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

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Abstract

<p id="d3385347e168">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. </p>

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Mitochondrial function in the human oocyte and embryo and their role in developmental competence.

Jonathan van Eyll, JONATHAN VAN BLERKOM (2011)

The role of mitochondria as a nexus of developmental regulation in mammalian oogenesis and early embryogenesis is emerging from basic research in model species and from clinical studies in infertility treatments that require in vitro fertilization and embryo culture. Here, mitochondrial bioenergetic activities and roles in calcium homeostasis, regulation of cytoplasmic redox state, and signal transduction are discussed with respect to outcome in general, and as possible etiologies of chromosomal defects, maturation and fertilization failure in human oocytes, and as causative factors in early human embryo demise. At present, the ability of mitochondria to balance ATP supply and demand is considered the most critical factor with respect to fertilization competence for the oocyte and developmental competence for the embryo. mtDNA copy number, the timing of mtDNA replication during oocyte maturation, and the numerical size of the mitochondrial complement in the oocyte are evaluated with respect to their relative contribution to the establishment of developmental competence. Rather than net cytoplasmic bioenergetic capacity, the notion of functional compartmentalization of mitochondria is presented as a means by which ATP may be differentially supplied and localized within the cytoplasm by virtue of stage-specific changes in mitochondrial density and potential (ΔΨm). Abnormal patterns of calcium release and sequestration detected at fertilization in the human appear to have coincident effects on levels of mitochondrial ATP generation. These aberrations are not uncommon in oocytes obtained after ovarian hyperstimulation for in vitro fertilization. The possibility that defects in mitochondrial calcium regulation or bioenergetic homeostasis could have negative downstream development consequences, including imprinting disorders, is discussed in the context of signaling pathways and cytoplasmic redox state. Copyright © 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

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Age-associated alteration of gene expression patterns in mouse oocytes.

Toshio Hamatani, Geppino Falco, Mark Carter … (2004)

Decreasing oocyte competence with maternal aging is a major factor in human infertility. To investigate the age-dependent molecular changes in a mouse model, we compared the expression profiles of metaphase II oocytes collected from 5- to 6-week-old mice with those collected from 42- to 45-week-old mice using the NIA 22K 60-mer oligo microarray. Among approximately 11,000 genes whose transcripts were detected in oocytes, about 5% (530) showed statistically significant expression changes, excluding the possibility of global decline in transcript abundance. Consistent with the generally accepted view of aging, the differentially expressed genes included ones involved in mitochondrial function and oxidative stress. However, the expression of other genes involved in chromatin structure, DNA methylation, genome stability and RNA helicases was also altered, suggesting the existence of additional mechanisms for aging. Among the transcripts decreased with aging, we identified and characterized a group of new oocyte-specific genes, members of the human NACHT, leucine-rich repeat and PYD-containing (NALP) gene family. These results have implications for aging research as well as for clinical ooplasmic donation to rejuvenate aging oocytes.

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Female age-related fertility decline. Committee Opinion No. 589.

(2014)

The fecundity of women decreases gradually but significantly beginning approximately at age 32 years and decreases more rapidly after age 37 years. Education and enhanced awareness of the effect of age on fertility are essential in counseling the patient who desires pregnancy. Given the anticipated age-related decline in fertility, the increased incidence of disorders that impair fertility, and the higher risk of pregnancy loss, women older than 35 years should receive an expedited evaluation and undergo treatment after 6 months of failed attempts to conceive or earlier, if clinically indicated. In women older than 40 years, more immediate evaluation and treatment are warranted. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.