Redox imbalance in age-related ovarian dysfunction and perspectives for its prevention.

The age at which women have their first child is increasing. This change represents a major health problem to society because advanced maternal age is related with a decay in fertility and an increase in the incidence of a variety of pregnancy complications and offspring health issues. The ovary stands as the main contributor for female reproductive ageing because of the progressive age-related decrease in follicle number and oocyte quality. Loss of redox homeostasis and establishment of an ovarian oxidative microenvironment are seen as major underlying causes for such downfall and impairment of ovarian function. Thus, the use of antioxidants to preserve fertility became an important field of research. In this review, new insights on mechanisms underlying the establishment of oxidative stress and its repercussions on ovarian ageing are addressed, along with the current state of knowledge on antioxidant supplementation and its contribution for healthy ageing and extension of ovarian lifespan.

Age-related oxidative modifications to uterine albumin impair extravillous trophoblast cells function.

Advanced maternal age is associated not only with a significant reduction in fertility but also with an additional risk of developing pregnancy-related disorders. Most of these disorders are now believed to be the clinical manifestation of an incorrect placentation, namely deficient transformation of maternal spiral arteries and ineffective trophoblast invasion through uterine stroma. In the present study it was hypothesized that an age-related loss in uterine redox homeostasis interferes with the function of extravillous trophoblasts (EVTs) and placentation. To test this hypothesis, relative levels of oxidatively modified proteins were evaluated in human samples from placenta and placental bed, and the role of specific oxidative modifications to proteins in placentation was studied using a cell culture model of EVTs. In the placental bed, the carbonylation level of a 66 kDa protein (identified as albumin) presented a strong, positive and significant correlation with maternal age. Albumin was immunodetected preferentially in endothelial cells and connective tissue between muscle fascicles. In vitro results showed that carbonylated albumin overload did not alter cell viability, but reduced EVTs motility and triggered cell stress response pathways. Moreover, EVTs presented decreased ability to adhere to and invade a collagen extracellular matrix pre-treated with carbonylated albumin. In conclusion, reproductive ageing is accompanied by an increase in maternal uterine carbonylated albumin, that may have a deleterious role in the modulation of EVTs function.

Apocynin Dietary Supplementation Delays Mouse Ovarian Ageing.

Advanced maternal age is associated with higher infertility rates, pregnancy-associated complications, and progeny health issues. The ovary is considered the main responsible for these consequences due to a continuous decay in follicle number and oocyte quality. Intracellular imbalance between oxidant molecules and antioxidant mechanisms, in favour of the former, results in oxidative stress (OS) that is believed to contribute to ovarian ageing. This work is aimed at evaluating whether an age-related increase in ovarian OS, inflammation, and fibrosis may contribute to tissue dysfunction and whether specific antioxidant supplementation with a NADPH oxidase inhibitor (apocynin) could ameliorate them. Mice aged 8-12 weeks (reproductively young) or 38-42 weeks (reproductively aged) were employed. Aged mice were divided into two groups, with one receiving apocynin (5 mM) in the drinking water, for 7 weeks, upon which animals were sacrificed and their ovaries collected. Ovarian structure was similar at both ages, but the ovaries from reproductively aged mice exhibited lipofuscin deposition, enhanced fibrosis, and a significant age-related reduction in primordial and primary follicle number when compared to younger animals. Protein carbonylation and nitration, and markers of OS were significantly increased with age. Moreover, mRNA levels of inflammation markers, collagens, metalloproteinases (MMPs), and tissue inhibitor MMPs (TIMPs) were upregulated. Expression of the antifibrotic miRNA29c-3p was significantly reduced. Apocynin supplementation ameliorated most of the age-related observed changes, sometimes to values similar to those observed in young females. These findings indicate that there is an age-related increase in OS that plays an important role in enhancing inflammation and collagen deposition, contributing to a decline in female fertility. Apocynin supplementation suggests that the imbalance can be ameliorated and thus delay ovarian ageing harmful effects.