Aging is a complex biological process that involves the accrual of bodily changes over a long life span. In humans, advanced maternal age is associated with infertility and adverse pregnancy complications. Cellular and organic senescence is hypothesized to contribute to the age-related decline in reproductive function. Accumulating evidence suggests that immune cells play pivotal roles in physiological reproductive function and pregnancy. The concept of “inflammaging” has recently emerged- an age-dependent, low-grade, chronic, and systemic inflammatory state induced by the senescence-associated secretory phenotype (SASP), which is produced by the innate immune, parenchymal, and nonparenchymal cells within the organs. In the present review, we discuss how cellular senescence and inflammaging accelerate reproductive failure in women by promoting SASP and immune-senescence during the establishment of pregnancy. In addition, we discuss the role of immune cells and their senescence in reproductive function, particularly in the ovaries (the corpus luteum), oviduct, and uterus.

Despite the increasing commercial use of nanoparticles, little is known about their effects on placental inflammation and pregnancy complications. In this study, nanosilica (NS) particles upregulated the inflammasome component nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) and induced placental inflammation and reactive oxygen species (ROS) generation, resulting in pregnancy complications. Furthermore, NS-induced pregnancy complications were markedly improved in Nlrp3^−/− mice but not in component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-deficient (Asc^−/−) mice, indicating the independence of NLRP3 inflammasomes. Pregnancy complications in Nlrp3^−/− and Asc^−/− mice phenotypes were dependent on the balance between interleukin (IL)-1α and IL-10. NS-induced pregnancy complications were completely prevented by either inhibition of ROS generation or forced expression of IL-10. Our findings provide important information about NS-induced placental inflammation and pregnancy complications and the novel pathophysiological roles of NLRP3 and ASC in pregnancy.

Macrophages are essential for regulating the physiology of pregnancy; however, excessive inflammatory responses to macrophages, induced by infection and/or endogenous danger signals, may potentially result in complications during pregnancy. Advanced glycation end‑products (AGE) and lipopolysaccharides (LPS) are known to induce inflammation and are associated with adverse developmental outcomes. The aim of the present study was to examine the effect of AGE and LPS on cytokines in the J774 murine macrophage cell line and the potential effect of resveratrol on AGE‑ and LPS‑induced inflammation in macrophages. AGE and LPS significantly increased IL‑6 mRNA expression and secretion in J774 macrophages (P<0.05). Although AGE and LPS significantly stimulated IL‑1β mRNA expression (P<0.05), they had no significant effect on IL‑1β secretion. To assess the receptors for AGE and LPS, including receptor for AGE (RAGE) and Toll‑like receptor (TLR4), blocking reagents (RAGE antagonist or TLR4 inhibitor) were added to the J774 macrophages. IL‑6 secretion induced by AGE or LPS was significantly inhibited by pretreatment with RAGE antagonist (P<0.05) or TLR4 inhibitor (P<0.05). IL‑6 secretion was dependent on nuclear factor (NF)‑κB activation and the production of reactive oxygen species (ROS; P<0.05). Resveratrol suppressed mRNA expression and intracellular IL‑6 production, resulting in significantly decreased IL‑6 secretion after treatment with LPS or AGE (P<0.01). Furthermore, treatment with Ex527, which is a sirtuin‑1 (SIRT1) inhibitor, significantly attenuated the anti‑inflammatory effect of resveratrol (P<0.05), and treatment with 5‑aminoimidazole‑4‑carboxamide ribonucleotide, which is a 5' adenosine monophosphate‑activated protein kinase (AMPK) activator, resulted in a significant decrease in IL‑6 secretion in J774 macrophages (P<0.05). The results of the present study indicated that AGE and LPS increase IL‑6 secretion depending on NF‑κB activation and ROS production through RAGE and/or TLR4 in the J774 murine macrophage cell line. Based on the present study, resveratrol appears to be an effective regulator of the inflammatory responses associated with SIRT1 and AMPK activation in macrophages. These results suggest that resveratrol may have therapeutic applications for controlling immune responses during pregnancy.