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Ovarian aging reduced the quality of oocytes, resulting in age-related female infertility. It is reported that mesenchymal stem cells (MSCs) therapy can improve age-related ovarian function decline and the success rate of in vitro maturation (IVM) in assisted reproductive therapy. In order to investigate the effectiveness and mechanisms of MSCs to enhance oocyte quality of cumulus oocyte complexes (COCs) in advanced age, this study focus on the respective functional improvement of oocytes and granulosa cells (GCs) from aging mice and further to explore and verify the possible mechanisms. Here, we studied a popular but significant protein of follicular development, Forkhead box O-3a (FOXO3a), which is a transcription factor that mediates a variety of cellular processes, but the functions of which in regulating oocyte quality in MSCs therapy still remain inconclusive. In this study, the RNA-seq data of metaphase II (MII) oocytes and GCs isolated from COCs confirmed that, GCs of immature follicles show the most potential to be the targeted cells of bone marrow mesenchymal stem cells (BMSCs) by FOXO3a signaling pathway. Furthermore, we demonstrated the effectiveness of BMSCs co-culture with aging COCs to enhance oocyte quality and found its mechanism to function via ameliorating the biological function of GCs by alleviating FOXO3a levels. These results provide significant fundamental research on MSCs therapy on ovarian aging, as well as offering guidance for raising the success rate of assisted reproductive technology such IVM in clinical and non-clinical settings., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Late-onset hypogonadism (LOH) is a syndrome in middle-aged and elderly men caused by age-related testosterone deficiency. Age-related change of total testosterone (TT) of Asian males is different from Caucasian population, suggesting difference for LOH identification in Asians. A nationwide cross-sectional study involving six centers in China was conducted. Totally 6296 men aged 40-79 were recruited. After exclusions 5980 men were left for analyses. The serum TT level, was neither decreased with aging nor correlated with most hypogonadal symptoms. Instead, ten hypogonadal symptoms were found to be significantly correlated with free testosterone and testosterone secretion index, thus were chosen to form a concise scale. Further analysis identified a level of free testosterone <210 pmol/L, testosterone secretion index <1.8, and the concise scale score ≧17 could be diagnosed as having significantly aggravated LOH. This study developed an evidence-based criteria for LOH identification in Chinese population and may be adopted in other Asians. It includes the impaired testosterone secretion ability and deficiency of bioavailable testosterone, which should be the main cause in LOH pathogenesis despite normal TT levels, as well as correlated multiple hypogonadal symptoms. Our results may guide the LOH treatment to increase testicular function of testosterone secretion and bioavailable testosterone.

Circular RNA (circRNA) is a class of newly discovered noncoding RNA (ncRNA), presenting as a special covalent loop without a 5' cap or 3' tail. Multiple biological properties of circRNA have been revealed during the past decades, such as widespread expression, high conservation, cell-specificity, tissue-specificity and developmental stage-specific expression patterns, as well as resistance to RNase R digestion. CircRNA also exhibits diverse biological functions, including regulation of host genes, alternative splicing, miRNA sponges, protein traps and even protein synthesis. Recently, a global accumulation of circRNAs during aging has been identified across different species, indicating a potential role as a causal factor in aging and age-related disease. The high stability could be one of the mechanisms contributing to this phenomenon. CircRNA could play a role in aging, such as neural aging, muscle aging, reproductive aging, skin aging, immunosenescence, visual aging and age-related diseases like Alzheimer's disease, via interaction with miRNAs, RNA binding proteins, modulation of parental gene transcription, mainly at the transcriptional and posttranscriptional levels. The present study will focus on the advancement of circRNA regarding aging and age-related diseases. We will also discuss the biogenesis, properties, biological functions, and the perspectives of circRNA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Research Question: Is low MFN2 expression associated with ageing in granulosa cells as well as assisted reproductive technology (ART) outcome, and what is the underlying mechanism of action of MFN2?, Design: In a prospective study, fresh granulosa cells were obtained from 161 women aged 20-40 years who underwent IVF with embryo transfer and who were divided into two groups: the diminished ovarian reserve (DOR) group (n = 51) and the control group (n = 110). Patient characteristics including age, infertility duration, body mass index, FSH, anti-Müllerian hormone (AMH), antral follicle count (AFC) and husband's semen parameters and granulosa cell MFN2 expression levels, cell apoptosis, mitochondrial membrane potential (ΔΨm) and ATP levels were analysed., Results: There were no significant differences between the DOR and control groups in terms of age, infertility duration and husband'' semen parameters; however, significant (P< 0.05) changes were found between the two groups in FSH, AMH and AFC levels. MFN2 expression was remarkably lower in granulosa cells from the DOR group and decreased in both groups as age increased. Furthermore, among young patients, MFN2 levels significantly increased in patients with pregnancy. MFN2 protein levels and cell apoptosis were lower in the MFN2 knockdown (MFN2-siRNA) group than in the control (Cy3-siRNA) group. ΔΨm and ATP levels were reduced in the MFN2-siRNA group compared with the Cy3-siRNA group., Conclusions: Low MFN2 expression levels in granulosa cells were related to ageing, which may be involved in the clinical outcome of ART by promoting cell apoptosis and affecting mitochondrial function., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Circular RNAs (circRNAs) have recently been shown to exert effects on multiple pathological processes by acting as miRNA sponges. However, the roles of circRNAs in ovarian senescence are largely unknown. The objective of this study was to identify the circRNAs involved in ovarian aging and predict their potential biological functions. We first performed RNA-sequencing to generate ovarian circRNA expression profiles from young (n = 3) and aging (n = 3) groups. In total, 48,220 circRNAs were identified, of which 194 circRNAs were significantly up-regulated and 207 circRNAs were down-regulated during aging (fold change > 2, P < 0.05). Bioinformatics analysis demonstrated that the metabolic process, regulated secretory pathway, oxidation-reduction process, steroid hormone biosynthesis, and insulin secretion pathways, which may be associated with ovarian aging, were significantly enriched ( P < 0.05). The biological characteristics of ovary-derived circRNA, such as back-splicing, RNase R resistance, stability, and alternative splicing, were further validated. Bioinformatics predicted that most of the circRNAs harboured miRNA binding sites, of which circDDX10 - miR-1301-3p/miR-4660 - SIRT3 axis may be involved in the regulation of ovarian function. Our study indicates that circRNAs are aberrantly expressed in the aging ovary and may play potential roles in the development of ovarian senescence.

The senescence of bone marrow mesenchymal stem cells (BMSCs) contributes to the development of degenerative skeletal conditions. To date, the molecular mechanism resulting in BMSC senescence has not been fully understood. In this study, we identified a small non‐coding RNA, miR‐203‐3p, the expression of which was elevated in BMSCs from aged mice. On the other hand, overexpression of miR‐203‐3p in BMSCs from young mice reduced cell growth and enhanced their senescence. Mechanistically, PDZ‐linked kinase (PBK) is predicted to be the target of miR‐203‐3p. The binding of miR‐203‐3p to Pbk mRNA could decrease its expression, which in turn inhibited the ubiquitination‐mediated degradation of p53. Furthermore, the intravitreal injection of miR‐203‐3p‐inhibitor into the bone marrow cavity of aged mice attenuated BMSC senescence and osteoporosis in aged mice. Collectively, these findings suggest that targeting miR‐203‐3p to delay BMSC senescence could be a potential therapeutic strategy to alleviate age‐related osteoporosis. [ABSTRACT FROM AUTHOR]