Oocyte aging: looking beyond chromosome segregation errors

Abstract

The age‐associated decline in female fertility is largely ascribable to a decrease in oocyte quality. This phenomenon is multifaceted and influenced by numerous interconnected maternal and environmental factors. An increase in the rate of meiotic errors is the major cause of the decline in oocyte developmental competence. However, abnormalities in the ooplasm accumulating with age — including altered metabolism, organelle dysfunction, and aberrant gene regulation — progressively undermine oocyte quality. Stockpiling of maternal macromolecules during folliculogenesis is crucial, as oocyte competence to achieve maturation, fertilization, and the earliest phases of embryo development occur in absence of transcription. At the same time, crucial remodeling of oocyte epigenetics during oogenesis is potentially exposed to interfering factors, such as assisted reproduction technologies (ARTs) or environmental changes, whose impact may be enhanced by reproductive aging. As the effects of maternal aging on molecular mechanisms governing the function of the human oocyte remain poorly understood, studies in animal models are essential to deepen current understanding, with translational implications for human ARTs. The present mini review aims at offering an updated and consistent view of cytoplasmic alterations occurring in oocytes during aging, focusing particularly on gene and epigenetic regulation. Appreciation of these mechanisms could inspire solutions to mitigate/control the phenomenon, and thus benefit modern ARTs.

DNA methylation abnormalities induced by advanced maternal age in villi prime a high-risk state for spontaneous abortion

“…Consistent with this phenomenon, it has been widely reported that AMA induces aneuploidies, mitochondrial dysfunction, and transcriptional alterations in human oocytes [ 25 – 27 ]. AMA mouse modeling has further revealed reduced expression in oocytes for genes involved in the establishment and maintenance of DNA methylation, such as Dnmt1 , Dnmt3a , Dnmt3b, and Dnmt3L [ 28 ], along with lower genome-wide DNA methylation in both oocytes and following embryos [ 29 , 30 ]. Meanwhile, with increased maternal age, maternal age-dependent changes have also been observed in the local DNA methylome of human ovarian granulosa cells [ 31 , 32 ], in the specific CpG sites of umbilical cord blood, and even in the specific CpG sites of the peripheral blood of adult daughters [ 33 – 35 ].…”

Superovulation and aging perturb oocyte-granulosa cell communication

“…33 Current models that explain the lower quality of superovulated eggs as reflecting developmental immaturity were based on morphological and biochemical characterization, [34][35][36][37] fertilization and implantation rates, [38][39][40] and oocyte epigenetics. [41][42][43] Final oocyte maturation occurs via nuclear and cytoplasmic changes, 44 requiring correct chromosomal separation 45 and maternal transcript remodeling, [46][47][48] respectively. However, the oocyte can only mature if it establishes correct bi-directional communication with the surrounding cumulus granulosa cells.…”

Supplementation of mitochondria from endometrial mesenchymal stem cells improves oocyte quality in aged mice

“…Decreased quality of oocytes is considered to be the vital contributor to age‐related declines in fertility, but the problem of maternal age can be effectively abrogated by oocyte donation. For elder women, it has been reported that the defects in meiotic and cytoplasmic ability are associated with oocyte ageing 3,4 . After 35 years, female fertility declines significantly, and approximately 50%–70% of mature oocytes from 40‐year‐old women have chromosomal abnormalities 5 .…”

“…For elder women, it has been reported that the defects in meiotic and cytoplasmic ability are associated with oocyte ageing. 3,4 After 35 years, female fertility declines significantly, and approximately 50%-70% of mature oocytes from 40-year-old women have chromosomal abnormalities. 5 Additionally, mitochondrial dysfunction is one of the most notable cytoplasmic changes in aged oocytes and causes decreased cytoplasmic competence.…”