Advanced maternal age induced altered FoxO1 activation and cellular senescence in early placenta development in rats

Advanced maternal age (AMA) is associated with increased risks of adverse pregnancy outcomes partly due to placental dysfunction; however, the underlying mechanisms remain poorly understood. This study aimed to investigate early placental development in AMA pregnancies, focusing on FoxO1 activation and its role in cellular senescence and oxidative stress.

Three-month-old (Control) and 10-month-old (AMA) Wistar rats were mated with young males. On day 12 of pregnancy, FOXO1 activity and the expression of its target genes, oxidative status and morphometry were evaluated in the decidua and developing placenta.

AMA rats exhibited a reduced number of implantation sites, fewer viable embryos, and decreased embryonic crown-rump length, indicating restricted growth. Markers of oxidative stress were increased in the decidua. At the molecular level, FOXO1 phosphorylation was reduced in the decidua, suggesting increased FOXO1 activation, whereas in the developing placenta, FOXO1 phosphorylation was elevated, indicating its inactivation. SGK1, a kinase that regulates FOXO1 phosphorylation, showed decreased phosphorylation in the decidua of AMA rats. Moreover, the senescence markers Cdkn1a (P21) and Cdkn2a (P16), known FOXO1 target genes, were upregulated in the decidua and downregulated in the developing placenta. These changes were associated with impaired cell proliferation in the decidua and a reduced syncitiotrophoblast layer in the developing placenta.

These findings highlight the differential regulation of FOXO1 in the decidua and placenta during AMA pregnancies. Increased FOXO1 activity in the decidua, likely driven by oxidative stress, and reduced SGK1 phosphorylation, may impair decidual function and contribute to altered placenta development with reduced FOXO1 activity.