ACEs, SIRT1, and Premature Vascular Aging in Humans

Официальное название

Adverse Childhood Experiences and Premature Vascular Aging in Humans: The Role of SIRT1

Обзор

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) supplementation approach to increase SIRT1 activity by increasing cellular NAD+ in ACE+ (n=15/group) to accomplish the following specific aims: 1. Determine the mechanisms by which ACE exposure alters the regulation of VEF by SIRT1. We hypothesize that compared to those without ACEs (ACE-), ACE+ will have (H1a) elevated endothelial oxidative stress and inflammation, (H1b) accompanied by reduced endothelial SIRT1 expression and increased p66SHC expression and acetylation of p65 and p53, (H1c) in association with lower VEF. 2. Determine how targeting SIRT1 by increasing NAD+ bioavailability affects VEF in young adults with ACEs. We hypothesize that systemic NR supplementation will (H2a) augment cellular SIRT1 activity and (H2b) improve VEF in ACE+. \[1\] Felitti, V.J., Anda, R.F., Nordenberg, D., Williamson, D.F., Spitz, A.M., Edwards, V., Koss, M.P., \& Marks, J.S. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The adverse childhood experiences (ace) study. American Journal of Preventive Medicine, 14(4), 245-258. https://doi.org/10.1016/S0749-3797(98)00017-8. \[2\] Jenkins, N.D.M., \& Robinson, A.T. (2022). How do adverse childhood experiences get under the skin to promote cardiovascular disease? A focus on vascular health. Function (Oxf), 3(4), zqac032. PMC9279110. 10.1093/function/zqac032. \[3\] Rodriguez-Miguelez, P., Looney, J., Blackburn, M., Thomas, J., Pollock, J.S., \& Harris, R.A. (2022). The link between childhood adversity and cardiovascular disease risk: Role of cerebral and systemic vasculature. Function. 10.1093/function/zqac029. \[4\] Thompson, A. M., Wagner, R., \& Rzucidlo, E. M. (2014). Age-related loss of SirT1 expression results in dysregulated human vascular smooth muscle cell function. American Journal of Physiology-Heart and Circulatory Physiology, 307(4), H533-H541. \[5\] Jenkins, N.D.M., Rogers, E.M., Banks, N.F., Tomko, P.M., Sciarrillo, C.M., Emerson, S.R., Taylor, A., \& Teague, T.K. (2021). Childhood psychosocial stress is linked with impaired vascular endothelial function, lower sirt1, and oxidative stress in young adulthood. Am J Physiol Heart Circ Physiol, 321(3), H532-H541. PMC8461842. 10.1152/ajpheart.00123.2021

Вмешательства

• Пищевая добавка Nicotinamide Riboside
  Participants will consume 1,000 mg of nicotinamide riboside (NR) upon waking and with an evening meal, and complete a daily supplementation log to assist with compliance monitoring. NR is a naturally occurring vitamin B3 derivative readily taken up by cells as a direct NAD+ precursor. Similar NR supplementation protocols are well-tolerated, boost NAD+ concentrations by \~100-140% achieving a steady state within 1-2 weeks, and increase SIRT activity in humans.
• Пищевая добавка Placebo
  Participants will consume 1,000 mg of placebo (microcrystalline cellulose) upon waking and with an evening meal, and complete a daily supplementation log to assist with compliance monitoring.

Первичные конечные точки

• Vascular endothelial function [Срок оценки: Before (0 Weeks) and after 4-week supplementation period (4 Weeks)]

Вторичные конечные точки (4)

• Endothelial SIRT1 Expression [Срок оценки: Before (0 Weeks) and after 4-week supplementation period (4 Weeks)]
• Endothelial SIRT1 Activity [Срок оценки: Before (0 Weeks) and after 4-week supplementation period (4 Weeks)]
• Cellular SIRT1 Activity in PBMCs [Срок оценки: Before (0 Weeks) and after 4-week supplementation period (4 Weeks)]
• Cellular NAD+ metabolites [Срок оценки: Before (0 Weeks) and after 4-week supplementation period (4 Weeks)]

Критерии участия

Критерии включения

• 18 - 30 years
• ACE score of 0 OR ≥4 (Aim 1); ACE score ≥4 (Aim 2)

Критерии исключения

• Resting arterial blood pressure >140/90 mmHg
• BMI ≥30 kg/m2 and/or weight unstable (>2.27 kg change) last 6 month
• Cardiovascular, metabolic, or pulmonary disease
• Cardiovascular or metabolic prescription drug use
• Vasoactive antidepressant drug use (SSRIs and clonidine)
• Currently pregnant or breastfeeding
• Heavy alcohol consumption (AUDIT screening)
• Use of illicit drugs
• Current tobacco use
• Regular vigorous (>6 MET s) aerobic exercise (>4 bouts/week, >30 min/bout)
• Dietary supplementation with antioxidants or habitual use of NSAIDs

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Фундаментальное исследование

Центры проведения

США · 1 центр

• Integrative Laboratory of Applied Physiology and Lifestyle Medicine — Iowa City

Идентификаторы

NCT: NCT07073352 · 202407275

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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