Women With a History of Preeclampsia Exhibit Accelerated Aging and Unfavorable Profiles of Senescence Markers

Abstract

Background: Senescence, a mechanism of cellular aging, which is characterized by irreversible proliferation arrest and a proinflammatory secretory phenotype, has been documented in women with preeclampsia. As cellular senescence can persist and progress, we postulated that it is associated with accelerated aging phenotype and accumulation of comorbidities in women with a history of preeclampsia.

Methods: We included a cohort of women with a history of preeclampsia (n=40) age- and parity-matched to a group of referent women with normotensive pregnancies (n=40). Women with prior major cardiovascular events, neurological, or autoimmune conditions were excluded. We collected urine and blood samples to study markers of aging, data on multimorbidity at the time of enrollment, and prospectively followed them for events over the course of 6 years, on average.

Results: Women with a history of preeclampsia exhibited unfavorable aging profiles compared with referent women, including decreased urinary α-Klotho (P=0.018); increased leptin (P=0.016) and leptin/adiponectin ratio (P=0.027), and increased extracellular vesicles positive for tissue factor (P=0.025). Women with a history of preeclampsia likewise had a higher rate of comorbidities at the time of enrollment (P=0.003) and had a 4× higher risk of developing major cardiovascular events compared with referent women (P=0.003).

Conclusions: Our data suggest that a history of preeclampsia is associated with accelerated aging as indicated by senescence marker differences and the accumulation of multimorbidity later in life. Targeting cellular senescence may offer novel, mechanism-based approaches for the diagnosis and treatment of adverse health outcomes in women with a history of preeclampsia.

Keywords: aging; cardiovascular diseases; high blood pressure; hypertension; preeclampsia; pregnancy.

Figure 1.. Frequency of multimorbidity between women with a history of PE, with and without future HTN.

When all comorbidities are accounted for, 68% of women with a history of PE had two or more conditions at the time of enrollment compared to 23% of their normotensive peers (panel on the left). If hypertension is excluded, history of PE is still associated with unfavorable counts of multimorbidity (panel on the right). Kruskal-Wallis method was used to test the differences among the groups (n=80).

Figure 2.. Age- and parity-matched normotensive peers and senescence, urinary profiles, and EV⁺TF levels by multimorbidity count.

Women with two or more comorbidities had significantly decreased adiponectin (n=79) (A), and increased concentrations of leptin (n=79) (B), and a higher leptin/adiponectin ratio (n=79) (C). Decrease of the urinary marker of aging. α-Klotho (n=76) (D), was also associated with accumulation of comorbidities, whereas α-Klotho /creatinine ratio (n=76) (E), and EV⁺TF (n=80) (F) were not. Associations between multimorbidity counts and senescence profiles among all patients were evaluated using the Kruskal-Wallis test.

Figure 3.. Cumulative incidence plots of time to the composite events consisting of CAD, CHF, TIA/stroke, or CKD, by PE status.

After an average follow-up of 6 years, women with a history of PE (upper, red line) had a significant increase in development of new events compared to their normotensive peers (lower, blue line). The risk of developing one of the events (CAD, CHF, TIA, stroke, or CKD), compared to women without a history of PE was elevated, HR [95% CI]: 4.34 [1.67 to 11.30], P=0.003. Cox proportional hazards model was used to calculate the hazard ratio, and the Kaplan-Meier method was used to generate the accumulation of composite events over time (n=78). CAD-coronary artery disease, CHF-chronic heart failure, TIA-transient ischemic attack, CKD-chronic kidney disease