Pregnancy, preeclampsia and maternal aging: From epidemiology to functional genomics

Abstract

Women live longer than men but experience greater disability and a longer period of illness as they age. Despite clear sex differences in aging, the impact of pregnancy and its complications, such as preeclampsia, on aging is an underexplored area of geroscience. This review summarizes our current knowledge about the complex links between pregnancy and age-related diseases, including evidence from epidemiology, clinical research, and genetics. We discuss the relationship between normal and pathological pregnancy and maternal aging, using preeclampsia as a primary example. We review the results of human genetics studies of preeclampsia, including genome wide association studies (GWAS), and attempted to catalog genes involved in preeclampsia as a gateway to mechanisms underlying an increased risk of later life cardio- and neuro- vascular events. Lastly, we discuss challenges in interpreting the GWAS of preeclampsia and provide a functional genomics framework for future research needed to fully realize the promise of GWAS in identifying targets for geroprotective prevention and therapeutics against preeclampsia.

Figure 1.

Interconnected environmental, social, and innate factors affecting women’s states of health and disease in pregnancy and beyond that may alter risk for aging and age-related diseases.

Figure 2.

Functional genomics of preeclampsia illustrating challenges in interpreting GWAS. (A) In silico analysis to identify candidate causal variants and genes of preeclampsia informed by GWAS. (B) High-throughput screens such as a massive parallel reporter assay (MPRA) to investigate a large number of regulatory variants within a single experiment for identification and prioritization of functional variants. (C) Cell modeling using CRISPR-engineered pluripotent stem cell followed by differentiation into multiple cell types to study cell type-specific functional impact of variants in vitro. (D) Mouse modeling to study the functional impact of variants in vivo.