Advanced maternal age induces fetal growth restriction through decreased placental inflammatory cytokine expression and immune cell accumulation in mice

J Reprod Dev. 2021 Aug 27;67(4):257-264. doi: 10.1262/jrd.2021-034. Epub 2021 Jun 28.


Advanced maternal age is a risk factor for female infertility, and placental dysfunction is considered one of the causes of pregnancy complications. We investigated the effects of advanced maternal aging on pregnancy outcomes and placental senescence. Female pregnant mice were separated into three groups: young (3 months old), middle (8-9 months old), and aged (11-13 months old). Although the body weights of young and middle dams gradually increased during pregnancy, the body weight of aged dams only increased slightly. The placental weight and resorption rate were significantly higher, and live fetal weights were reduced in a maternal age-dependent manner. Although mRNA expression of senescence regulatory factors (p16 and p21) increased in the spleen of aged dams, mRNA expression of p16 did not change and that of p21 was reduced in the placenta of aged dams. Using a cytokine array of proteins extracted from placental tissues, the expression of various types of senescence-associated secretory phenotype (SASP) factors was decreased in aged dams compared with young and middle dams. The aged maternal placenta showed reduced immune cell accumulation compared with the young placenta. Our present results suggest that models using pregnant mice older than 8 months are more suitable for verifying older human pregnancies. These findings suggest that general cellular senescence programs may not be included in the placenta and that placental functions, including SASP production and immune cell accumulation, gradually decrease in a maternal age-dependent manner, resulting in a higher rate of pregnancy complications.

Keywords: Aging; Cellular senescence; Immune cells; Inflammaging; Senescence-associated secretory phenotype (SASP).

MeSH terms

  • Animals
  • Cytokines / metabolism*
  • Female
  • Fetal Development
  • Fetal Growth Retardation*
  • Fetal Weight
  • Immunity / physiology*
  • Leukocyte Common Antigens / analysis
  • Leukocytes / immunology
  • Maternal Age*
  • Mice
  • Mice, Inbred ICR
  • Placenta / immunology
  • Placenta / metabolism*
  • Pregnancy
  • Pregnancy Outcome
  • Senescence-Associated Secretory Phenotype / physiology


  • Cytokines
  • Leukocyte Common Antigens