Oocyte aging underlies female reproductive aging: biological mechanisms and therapeutic strategies

Abstract

In recent years, postponement of marriage and childbearing in women of reproductive age has led to an increase in the incidence of age-related infertility. The reproductive aging process in women is assumed to occur due to a decrease in both the quantity and quality of the oocytes, with the ultimate result being a decline in fecundity. This age-related decline in fecundity is strongly dependent on oocyte quality, which is critical for fertilization and subsequent embryo development. Aged oocytes display increased chromosomal abnormality and dysfunction of cellular organelles, both of which factor into oocyte quality. In particular, mitochondrial dysfunction has been suggested as a major contributor to the reduction in oocyte quality as well as to chromosomal abnormalities in aged oocytes and embryos. Participation of oxidative stress in the oocyte aging process has been proposed because oxidative stress has the capacity to induce mitochondrial dysfunction and directly damage many intracellular components of the oocytes such as lipids, protein, and DNA. In an attempt to improve mitochondrial function in aged oocytes, several therapeutic strategies have been investigated using both animal models and assisted reproductive technology. Here, we review the biological mechanisms and present status of therapeutic strategies in the female reproductive aging field and indicate possible future therapeutic strategies.

Keywords: Endoplasmic reticulum; Mitochondria; Oocyte aging; Oxidative stress; Reproductive aging.

Figure 1

Percentage of transfers that resulted in live births for ART cycles using fresh embryos from the patient's own eggs and ART cycles using fresh embryos from donor eggs, according to the age of the women, in 2011. Reprinted with permission from the U.S. Centers for Disease Control and Prevention (http://www.cdc.gov/art/ART2011/PDFs/ART_2011_National_Summary_Report.pdf)

Figure 2

The reproductive aging process is assumed to result in decreases in the quantity (solid line) and increases in poor‐quality oocytes held within the follicles present in the ovarian cortex. Modified with permission from Ref. [15]

Figure 3

Schematic illustration of putative mechanisms of poor embryonic development observed in aged oocytes. Oocyte aging results in increased mitochondrial oxidative stress that induces mitochondrial dysfunction followed by low ATP production. A decrease in intracellular ATP levels reduces the capacity for Ca²⁺ restoration by Ca²⁺‐ATPase (Ca²⁺ pump) in the endoplasmic reticulum (ER) membrane. Simultaneously, decrease in Ca²⁺ release via the inositol 1,4,5‐triphosphate (InsP₃) receptor on the ER and reduction in ER Ca²⁺ stores occur during oocyte aging. The abnormal Ca²⁺ homeostasis in aged oocytes induces changes in Ca²⁺ oscillation patterns characterized by both high frequency and low amplitude of Ca²⁺ transients. Low ATP levels involved in mitochondrial dysfunction could result in poor embryonic development. Furthermore, the abnormal pattern of Ca²⁺ oscillations may contribute to oocyte aging. These mechanisms have mainly been studied using post‐ovulatory‐age oocytes (from Refs. [31, 32, 43, 53])