Aging of women affects the final critical stage of egg maturation

The fertility of the women is adversely affected by age through the alteration of RNA levels, which in turn disrupt the function of genes involved in key biological pathways during the last stage of egg maturation. These are the conclusions of a new study published in the journal Aging Cell.

The team sequenced the RNA molecules – also known as transcriptome– within oocytes to understand which genes are affected in their activity by age. They carried out single cell sequencing to analyze the transcriptome of 72 oocytes individuals from 37 donors between 18 and 43 years old.

The scientists found that the number of gene transcripts involved in chromosome segregation and RNA processing progressively increased with age, while the number of transcripts related to mitochondrial metabolism decreased.

Age has an effect on the last step of oocyte maturation, a fundamental stage for reproduction because it provides the material that new embryos need to develop normally and survive.

Bernhard Payer, Group Leader at CRG

Changes in the transcriptome only occurred when the eggs reached their final stage of development during in vitro maturation. Thus, the transcriptome was less affected by age in immature eggs. According to experts, age can influence an oocyte’s ability to process genetic products critical to the last steps of its development.

Further analysis revealed a possible series of master regulatory genes, which are affected by age. These genes are the ones at the top of the regulatory hierarchy. Future research will be able to determine whether these genes play a critical role in oocyte aging.

“Age has an effect on the last step of oocyte maturation, a fundamental stage for reproduction because it provides the material that new embryos need to develop normally and survive,” he says. Bernhard Payer, group leader at the Center for Genomic Regulation (CRG) and co-author of the study. “What we still do not know is which of these changes are simply a consequence of the aging process and which can directly contribute to the decline in oocyte quality with age.”

human oocytes

Examples of the different stages of human oocytes used in this study. On the left, a germinal vesicle oocyte, which is an immature stage characterized by the presence of a visible nucleus (white arrow). On the right, an in vitro matured metaphase II oocyte (IVM-MII), which is the equivalent of in vivo mature eggs. The polar body can be detected (black arrow), a result of the maturation process. Most of the age-related changes were observed in this second stage of the oocytes. / Montserrat Barragan | Eugin Clinic

Passage of time, weight and fertility

Fertility in women generally declines with age. One of the main reasons for this is due to the depletion of the ovarian reserve, since women are born with all the oocytes that they will have throughout their life, and from which mature eggs will develop.

Another reason is that egg quality decreases over time, which is believed to be one of the main reasons why the highest rates of infertility occur after 35 years. Being overweight or underweight is also associated with poor oocyte quality and reproductive outcomes.

The decline in fertility caused by age could have different fundamental mechanisms than that caused by an abnormal body mass index

The team used information on the weight and height of the donors to assess the impact of the body mass index (BMI) in the transcriptome. Unlike age, the abnormal BMI mainly affected the transcriptome of immature oocytes.

According to specialists, the finding suggests that the decline in fertility caused by age could have different fundamental mechanisms than that caused by an abnormal BMI.

Although more studies are required, these results may result in the future development of new diagnostic tools to better assess the quality of oocytes for use in the reproductive medicine. In addition, they could also aid in potential drug treatments that modulate affected pathways to rejuvenate aging oocytes, the authors conclude.

Reference:

Llonch S, Barragán M, Nieto P, et al. Single human oocyte transcriptome analysis reveals distinct maturation stage-dependent pathways impacted by age. Aging Cell. 2021; 00: e13360. https://doi.org/10.1111/acel.13360

Funding: EUGIN Clinic; State Research Agency (AEI), Grant / Award Number: EUR2019-103817; Catalan Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Grant / Award Number: 2017 SGR 346; European Commission, Grant / Award Number: 754422; AXA Research Fund; Spanish Ministry of Science, Innovation and Universities, Grant / Award Number: BFU2017-88407-P

Rights: Creative Commons.