs (ncRNAs). We will focus on the mitochondrial ncRNAs (i.e., mitomiRs and mtlncRNAs), that retranslocate from the mitochondria to the nucleus, as active players in aging and describe their role in the nuclear-mitochondrial crosstalk and its modulation by the pituitary-ovarian hormone dependent pathways. In this review, we will illustrate mitochondria as targets of the signaling pathways dependent on hormones and peptides active along the pituitary/ovarian axis and as transducers, with a particular focus on the molecules retrieved in the mitochondria, mainly ncRNAs. Given their regulatory function in cellular activities we propose them as potential diagnostic markers and/or therapeutic targets.

Estrogens and the Schrödinger's Cat in the Ovarian Tumor Microenvironment.

Simple SummaryOvarian cancer is a complex pathology for which we require effective screening and therapeutical strategies. Apart from the cancer cell portion, there exist plastic immune and non-immune cell populations, jointly constituting the context-adaptive tumor microenvironment, which is pivotal in tumorigenesis. Estrogens might be synthesized in the ovarian tumor tissue and actively contribute to the shaping of an immunosuppressive microenvironment. Current immune therapies have limited effectiveness as a multitude of factors influence the outcome. A thorough understanding of the ovarian cancer biology is crucial in the efforts to reestablish homeostasis.Ovarian cancer is a heterogeneous disease affecting the aging ovary, in concert with a complex network of cells and signals, together representing the ovarian tumor microenvironment. As in the “Schrödinger’s cat” thought experiment, the context-dependent constituents of the—by the time of diagnosis—well-established tumor microenvironment may display a tumor-protective and -destructive role. Systemic and locally synthesized estrogens contribute to the formation of a pro-tumoral microenvironment that enables the sustained tumor growth, invasion and metastasis. Here we focus on the estrogen biosynthetic and metabolic pathways in ovarian cancer and elaborate their actions on phenotypically plastic, estrogen-responsive, aging immune cells of the tumor microenvironment, altogether highlighting the multicomponent-connectedness and complexity of cancer, and contributing to a broader understanding of the ovarian cancer biology.

The Interrelationship Between Female Reproductive Aging and Survival.

The link between survival and reproductive function is demonstrated across many species and is under both long-term evolutionary pressures and short-term environmental pressures. Loss of reproductive function is common in mammals and is strongly correlated with increased rates of disease in both males and females. However, the reproduction-associated change in disease rates is more abrupt and more severe in women, who benefit from a significant health advantage over men until the age of menopause. Young women with early ovarian failure also suffer from increased disease risks, further supporting the role of ovarian function in female health. Contemporary experiments where the influence of young ovarian tissue has been restored in postreproductive-aged females with surgical manipulation were found to increase survival significantly. In these experiments, young, intact ovaries were used to replace the aged ovaries of females that had already reached reproductive cessation. As has been seen previously in primitive species, when the young mammalian ovaries were depleted of germ cells prior to transplantation to the postreproductive female, survival was increased even further than with germ cell-containing young ovaries. Thus, extending reproductive potential significantly increases survival and appears to be germ cell and ovarian hormone-independent. The current review will discuss historical and contemporary observations and theories that support the link between reproduction and survival and provide hope for future clinical applications to decrease menopause-associated increases in disease risks.

The m6A mRNA demethylase FTO in granulosa cells retards FOS-dependent ovarian aging

Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3′UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.

Therapeutic Potential of HUMSCs in Female Reproductive Aging.

With the development of regenerative medicine, stem cells are being considered more frequently for the treatment of reproductive aging. Human umbilical cord mesenchymal stem cells have been reported to improve the reserve function of aging ovaries through their homing and paracrine effects. In this process, paracrine factors secreted by stem cells play an important role in ovarian recovery. Although the transplantation of human umbilical cord mesenchymal stem cells to improve ovarian function has been studied with great success in animal models of reproductive aging, their application in clinical research and therapy is still relatively rare. Therefore, this paper reviews the role of human umbilical cord mesenchymal stem cells in the treatment of reproductive aging and their related mechanisms, and it does so in order to provide a theoretical basis for further research and clinical treatment.

Macrophage-derived multinucleated giant cells: hallmarks of the aging ovary.

Inflammaging is a state of chronic, low-grade inflammation associated with aging which contributes to age-related diseases. Recently, an age-associated increase in inflammation has been documented in the mammalian ovary, which is accompanied by a shift in the immune cell profile. In this Point of View article, we consider a unique population of macrophage-derived multinucleated giant cells, found in reproductively old mouse ovaries, as potential markers or functional drivers of inflammation in ovarian aging.

High Frequency of Intravenous Injection of Human Adipose Stem Cell Conditioned Medium Improved Embryo Development of Mice in Advanced Maternal Age through Antioxidant Effects.

Simple SummaryIn this study, we examined the anti-oxidative effect of human adipose stem cell conditioned medium (ASC-CM) on the ovary and uterus of mice in advanced maternal age (AMA) and the optimal conditions of intravenous injection for ASC-CM administration. Human ASC-CM upregulated expression of antioxidant genes, restored the quality of oocytes derived from aged ovaries and resulted in improved in vitro and in vivo embryo development. The anti-oxidative effect human ASC-CM was optimized with high frequency of administration. Comprehensively, our study successfully introduced the potential of ASC-CM as an antioxidant intervention against age-related infertility in AMA.Advanced maternal age (AMA) has become prevalent globally. With aging, weakened antioxidant defense causes loss of normal function in the ovary and uterus due to oxidative stress. Here, we aimed to improve embryo development in AMA mice by intravenous injection (IV) of human adipose stem cell conditioned medium (ASC-CM) at various frequencies and intervals as an antioxidant intervention. Four- and six-month-old female ICR (Institute of Cancer Research) mice were randomly divided into groups IV treated with human ASC-CM under different conditions, and in vitro and in vivo embryo development were evaluated. Consequently, compared to the control group, blastocyst formation rate of parthenotes was significantly promoted in 4-month-old mice and the mean number of implanted fetuses after natural mating was significantly increased by approximately two-fold in 6-month-old mice. Through gene analysis, the anti-apoptotic and anti-oxidative effects of human ASC-CMs were confirmed in the ovaries and uterus of pregnant mice at both ages. In particular, ovarian expression of gpx1 and catalase drastically increased in 6-month-old mice. Furthermore, the levels of gpx1 and catalase were further increased, with a high frequency of injection regardless of age. Thus, we demonstrated for the first time the anti-oxidative effect of human ASC-CM administration against ovarian aging and the optimal injection condition.