ACEs, SIRT1, and Premature Vascular Aging in Humans

Adverse childhood experiences (ACEs) are directly related to cardiovascular morbidity and mortality, and impaired vascular endothelial function (VEF) is an independent predictor of future cardiovascular disease (CVD) risk \[1, 2\]. Previous work from our lab (IRB 202010095) and others \[3\] demonstrates impaired VEF in young adults with prior exposure to ACEs even in the absence of clinical CVD risk factors. Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC) that plays a role in regulating vascular homeostasis and reductions in SIRT1 are associated with age-related endothelial dysfunction \[4\]. We have shown that ACEs-related impairments in VEF are accompanied by reductions in SIRT1 \[5\]. However, the mechanisms by which ACE exposure promotes VEF remain unknown. The goal of this project is to establish proof of concept that alterations in vascular SIRT1 expression and activity mediate premature vascular aging in individuals with \>=4 ACEs compared to those with 0 ACEs and that, because NAD+ is an essential substrate for SIRT1, increasing NAD+ bioavailability will restore VEF in those with \>=4 ACEs. Thus, we will use a robust translational approach coupling in vivo and in vitro measures of endothelial function, inflammation, oxidative stress, and SIRT1 expression and activity in young adults with (n=30-35) versus without (n=30-35) ACE exposure in a cross-sectional study, and during a randomized controlled trial employing a novel 4-week nicotinamide riboside (NR) s…

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