ACEs, SIRT1, and Premature Vascular Aging in Humans

NCT07073352 | Recruiting

• 1 other identifier: 202407275
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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. 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. 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+.

Conditions

Adverse Childhood Experiences; Endothelial Dysfunction

Outcome Measures

Primary Outcomes (1)

• Vascular endothelial function

  Vascular endothelial function will be assayed in vivo using the brachial artery flow mediated dilation technique as the relative increase in brachial artery diameter in response to 5-minutes of forearm ischemia (peak - baseline diameter / baseline diameter \* 100).

  Before (0 Weeks) and after 4-week supplementation period (4 Weeks)

Secondary Outcomes (4)

• Endothelial SIRT1 Expression

  Before (0 Weeks) and after 4-week supplementation period (4 Weeks)

• Endothelial SIRT1 Activity

  Before (0 Weeks) and after 4-week supplementation period (4 Weeks)

• Cellular SIRT1 Activity in PBMCs

  Before (0 Weeks) and after 4-week supplementation period (4 Weeks)

• Cellular NAD+ metabolites

  Before (0 Weeks) and after 4-week supplementation period (4 Weeks)

Study Arms (2)

Nicotinamide Riboside

EXPERIMENTAL

4-weeks of twice daily, oral supplementation (2,000 mg/day) of NR (NIAGEN® , ChromaDEX, Irvine, CA).

Dietary Supplement: Nicotinamide Riboside

Placebo

PLACEBO COMPARATOR

Participants randomized to the control group will consume matched placebo capsules containing microcrystalline cellulose.

Dietary Supplement: Placebo

Interventions

Nicotinamide Riboside DIETARY_SUPPLEMENT

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.

Nicotinamide Riboside

Placebo DIETARY_SUPPLEMENT

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Nathaniel Jenkins: lead

Study Sites (1)

Integrative Laboratory of Applied Physiology and Lifestyle Medicine

Iowa City, Iowa, 52242, United States

RECRUITING

MeSH Terms

Interventions

nicotinamide-beta-riboside

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: June 30, 2025
• First Posted: July 18, 2025
• Study Start: March 27, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): June 30, 2027
• Last Updated: July 18, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Deidentified data will be made publically available within 1 year of study completion in perpetuity.

Locations

US (1)