Fibroinflammatory Signatures Increase with Age in the Human Ovary and Follicular Fluid

Machlin, Jordan H.; Barishansky, Seth J.; Kelsh, John M.; Larmore, Megan; Johnson, Brian W.; Pritchard, Michele T.; Pavone, Mary Ellen; Duncan, Francesca E.

doi:10.3390/ijms22094902

Cited by 19 publications

(9 citation statements)

References 69 publications

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“…The PDGF pathway, which has known roles in fibroinflammatory processes, was significantly enriched in all the cell types in the aged ovary (Fig. 3g), consistent with the finding of elevated fibroinflammatory cytokines in aged human ovarian follicular fluid 50 . In contrast to the age-related loss of interactions between granulosa and theca cells and oocytes (Fig.…”

Section: Mainsupporting

confidence: 86%

The regulatory landscapes of human ovarian ageing

Jin

Wang

Hudgins

et al. 2022

Preprint

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Summary paragraphThe ovary is the first organ to age in the human body, affecting both fertility and overall health in women1-8. However, the biological mechanisms underlying human ovarian ageing remain poorly understood. Here we performed single-nuclei multi-omics analysis of young and reproductively aged human ovaries to understand the molecular and cellular basis of ovarian ageing in humans. Our analysis reveals coordinated changes in transcriptomic output and chromatin accessibility across cell types during ageing, including elevated mTOR and MAPK signaling, decreased activity of the oxidative phosphorylation and DNA damage repair pathways, and an increased signature of cellular senescence. By constructing cell type-specific regulatory networks, we uncover enhanced activity of the transcription factor CEBPD across cell types in the aged ovary, with a corresponding significant loss of activity of most cell identity-associated transcription factors. Moreover, by performing integrative analyses of our single-nuclei multi-omics data with common genetic variants associated with age at natural menopause (ANM) from genome-wide association studies, we demonstrate a global impact of functional variants on changes in gene regulatory networks across ovarian cell types. Finally, we nominate about a dozen of functional non-coding variants, their target genes and cell types and regulatory mechanisms that underlie genetic association with ANM. This work provides a comprehensive multimodal landscape of human ovarian ageing and mechanistic insights into inherited variation of ANM.

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Section: Mainsupporting

confidence: 86%

The regulatory landscapes of human ovarian ageing

Jin

Wang

Hudgins

et al. 2022

Preprint

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“…The cytokine profile in FF also seems to play a role (Bouet et al, 2020; Machlin et al, 2021). Given that an increase in fibrosis and inflammatory cytokines is recognizably associated with tissue aging, Machlin et al explored the levels of inflammatory cytokines in the FF and found a positive correlation between six cytokines (IL‐3, IL‐7, IL‐15, TGFβ1, TGFβ3, and MIP‐1) and age (Machlin et al, 2021).…”

Section: Age‐related Oocyte Competence Declinementioning

confidence: 99%

Aging and oocyte competence: A molecular cell perspective

Ferreira

Soares

Almeida‐Santos

et al. 2023

WIREs Mechanisms of Disease

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Follicular microenvironment is paramount in the acquisition of oocyte competence, which is dependent on two interconnected and interdependent processes: nuclear and cytoplasmic maturation. Extensive research conducted in human and model systems has provided evidence that those processes are disturbed with female aging. In fact, advanced maternal age (AMA) is associated with a lower chance of pregnancy and live birth, explained by the age‐related decline in oocyte quality/competence. This decline has largely been attributed to mitochondria, essential for oocyte maturation, fertilization, and embryo development; with mitochondrial dysfunction leading to oxidative stress, responsible for nuclear and mitochondrial damage, suboptimal intracellular energy levels, calcium disturbance, and meiotic spindle alterations, that may result in oocyte aneuploidy. Nuclear‐related mechanisms that justify increased oocyte aneuploidy include deoxyribonucleic acid (DNA) damage, loss of chromosomal cohesion, spindle assembly checkpoint dysfunction, meiotic recombination errors, and telomere attrition. On the other hand, age‐dependent cytoplasmic maturation failure is related to mitochondrial dysfunction, altered mitochondrial biogenesis, altered mitochondrial morphology, distribution, activity, and dynamics, dysmorphic smooth endoplasmic reticulum and calcium disturbance, and alterations in the cytoskeleton. Furthermore, reproductive somatic cells also experience the effects of aging, including mitochondrial dysfunction and DNA damage, compromising the crosstalk between granulosa/cumulus cells and oocytes, also affected by a loss of gap junctions. Old oocytes seem therefore to mature in an altered microenvironment, with changes in metabolites, ribonucleic acid (RNA), proteins, and lipids. Overall, understanding the mechanisms implicated in the loss of oocyte quality will allow the establishment of emerging biomarkers and potential therapeutic anti‐aging strategies.This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology

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“…This notion is supported by the results of pilot studies reporting detectable Ab titers in selected FF (5,6). However, FF composition varies, and size, age, and inflammation affect BFB composition and properties (8,9) and ultimately influence the success of assisted reproductive technology (ART) (10). To obtain a more comprehensive view of the potential passage of Ab through the BFB, paired serum samples with several FF from the same donor were collected in the course of ART and characterized in terms of oocyte quality and Ab concentrations.…”

Section: Introductionmentioning

confidence: 96%

Antibodies to SARS-CoV-2 in follicular fluids and their association with assisted reproduction

Chillon

Weiss²,

Demircan

et al. 2023

Front. Immunol.

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IntroductionEvery second woman suffering from infertility asks for medical help. There is public concern that vaccination-induced antibodies (Ab) are negatively associated with fertility. A recent study has demonstrated an association between SARS-CoV-2 vaccination and a lower pregnancy rate in the subsequent 60 days. Consequently, Ab could affect fertility success in assisted reproduction.MethodsTo address this question, we compared fertilization outcomes of vaccinated (n=35) and nonvaccinated (n=34) women. Paired serum samples and multiple follicular fluids (FF) (up to 10 from the same donor) were collected during the course of assisted reproduction and characterized for oocyte quality, the presence of Ab and trace element concentrations.ResultsThe results showed a positive correlation of vaccination-induced neutralizing activity of SARS-CoV-2-Ab in serum and FF. On average, Ab concentrations in serum were higher than in the corresponding FF. However, wide variations in SARS-CoV-2 Ab titers were observed between different FF, correlating to trace element levels, even when retrieved from the same donor.DiscussionOverall, FF contents are highly variable, but no negative association was observed between Ab in serum or FF and fertilization success and oocyte development, supporting the safety of SARS-CoV-2 vaccination during assisted reproduction.

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Fibroinflammatory Signatures Increase with Age in the Human Ovary and Follicular Fluid

Cited by 19 publications

References 69 publications

The regulatory landscapes of human ovarian ageing

The regulatory landscapes of human ovarian ageing

Aging and oocyte competence: A molecular cell perspective

Antibodies to SARS-CoV-2 in follicular fluids and their association with assisted reproduction

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