Placental Ageing in Adverse Pregnancy Outcomes: Telomere Shortening, Cell Senescence, and Mitochondrial Dysfunction

Abstract

Preeclampsia is a multisystemic pregnancy disorder and a major cause of maternal and neonatal morbidity and mortality worldwide. The exact pathophysiology of preeclampsia remains unclear; however, it is speculated that the various pathologies can be attributed to impaired vascular remodelling and elevated oxidative stress within the placenta. Oxidative stress plays a key role in cell ageing, and the persistent presence of elevated oxidative stress precipitates cellular senescence and mitochondrial dysfunction, resulting in premature ageing of the placenta. Premature ageing of the placenta is associated with placental insufficiency, which reduces the functional capacity of this critical organ and leads to abnormal pregnancy outcomes. The changes brought about by oxidative insults are irreversible and often lead to deleterious modifications in macromolecules such as lipids and proteins, DNA mutations, and alteration of mitochondrial functioning and dynamics. In this review, we have summarized the current knowledge of placental ageing in the aetiology of adverse pregnancy outcomes and discussed the hallmarks of ageing which could be potential markers for preeclampsia and fetal growth restriction.

Placental and Cord Blood Telomere Length in Relation to Maternal Nutritional Status

“…Thus, there may be other mechanisms in place for a relation between maternal BMI and placental rTL. It is noteworthy that an interplay between oxidative stress, shorter placental TL, epigenetic alterations, and mitochondrial dysfunction has been proposed ( 5 , 45 ). TL may thus be affected by changes in DNA methylation ( 46 ), and folate status, which is essential for methylation through one-carbon metabolism, has been found to be positively associated with cord blood TL in US studies ( 7 , 23 ).…”

“…We then made a model 3 for placental rTL with additional adjustment for the other nutritional factors that showed an association in model 2—that is, vitamin B-12 and 25(OH)D 3 (including season of sampling). Pre-eclampsia has been associated with shorter trophoblast TL ( 5 ); however, this was not included as covariate, as none of the women with placental rTL data reported having pre-eclampsia. For cord blood rTL, model 2 included adjustment for maternal age, GW at birth, and birth weight, according to previous studies ( 33 ).…”

“…In highly proliferating tissues there is also a counteracting elongation process under the influence of telomerase, the main telomere-maintaining enzyme. The telomerase activity is strictly regulated in both placenta and embryo and appears to be important for successful fetal development ( 4 , 5 ). Still, the telomeres have a certain degree of plasticity, and recent studies show that the uterine environment may influence fetal telomere length (TL) ( 6–8 ).…”

Role of oxidative stress in the dysfunction of the placental endothelial nitric oxide synthase in preeclampsia

“…The presence of LPPs in PE placentas, could be indicative of their premature senescence, in agreement with the hypothesis that accelerated placental aging is involved in PE pathophysiology via oxidative stress [ 120 ]. Indeed, connections exist between oxidative stress, cell senescence and premature placental aging, with possible implication in PE pathophysiology [ [120] , [121] , [122] , [123] , [124] ]. Placental aging during normal pregnancy, is a physiological mechanism observed in the multinucleated syncitiotrophoblast layer which is continuously undergoing a senescent-associated secretory phenotype (SASP) [ 120 , 122 ].…”

Mechanisms of Endothelial Dysfunction in Pre-eclampsia and Gestational Diabetes Mellitus: Windows Into Future Cardiometabolic Health?

“…PE affects 2-8% of pregnancies and has large heterogeneity in its associated risk factors (14,15). The exact pathophysiology of PE remains a controversial issue, however it is well-accepted that complications originate during abnormal placentation and resulting placental insufficiency.…”