Epigenetic and senescence markers indicate an accelerated ageing-like state in women with preeclamptic pregnancies

Abstract

Background: Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria and/or multisystem involvement. Disease-specific therapy has yet to be developed due to the lack of understanding of underlying mechanism(s). We postulate that accelerated ageing in general, and particularly cellular senescence, play a role in its pathophysiology. Methods: We compared women with preeclampsia vs. normotensive pregnancies with respect to epigenetic markers of ageing and markers of senescence in tissues/organs affected by preeclampsia (blood, urine, adipose tissue, and kidney). Findings: We demonstrate that preeclamptic compared to normotensive pregnant women: (i) undergo accelerated epigenetic ageing during pregnancy, as demonstrated by an "epigenetic clock"; (ii) exhibit higher levels/expression of senescence-associated secretory phenotype factors in blood and adipose tissue; (iii) display increased expression of p16 INK4A in adipose tissue and renal sections, and (iv) demonstrate decreased levels of urinary a-Klotho (an anti-ageing protein) at the time of delivery. Finally, we provide data indicating that pre-treatment with dasatinib, a senolytic agent, rescues the angiogenic potential of mesenchymal stem cells (MSC) obtained from preeclamptic pregnancies, and promotes angiogenesis, even under pro-inflammatory conditions. Interpretation: Taken together, our results identify senescence as one of the mechanisms underpinning the pathophysiology of preeclampsia. Therapeutic strategies that target senescent cells may offer novel mechanism-based treatments for preeclampsia.

Pregnancy and Reproductive Risk Factors for Cardiovascular Disease in Women

“…It has been postulated that accelerated cellular senescence may represent one mechanism of accelerated cardiovascular aging in women with HDPs. 80,81 There appears to be a strong genetic contribution to preeclampsia risk. Women whose first-degree relatives had preeclampsia have a 2-to 3.5-fold risk of developing preeclampsia.…”

“…It has been postulated that accelerated cellular senescence may represent one mechanism of accelerated cardiovascular aging in women with HDPs. 80,81…”

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans

“…We will dissect such potential mechanisms in future studies. Additional future studies are needed to: (1) ascertain if CSF α-Klotho increases after administering senolytics to humans with Alzheimer's disease (currently being studied in the clinical trials, NCT04785300 and NCT04685590), (2) compare blood indices of senescent cell burden to urinary α-Klotho in patients across the age spectrum in other current and future clinical studies of senolytics, and (3) ascertain why in pre-eclampsia, a condition that we found is associated with increased senescent cells 86 and that has been linked to decreased urinary α-Klotho, 87 plasma α-Klotho is increased. 88 This discrepancy between α-Klotho in urine and plasma in pre-eclampsia is consistent with the previous finding that in chronic kidney disease (CKD), plasma α-Klotho is not related to kidney function and does not predict adverse outcomes.…”

TLR4 Modulates Senescence and Paracrine Action in Placental Mesenchymal Stem Cells via Inhibiting Hedgehog Signaling Pathway in Preeclampsia

“…Moreover, senescent cells are characterized by abnormal paracrine secreting mixture of cytokines, chemokines, and matrix metalloproteins to influence the neighboring cells and microenvironment [ 14 ]. Although there exists the physiological senescence in the placenta as pregnancy advances to term [ 15 ], the preeclamptic placentas showed accelerated senescence [ 16 – 18 ]. Thereinto, preeclamptic PMSCs showed abnormal proliferation [ 19 ], arrested cell cycle [ 8 ], overexpressed p16, overactivated SA- β -gal, and abnormal secretory phenotype [ 11 ].…”