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Your biological clock has a time stamp

Yale School of Medicine researchers have identified the molecular paths involved in aging of human eggs. Such research may eventually lead to correcting age-related damage and improve fertility in women 40 years and older.

Published in the journal Molecular Human Reproduction, the study examined reasons behind sharp declines in egg quality between 40 + and younger women, finding egg damage is linked to oxygen-deprived cells.

"More women are postponing childbearing, but with age, cumulus cells that surround and nurture the eggs begin dying. We found this is caused by lack of oxygen. Follicular hypoxia triggers a cascade of changes in cumulus cells which results in eggs of older women having chromosomal abnormalities."

Pasquale Patrizio MD, Director, Yale Fertility Center, Professor of Obstetrics, Gynecology & Reproductive Sciences, and senior author.

Patrizio and his team worked in collaboration with Anna Pyle, Howard Hughes Medical Institute investigator and professor, Department of Molecular, Cellular and Developmental Biology at Yale. They studied samples from 20 cumulus cells in 15 patients younger than age 35, comparing them to eggs of women age 40 and above. The team went looking for differences in RNA expression between both sets of patients — and found significant differences in RNA molecules in cumulus cells of older women as compared to RNA expressed in cells of women younger than 35.

Changes in the ovarian microenvironment, such as reduced oxygen getting to growing follicles, are likely causing ovarian aging, thinks Patrizio.

"Our data show cumulus cells from older women are affected by chronic exposure to suboptimal oxygen levels, as indicated by an increased expression of hypoxia-induced genes — when compared to the same cells collected in younger patients,"
he explained.

"Our findings shed light on the mechanisms responsible for human egg aging," Patrizio added. "We have always been intrigued by the questions: 'Who is the time keeper of egg aging?' and 'How are the eggs informed of the biological clock?' Now we know that changes in RNA of the cumulus cells triggered by aging-induced hypoxia, are the key messengers.

"The ability to screen cumulus cells for oxygen deprivation may help us identify healthier eggs, modify ovarian stimulation protocols, and ultimately lead to more successful in vitro fertilization treatments."

Pasquale Patrizio MD

STUDY HYPOTHESIS Can RNA sequencing of human cumulus cells (CC) reveal molecular pathways involved in the physiology of reproductive aging?

STUDY FINDING Senescent but not young cumulus cells, activate gene pathways associated with hypoxia and oxidative stress.

WHAT IS KNOWN ALREADY Shifts in socio-economic norms are resulting in larger numbers of women postponing childbearing. The reproductive potential is sharply decreased with aging and the reasons are poorly understood. Since CCs play an integral role in oocyte maturation and direct access to human oocytes is limited, we used whole transcriptome analysis of these somatic cells to gain insights into the molecular mechanisms playing a role in follicular senescence.

STUDY DESIGN, SAMPLES/MATERIALS, METHODS Twenty cumulus cells samples (from a total of 15 patients) were obtained from oocytes of either male factor or egg donor patients. RNA sequencing and bioinformatic tools were used to identify differentially expressed genes (DEGs) between CCs from seven aged and eight young patients (<35 (years old) y.o. vs >40 y.o.). Quantitative-PCR and immunoflourescent staining were used for validation.

MAIN RESULTS AND THE ROLE OF CHANCE RNA sequencing identified 11,572 genes expressed in CC of both age cohorts, 45 of which were differentially expressed. In CC collected from patients >40 y.o., genes involved in the hypoxia stress response (NOS2, RORA and NR4A3), vasculature development (NR2F2, PTHLH), glycolysis (RALGAPA2 and TBC1D4) and cAMP turnover (PDE4D) were significantly overexpressed when compared with CC of patients aged <35 y.o.

LIMITATIONS, REASONS FOR CAUTION This study focused almost exclusively on assessing the genetic differences in CC transcriptome between young and older women. These genetic findings were not fully correlated with embryonic development and clinical outcome.

WIDER IMPLICATIONS OF THE FINDINGS Our data provide a new hypothesis -follicular hypoxia- as the main mechanism leading to ovarian follicular senescence and suggest a link between cumulus cell aging and oocyte quality decay. If specific molecular findings of hypoxia would be confirmed also in oocytes, genetic platforms could screen cumulus cells for hypoxic damage and identify healthier oocytes. Protocols of ovarian stimulation in older patients could also be adjusted to diminish oocyte exposure time to hypoxic follicles.

Citation: Molecular Human Reproduction June 6, 2016

Other authors on the study included Emanuela Stella Molinari and B. Ido Haim.

The study was partially funded by the EMD Serono Grant for Fertility Innovation Return to top of page

Jun 9, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Yale School of Medicine researchers have identified the molecular pathways involved
in the aging of human eggs. This research could eventually lead to treatments
correcting age-related damage and improve fertility in women 40 and older.
Image Credit: Yale University



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