Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion

Ansere, Victor A.; Ali-Mondal, Samim; Sathiaseelan, Roshini; Garcia, Driele Neske; Isola, José Victor Vieira; Henseb, Jéssica D.; Saccon, Tatiana D.; Ocañas, Sarah R.; Tooley, Kyla B.; Stout, Michael B.; Schneider, Augusto; Freeman, Willard M.

doi:10.1016/j.mad.2020.111425

Cited by 49 publications

(50 citation statements)

References 91 publications

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“…Furthermore, our results suggested that the expression of miR-320a-3p levels were positively correlated with patient's age (r 2 =0.209, P=0.0033). Findings by Victor A Ansere et al revealed that cellular senescence may contribute to ovarian aging, and subsequently declines in ovarian follicular reserve (27). Indeed, in our study, the miR-320a-3p levels were positively associated with basal FSH (r 2 =0.257, P=0.0003).…”

Section: Discussionsupporting

confidence: 61%

miR-320a-3p Levels in Human Granulosa Cells: A Promising Bio-marker of Good Quality Embryo and Clinical Pregnancy after IVF/ICSI.

Liu

Mei

Shen

et al. 2021

Preprint

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BackgroundmiRNAs in body fluids are considered potential biomarkers of diseases. This study investigated whether miR-320a-3p and miR-483-5p levels in human granulosa cells from follicular fluids were associated with embryo developmental competence. MethodsWe collected 195 patients’ granulosa cells samples undergoing in vitro fertilization (n =147) or intracytoplasmic sperm injection (n =48) cycles, and gathered information about the outcomes of the treatment. miR-320a-3p and miR-483-5p levels were measured using qRT-PCR.ResultsThe miR-320a-3p levels in human granulosa cells across different patient groups were significantly different in the good quality embryo rates, with lowest levels in the Q4 intervals (P<0.05). The relative expression levels of miR-320a-3p were negatively associated with clinical pregnancy rate (P<0.05) and positively correlated with the patient age (P=0.0033). Moreover, both the basal FSH (P=0.0003) and ovarian stimulation protocol (P=0.006 and P=0.004) significantly and positively affected miR-320a-3p levels. The days of stimulation was negatively correlated with the relative expression of miR-320a-3p (P=0.0466). The relative expression levels of miR-483-5p were significantly positively correlated with AMH (P=0.0047). Neither miR-320a-3p nor miR-483-5p levels in granulosa cells were associated with normal fertilized rate, blastulation rate and abortion rate. ConclusionsThe miR-320a-3p levels in human granulosa cells were negatively correlated with the good quality embryo rate and clinical pregnancy rate and positively correlated with the patient age, indicating that miR-320a-3p can be used as a potential indicator to predict embryo development ability and clinical pregnancy.

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Section: Discussionsupporting

confidence: 61%

miR-320a-3p Levels in Human Granulosa Cells: A Promising Bio-marker of Good Quality Embryo and Clinical Pregnancy after IVF/ICSI.

Liu

Mei

Shen

et al. 2021

Preprint

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“…Correlation of metabolic changes with specific age-related regulons confirmed the robustness of the scRNA-seq strategy and reliability of our data. Consistently, bulk RNA-seq has revealed age-related metabolic dysfunction in mouse ovarian cells collected from 3mo to 12mo 34 .…”

Section: Discussionmentioning

confidence: 64%

“…We also performed Gene Set Enrichment Analysis (GSEA) and found significant enrichment of genes associated with HIF-1signaling pathway and glycolysis in hif1a knockout mouse dataset (Fig.5c). Meanwhile we examined the region around Hk2 , Ldha , Eno1 , Gapdh , Pkm and Pfkl in Hif1a knockout RNA-seq and ChIP-seq data combine with growing aging ovary RNA-seq data (Fig.5d,e, Extended Data Fig.7a-c) 34 . Interestingly, the promoter specific bound peak demonstrated a strong binding region by Hif1a.…”

Section: Resultsmentioning

confidence: 99%

HIF1A modulate glycolysis function to governs mouse ovarian microenvironment metabolic plasticity in aging single cell resolution

Zhang

Gunewardena

Liu

et al. 2022

Preprint

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The molecular machinery of ovarian aging and female age-related pathway remain unclear. Here, we utilized single-cell RNA-seq to profile over 9815 cells from both young and old female mouse and identified age-related alterations in the female somatic microenvironment. Interestingly, by aging-related signature calculation, we examined HIF1A in mouse ovarian cell aging regulated roles which effect pathways included glycolysis, TCA, OXPHOS and fatty acid metabolism. Additionally, inactivated HIF1A, decreased glycolysis was observed. Comparison analysis reveals the aging related regulon; metabolic and nutrient absorption changes provides a comprehensive understanding of the cell-type-specific mechanisms underlying mouse ovarian aging at single-cell resolution. This study, revealing new potential candidate biomarkers for the diagnosis of aging-associated ovary pathology.

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“…We found that the number of apoptotic granulosa cells and the expression of genes promoting cell apoptosis were increased in ovaries of CTX/BUL-treated mice. A recent study conducted by Victor et al indicated that cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion ( 52 ). In that study, they observed a significantly increased expression of genes related to pro-inflammatory stress and cell-cycle inhibition in naturally aged ovaries of mice.…”

Section: Discussionmentioning

confidence: 99%

PQQ Dietary Supplementation Prevents Alkylating Agent-Induced Ovarian Dysfunction in Mice

Dai

Wang

et al. 2022

Front. Endocrinol.

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Alkylating agents (AAs) that are commonly used for cancer therapy cause great damage to the ovary. Pyrroloquinoline-quinine (PQQ), which was initially identified as a redox cofactor for bacterial dehydrogenases, has been demonstrated to benefit the fertility of females. The aim of this study was to investigate whether PQQ dietary supplementation plays a protective role against alkylating agent-induced ovarian dysfunction. A single dose of busulphan (20 mg/kg) and cyclophosphamide (CTX, 120 mg/kg) were used to establish a mouse model of ovarian dysfunction. Feed containing PQQNa2 (5 mg/kg) was provided starting 1 week before the establishment of the mouse model until the date of sacrifice. One month later, estrous cycle period of mice were examined and recorded for consecutive 30 days. Three months later, some mice were mated with fertile male mice for fertility test. The remaining mice were sacrificed to collect serum samples and ovaries. One day before sacrifice, some mice received a single injection of BrdU to label proliferating cells. Serum samples were used for test hormonal levels. Ovaries were weighted and used to detect follicle counts, cell proliferation, cell apoptosis and cell senescence. In addition, the levels of inflammation, oxidative damage and Pgc1α expression were detected in ovaries. Results showed that PQQ treatment increased the ovarian weight and size, partially normalized the disrupted estrous cycle period and prevented the loss of follicles of mice treated with AAs. More importantly, we found that PQQ treatment significantly increased the pregnancy rate and litter size per delivery of mice treated with AAs. The protective effects of PQQ appeared to be directly mediated by promoting cell proliferation of granulosa, and inhibiting cell apoptosis of granulosa and cell senescence of ovarian stromal cells. The underlying mechanisms may attribute to the anti-oxidative stress, anti-inflammation and pro-mitochondria biogenesis effects of PQQ.Our study highlights the therapeutic potential of PQQ against ovarian dysfunction caused by alkylating agents.

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Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion

Cited by 49 publications

References 91 publications

miR-320a-3p Levels in Human Granulosa Cells: A Promising Bio-marker of Good Quality Embryo and Clinical Pregnancy after IVF/ICSI.

miR-320a-3p Levels in Human Granulosa Cells: A Promising Bio-marker of Good Quality Embryo and Clinical Pregnancy after IVF/ICSI.

HIF1A modulate glycolysis function to governs mouse ovarian microenvironment metabolic plasticity in aging single cell resolution

PQQ Dietary Supplementation Prevents Alkylating Agent-Induced Ovarian Dysfunction in Mice

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