The effects of advanced maternal age on T-cell subsets at the maternal–fetal interface prior to term labor and in the offspring: a mouse study

Abstract

Summary Women who conceive at 35 years of age or older, commonly known as advanced maternal age, have a higher risk of facing parturition complications and their children have an increased risk of developing diseases later in life. However, the immunological mechanisms underlying these pathological processes have yet to be established. To fill this gap in knowledge, using a murine model and immunophenotyping, we determined the effect of advanced maternal age on the main cellular branch of adaptive immunity, T cells, at the maternal–fetal interface and in the offspring. We report that advanced maternal age impaired the process of labor at term, inducing dystocia and delaying the timing of delivery. Advanced maternal age diminished the number of specific proinflammatory T‐cell subsets [T helper type 1 (Th1): CD4+IFN‐γ+, CD8+IFN‐γ+ and Th9: CD4+IL‐9+], as well as CD4+ regulatory T cells (CD4+CD25+FoxP3+ T cells), at the maternal–fetal interface prior to term labor. Advanced maternal age also altered fetal growth and survival of the offspring in early life. In addition, infants born to advanced‐age mothers had alterations in the T‐cell repertoire but not in CD71+ erythroid cells (CD3−CD71+TER119+ cells). This study provides insight into the immune alterations observed at the maternal–fetal interface of advanced‐age mothers and their offspring.

Delayed parenthood and its influence on offspring health: what have we learned from the mouse model

“…As described above, AMA is associated with increased delivery complications and perinatal mortality as well as with reduced body weight at birth [33,38], which per se are known risk factors for adult diseases [15]. Available data on postnatal development indicate an increased risk of cardio-metabolic and neurological disorders in AMA offspring [32,33,38,39,41,42]. Some authors reported that AMA offspring displayed high blood pressure, indicative of predisposition to cardiovascular diseases [32].…”

“…Decline of female reproductive functions over time is characterized by a decrease in oocyte reservoir, low oocyte quality and high risk of pregnancy loss or complications, as widely described in several mammalian species [31][32][33][34][35][36][37][38][39][40]. Mouse models showed that aged females (> 10 months old) are able to produce progeny, however pregnancies are characterized by smaller litter size and increased rate of complications/pregnancy lost when compared to pregnancy outcome in young females [32][33][34].…”

“…Regarding post implantation development, an association between AMA and increased risk of pregnancy complications (such as pregnancy loss and fetal malformations, impaired placental development, difficulties in spontaneous parturition, and low birth weight) has been widely described [33,34,[38][39][40]. For example, Woods et al [40] showed that at least two-thirds of fetuses conceived by aged mothers were characterized by fetal growth retardation, cardiac edema, brain and neural tube defects, as well as vascular defects (e.g., dilated dorsal aorta and/or major brain artery).…”

“…Also, altered T-cell phenotypes, which may suggest abnormalities in the immune system, have been reported in AMA offspring [38]. Velazquez et al [32] observed increased body weight and impaired glucose metabolism in adult female AMA offspring [32].…”

“…The poor reproductive outcome and the risk of postnatal diseases in offspring due to AMA, described in the paragraphs above [31][32][33][34][35][36][37][38][39][40][41][42], have been associated with poor quality of aging oocytes (i.e., increased chromosome aberrations, mutation, epigenetic defects), as well as to suboptimal uterine support to fetal development [34][35][36][37][38][39][40][41][42][43][44][45].…”