Role of Cellular Senescence in IUGR: Impact on Fetal Morbidity and Development

Abstract

Intrauterine growth restriction (IUGR) is a critical challenge in perinatal medicine and is associated with significant morbidity and mortality. This review explores the intricate involvement of early developmental senescence in IUGR. We highlight the dual role of cellular senescence in both normal development and pathological conditions, emphasizing the need for further research to elucidate these mechanisms and develop targeted interventions. We discuss how oxidative stress and mitochondrial dysfunction affect senescence determinants. We present emerging therapeutic strategies aimed at targeting senescence and inflammation in the placenta. We also introduce Rytvela, an interleukin-1 (IL-1) receptor modulator developed in our laboratory, which selectively attenuates pro-inflammatory signaling while preserving essential immune responses, which in turn mitigate senescence. By addressing senescence-related dysfunctions, such interventions may improve placental performance and fetal outcomes, opening up new directions for the clinical management of IUGR.

Keywords: IUGR; Rytvela; development; oxidative stress; senescence.

Figure 1

Telomere shortening contributes to placental dysfunction and IUGR. Progressive telomere shortening in trophoblast cells activates a DNA damage response (DDR), mediated by the activation of Ataxia Telangiectasia Mutated (ATM) and ATM and Rad3-Related (ATR) kinases. This leads to the activation of p53, inducing cell cycle arrest and cellular senescence (Steps 1–2). The accumulation of senescent cells results in impaired placental function, reducing oxygen and nutrient delivery to the fetus (Step 3), and ultimately causing the restricted fetal growth seen in IUGR (Step 4). This sequence provides a mechanistic link between cellular senescence processes and adverse pregnancy outcomes, specifically IUGR. Created with www.BioRender.com.

Figure 2

Oxidative stress-driven mitochondrial and endoplasmic reticulum (ER) dysfunction contributes to IUGR. Oxidative stress leads to mitochondrial dysfunction—characterized by increased reactive oxygen species (ROS) leakage, decreased ATP production, and calcium overload—and to ER stress, marked by protein misfolding, unfolded protein response (UPR) activation, and CHOP-mediated apoptosis. These stress responses trigger cellular senescence through the upregulation of p53, p21, and p16, along with the secretion of pro-inflammatory factors (SASP). The senescence of placental trophoblasts compromises placental perfusion and function, ultimately resulting in restricted fetal growth and an increased risk of chronic diseases in the offspring. Created with www.BioRender.com.

Figure 3

Overview of therapeutic interventions targeting cellular stress and senescence pathways implicated in IUGR. The figure summarizes four major strategies: antioxidant therapies, senotherapeutics (senolytics and senomorphics), inflammation modulation, and targeted delivery approaches. These therapies aim to improve placental function, reduce oxidative and inflammatory stress, restore telomere integrity, and ultimately improve fetal growth and maternal–fetal outcomes.