Mechanisms of ovarian aging

Abstract

Ovarian aging in women correlates with the progressive loss of both the number and quality of oocytes. When these processes occur early or are accelerated, their clinical correlates are diminished ovarian reserve and/or premature ovarian insufficiency. Both these conditions have important consequences for the reproductive and general health of women, including infertility. Although there are many contributing factors, the molecular mechanisms underlying many of the processes associated with ovarian aging have not been fully elucidated. In this review, we highlight some of the most critical factors that impact oocyte quantity and quality with advancing age. We discuss chromosomal factors including cohesion deterioration and mis-segregation, errors in meiotic recombination, and decreased stringency of the spindle assembly checkpoint. DNA damage, telomere changes, reactive oxygen species and mitochondrial dysfunction as they relate to ovarian aging, and well-known gene mutations associated with primary ovarian insufficiency and diminished ovarian reserve are also discussed. Additionally, studies investigating recently acknowledged cytoplasmic factors associated with ovarian aging including protein metabolic dysregulation and microenvironmental alterations in the ovary are presented. We use both mouse and human studies to support the roles these factors play in physiologic and expedited ovarian aging, and we propose directions for future studies. A better understanding of the molecular basis of ovarian aging will ultimately lead to diagnostic and therapeutic advancements that would provide women with information to make earlier choices about their reproductive health.

The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA?

“…On the other hand, several studies were performed to evaluate the association of point mutations in mtDNA and ovarian ageing, though the topic remains highly debated [ 48 , 52 , 55 , 56 , 57 ]. Indeed, mtDNA may be more susceptible to damage than nuclear DNA (nDNA) due to its proximity with the free radical-respiratory chain, the lack of protective histones lower fidelity of mitochondrial polymerase γ (POLG), and limited repair mechanisms [ 48 , 54 , 58 , 59 ]. As the mitochondrial producing genome, similar to its bacterial ancestors, has no introns and only one major non-coding region (NCR), any point mutation or deletion could disrupt cellular respiration [ 60 , 61 ].…”

“…Oxidative stress is considered as one of the factors negatively influencing mtDNA. The hypothesised mechanism involves the damage induced by ROS, a by-product of OXPHOS, which can compromise the integrity of the respiratory chain leading to mitochondria-dependent ageing [ 47 , 48 , 58 , 59 ]. ROS are known to react with surroundings proteins, lipids, and DNA, leading to mutations and macromolecule damage [ 48 ].…”

“…Additionally, the ROS-induced formation of mtDNA double-strand breaks seems to be involved in the somatic mtDNA deletions generation [ 59 ]. Under physiological conditions, in response, the expression levels of antioxidants enzymes and intracellular proteins rapidly increase [ 48 , 58 ]. However, when ROS are overproduced, these compounds cause oxidative stress and cellular damage.…”

“…However, when ROS are overproduced, these compounds cause oxidative stress and cellular damage. Their high concentration in cells leads not only to mitochondrial and nuclear DNA damage but also apoptosis [ 58 ]. Furthermore, conducted experiments found the reducing defense against ROS with ovarian ageing due to the observed age-related down-regulation of genes SOD1 , SOD2 , and catalase mRNA encoding key antioxidant enzymes [ 62 ].…”

“…The proper positioning and segregation of chromosomes depend on the assembly and disassembly of microtubules which is one of the most energy-demanding processes within the oocyte. When oocytes age, their ability to produce adequate spindle microtubules decreases, which in consequence leads to increased incidence of aneuploidy [ 39 , 44 , 58 ].…”