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

AbstractMultifunctional 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.

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Ovarian aging in squirrel monkeys (Saimiri sciureus)

Reproduction ◽

10.1530/rep-08-0449 ◽

2009 ◽

Vol 138 (5) ◽

pp. 793-799 ◽

Cited By ~ 24

Author(s):

Margaret L Walker ◽

Daniel C Anderson ◽

James G Herndon ◽

Lary C Walker

Keyword(s):

Granulosa Cell ◽

Granulosa Cells ◽

Reproductive Potential ◽

Reproductive Period ◽

Squirrel Monkeys ◽

Saimiri Sciureus ◽

Primordial Follicles ◽

Granulosa Cell Tumors ◽

Ovarian Aging ◽

Age Related

In female squirrel monkeys (Saimiri sciureus), the reproductive period normally extends from ∼2.5 years to the mid-teens. In the present study, we examined the age-associated cytological changes in the ovaries of 24 squirrel monkeys ranging in age from newborn to ∼20 years. We found a significant, age-related decline in the number of primordial follicles, with the most pronounced loss occurring between birth and 5 years. After ∼8 years of age, relatively few primordial follicles were evident in the ovarian sections examined. An unusual feature of the aging squirrel monkey ovary is the emergence of highly differentiated, encapsulated clusters of granulosa cells that increase in size and number, particularly after the age of 8 years. Many of these cells express anti-Müllerian hormone, and, histologically, the clusters resemble granulosa cell tumors in humans. However, granulosa cell clusters (GCCs) are present in both ovaries of all older squirrel monkeys, and they display no obvious signs of malignancy, suggesting that they are a normal feature of ovarian aging in this species. Our findings indicate that reproductive senescence in female squirrel monkeys, as in other primates, involves the inexorable depletion of ovarian follicles. In addition, the consistent appearance of abundant, well-differentiated clusters of granulosa cells in older squirrel monkeys, prior to the cessation of reproduction, suggests that these structures may influence the later stages of reproductive potential in this species. Analysis of GCCs in older squirrel monkeys also could yield insights into the pathophysiology of granulosa cell tumors in humans.

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Inhibition of the NLRP3 inflammasome prevents ovarian aging

Science Advances ◽

10.1126/sciadv.abc7409 ◽

2021 ◽

Vol 7 (1) ◽

pp. eabc7409

Author(s):

José M. Navarro-Pando ◽

Elísabet Alcocer-Gómez ◽

Beatriz Castejón-Vega ◽

Elena Navarro-Villarán ◽

Mónica Condés-Hervás ◽

...

Keyword(s):

Granulosa Cells ◽

Nlrp3 Inflammasome ◽

Therapeutic Target ◽

Female Fertility ◽

Reproductive Aging ◽

Ovarian Insufficiency ◽

Ovarian Aging ◽

Age Dependent ◽

Estradiol Levels

Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging. High expression of NLRP3, caspase-1, and IL-1β was also observed in granulosa cells from patients with ovarian insufficiency. Ablation of NLRP3 improved the survival and pregnancy rates and increased anti-Müllerian hormone levels and autophagy rates in ovaries. Deficiency of NLRP3 also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3−/− mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.

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Constitutive Expression of TERT Enhances β-Klotho Expression and Improves Age-Related Deterioration in Early Bovine Embryos

International Journal of Molecular Sciences ◽

10.3390/ijms22105327 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5327

Author(s):

Lianguang Xu ◽

Muhammad Idrees ◽

Myeong-Don Joo ◽

Tabinda Sidrat ◽

Yiran Wei ◽

...

Keyword(s):

Granulosa Cells ◽

Constitutive Expression ◽

Growth Factor Receptor ◽

Oocyte Quality ◽

Low Fertility ◽

Treatment Groups ◽

Age Related ◽

Early Embryos ◽

Plasmid Injection ◽

Telomere Lengthening

Age-associated decline in oocyte quality is one of the dominant factors of low fertility. Aging alters several key processes, such as telomere lengthening, cell senescence, and cellular longevity of granulosa cells surrounding oocyte. To investigate the age-dependent molecular changes, we examined the expression, localization, and correlation of telomerase reverse transcriptase (TERT) and β-Klotho (KLB) in bovine granulosa cells, oocytes, and early embryos during the aging process. Herein, cumulus-oocyte complexes (COCs) obtained from aged cows (>120 months) via ovum pick-up (OPU) showed reduced expression of β-Klotho and its co-receptor fibroblast growth factor receptor 1 (FGFR1). TERT plasmid injection into pronuclear zygotes not only markedly enhanced day-8 blastocysts’ development competence (39.1 ± 0.8%) compared to the control (31.1 ± 0.5%) and D-galactose (17.9 ± 1.0%) treatment groups but also enhanced KLB and FGFR1 expression. In addition, plasmid-injected zygotes displayed a considerable enhancement in blastocyst quality and implantation potential. Cycloastragenol (CAG), an extract of saponins, stimulates telomerase enzymes and enhances KLB expression and alleviates age-related deterioration in cultured primary bovine granulosa cells. In conclusion, telomerase activation or constitutive expression will increase KLB expression and activate the FGFR1/β-Klotho pathway in bovine granulosa cells and early embryos, inhibiting age-related malfunctioning.

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Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders

Journal of Ovarian Research ◽

10.1186/s13048-020-00757-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yan Gong ◽

Jesse Li-Ling ◽

Dongsheng Xiong ◽

Jiajing Wei ◽

Taiqing Zhong ◽

...

Keyword(s):

Granulosa Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Mrna Levels ◽

Clinical Trial Registry ◽

Altered Expression ◽

Vitro Fertilization ◽

Age Related ◽

Tertiary Teaching ◽

Poor Ovarian Responders

Abstract Background Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes play important roles in folliculogenesis. Altered expression of the two have been found among patients with poor ovarian response (POR). In this prospective cohort study, we have determined the expression of the GDF9 and BMP15 genes in follicle fluid (FF) and granulosa cells (GCs) derived from poor ovarian responders grouped by age, and explored its correlation with the outcome of in vitro fertilization and embryo transfer (IVF-ET) treatment. Methods A total of 196 patients with POR were enrolled from a tertiary teaching hospital. The patients were diagnosed by the Bologna criteria and sub-divided into group A (< 35 year old), group B (35–40 year old), and group C (> 40 year old). A GnRH antagonist protocol was conducted for all patients, and FF and GCs were collected after oocyte retrieval. Expression of the GDF9 and BMP15 genes in the FF and GCs was determined with enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Results Compared with group C, groups A and B had significantly more two pronuclei (2PN) oocytes and transplantable embryos, in addition with higher rates of implantation and clinical pregnancy (P < 0.05). The expression level of GDF9 and BMP15 genes in the FF and GCs differed significantly among the three groups (P < 0.05), showing a trend of decline along with age. The ratio of GDF9/BMP15 mRNA levels were similar among the three groups (P > 0.05). The relative levels of GDF9 and BMP15 proteins in GCs have correlated with the relative mRNA levels in GCs and protein concentrations in FF (P < 0.05). Conclusions For poor ovarian responders, in particular those over 40, the expression of GDF9 and BMP15 is declined along with increased age and in accompany with poorer oocyte quality and IVF outcome, whilst the ratio of GDF9/BMP15 mRNA levels remained relatively constant. Trial registration Chinese Clinical Trial Registry Center (ChiCTR1800016107). Registered on 11 May 2018.

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LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

JCI Insight ◽

10.1172/jci.insight.131928 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 7

Author(s):

Mayur Choudhary ◽

Ebraheim N. Ismail ◽

Pei-Li Yao ◽

Faryan Tayyari ◽

Roxana A. Radu ◽

...

Keyword(s):

Macular Degeneration ◽

Therapeutic Target ◽

Age Related Macular Degeneration ◽

Potential Therapeutic Target ◽

Age Related

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Targeting lateral inhibition to improve vision following macular degeneration

10.1101/2020.02.21.953828 ◽

2020 ◽

Author(s):

M Rizzi ◽

K Powell ◽

MR Robinson ◽

T Matsuki ◽

J Hoke ◽

...

Keyword(s):

Macular Degeneration ◽

Lateral Inhibition ◽

Visual Function ◽

Therapeutic Target ◽

Age Related Macular Degeneration ◽

Photoreceptor Degeneration ◽

Specific Mechanism ◽

Inhibitory Circuits ◽

Age Related ◽

Developed World

AbstractMacular degeneration is the leading cause of blindness in the developed world. Whilst most patients lose sight owing to atrophic changes, no treatments currently exist that improve the vision deficit due to atrophy. Here, we identify loss of lateral inhibition as a specific mechanism by which photoreceptor degeneration reduces visual function beyond the atrophic area. We find that this inhibition is adaptive, and that if modulated can improve visual function, making inhibitory circuits an unexpected therapeutic target for age related macular degeneration and related disorders.

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Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review

Advances in Therapy ◽

10.1007/s12325-020-01287-0 ◽

2020 ◽

Vol 37 (4) ◽

pp. 1407-1424 ◽

Cited By ~ 3

Author(s):

Mateo Amaya-Montoya ◽

Agustín Pérez-Londoño ◽

Valentina Guatibonza-García ◽

Andrea Vargas-Villanueva ◽

Carlos O. Mendivil

Keyword(s):

Cellular Senescence ◽

Therapeutic Target ◽

Age Related

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BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging

Human Reproduction Update ◽

10.1093/humupd/dmz043 ◽

2019 ◽

Vol 26 (1) ◽

pp. 43-57 ◽

Cited By ~ 12

Author(s):

Volkan Turan ◽

Kutluk Oktay

Keyword(s):

Clinical Evidence ◽

Strand Break ◽

Oocyte Quality ◽

Repair Pathway ◽

Dsb Repair ◽

Ovarian Aging ◽

Age Related ◽

Dna Double Strand Break ◽

Targeted Treatments ◽

Oocyte Aging

Abstract BACKGROUND Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated (ATM)-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and ATM-mediated DNA DSB repair in ovarian aging. OBJECTIVE AND RATIONALE Although there are several competing or complementary theories, given the growing evidence tying BRCA function and ATM-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. SEARCH METHODS We searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. OUTCOMES Laboratory studies provided robust and reproducible evidence that BRCA1 function and ATM-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other ATM-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related ATM-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. WIDER IMPLICATIONS The existing data suggest that the BRCA-related ATM-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.

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