Aging Clinical Trial
Official title:
The Short-chain Fatty Acid Acetate for Improving Age-associated Arterial Dysfunction
Cardiovascular diseases are the leading cause of morbidity and mortality and contribute most to healthcare costs in the U.S. Age is the strongest cardiovascular disease risk factor, with >90% of all deaths from cardiovascular disease occurring in adults >50 years old. The age-associated increased risk of cardiovascular disease is due, in large part, to the development of arterial dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries. Therefore, novel, effective interventions that improve arterial function will have a large public health impact by decreasing the risk of cardiovascular diseases. The short-chain fatty acid acetate is endogenously produced by the gut microbiome from fermentation of dietary soluble fiber. High-fiber diets reduce risk of cardiovascular diseases, but unfortunately, a low percentage of Americans meet guidelines for adequate dietary fiber intake and, despite nationwide efforts to improve this, trends in fiber intake have not improved over the last 20+ years. Thus, directly supplementing acetate may be a more practical and feasible intervention for effectively improving arterial function in older adults and reducing the risk of cardiovascular diseases. The investigators will conduct a study to determine the efficacy of 12 weeks of oral supplementation with acetate for improving arterial function in late middle-aged and older (50+ years) adults. They will also assess the safety and tolerability of acetate supplementation in these adults and perform innovative mechanistic analyses to determine how acetate supplementation improves arterial function. The investigators hypothesize that oral acetate supplementation will improve arterial function by decreasing oxidative stress and increasing nitric oxide bioavailability, and also hypothesize that acetate supplementation will be safe and promote high rates of adherence.
Status | Recruiting |
Enrollment | 66 |
Est. completion date | September 1, 2025 |
Est. primary completion date | July 1, 2025 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 50 Years and older |
Eligibility | Inclusion Criteria: - Able to provide informed consent; - Age 50+ years; - Serum phosphorus levels >= 2.5 mg/dl at screening; - Habitual dietary fiber intake <30 g/day for men or <21 g/day for women, based on Block Fiber Screener conducted at screening; - Weight-stable in the 3 months prior to enrollment (self-report); - Willing to abstain from dietary supplements for 48 hours and from alcohol, tobacco, and cannabis products for 24 hours before all visits; Exclusion Criteria: - History of current serious, chronic clinical disease, e.g., cardiovascular disease, diabetes, liver disease, Alzheimer's disease and related dementias, cancer; - Major changes in health in the past 3 months, e.g., hospitalizations, major surgeries, significant changes in medications; - Currently taking calcium acetate or any other calcium supplementation; - Screening FMDba > 8%; - Body mass index > 40 kg/m^2 at screening; - Regular vigorous/aerobic endurance >4 bouts/week for >30 min/bout at a workload of >6 METS; - Any apparent dependence on or abuse of alcohol, tobacco, and cannabis products; - Pregnancy, breast-feeding, or plans to become pregnant during the duration of the study; - Any finding on the medical history, physical exam, or standard clinical blood labs that, in the opinion of the physician of record, would put the subject at increased risk with calcium supplementation. |
Country | Name | City | State |
---|---|---|---|
United States | University of Colorado Anschutz Medical Campus | Aurora | Colorado |
Lead Sponsor | Collaborator |
---|---|
University of Colorado, Denver |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Change in 24-hour ambulatory blood pressure | Brachial artery blood pressure (mmHg) will be measured automatically every 20 minutes for a 24-hour period by an ambulatory blood pressure monitor (Oscar 2, SunTech Medical) validated according to British Hypertension Society Standards. Participants will be outfitted with the ambulatory blood pressure monitor by a trained investigator. The blood pressure cuff will be placed securely on the participant's non-dominant arm. Participants will be given written and verbal instructions on monitor operation. Ambulatory blood pressure recordings will be analyzed for mean 24-hour (averaged over the entire 24-hour period) SBP, and the change in 24-hour SBP from baseline to end-intervention will be determined. | 12 weeks | |
Other | Incidence of enrolled subjects dropping out of the study due to adverse events | The rate at which enrolled subjects drop out of the study due to adverse events, as an indicator of the degree to which overt adverse effects can be tolerated by our subjects. | 12 weeks | |
Other | % of prescribed amount of drug that is consumed | Adherence to the intervention will be assessed by determining the average % of prescribed study drug that is actually consumed by subjects across the intervention. | 12 weeks | |
Other | Change in serum acetate | Venous blood samples will be analyzed for concentrations of acetate using commercially available kit. | 12 weeks | |
Other | Change in gut microbiome composition | 16S rRNA genes isolated from fecal bacterial DNA (3 fecal swabs) will be amplified at the V4 region and subjected to multiplex Illumina sequencing. Raw sequences will be processed using the Qiita deblur pipeline and assigned taxonomic classification using the feature-classifier/classify-sklearn plugin in QIIME2. Differential abundance across time into the interventions and across groups (acetate vs. placebo) will be analyzed via ANCOM. | 12 weeks | |
Other | Change in Suppression of Brachial Artery Flow-Mediated Dilation by Oxidative Stress | Suppression of FMDba will be determined as the difference in FMDba (%change units) following 20 minutes of intravenous infusion with vitamin C (0.06 g/kg fat-free mass) vs. following 20 minutes of intravenous infusion with saline. The change in this outcome will be determined from baseline to end-intervention. | Baseline, 12 weeks | |
Other | Change in Endothelial Cell Markers of Oxidative Stress | Endothelial cells will be obtained from an antecubital vein via clinical endovascular biopsy--2 sterile 0.025-inch J-wires will briefly advanced through an intravenous catheter. Cells will be recovered by centrifugation, fixed with formaldehyde, and slides will be prepared and frozen. Slides will be stained for the primary antibody of interest and a complementary fluorescent secondary Alexafluor 647 antibody (Invitrogen). Slides will also be stained for the extracellular domain of vascular endothelial cadherin (Abcam) for positive identification of endothelial phenotype and DAPI for nuclear integrity. Images will be digitally captured and analyzed using Metamorph Software (Universal Imaging Corp). Values will be reported as ratios of subject endothelial cell protein expression to human umbilical vein endothelial cell control cells protein expression. We will determine the change in expression of proteins related to oxidative stress (e.g., nitrotyrosine and NADPH oxidase). | 12 weeks | |
Primary | Change in Brachial Artery Flow-Mediated Dilation | Nitric oxide-mediated endothelium dependent dilation (vascular endothelial function) will be assessed at baseline and end-intervention by flow-mediated dilation of the brachial artery determined using high-resolution ultrasonography (Canon Xario 200) and analyzed with a commercially available software package (Vascular Analysis Tools, Medical Imaging Applications, LLC). Brachial artery flow-mediated dilation will be assessed by measuring brachial artery diameter and forearm blood flow at baseline and for 2 minutes following reactive hyperemia induced by 5 minutes of forearm blood flow occlusion (upper forearm cuff placement). Data will be expressed as a percent change in arterial diameter from pre-cuff inflation diameter, and then as a change in this % from baseline to end-intervention. | 12 weeks | |
Secondary | Change in Carotid-Femoral Pulse Wave Velocity (CFPWV) | A transcutaneous tonometer (Noninvasive Hemodynamics Workstation, Cardiovascular Engineering Inc.) will be positioned at the carotid and femoral arteries, and CFPWV will be calculated as the mean distance/time between the foot of the carotid and femoral arterial waveforms calculated over >30 heart cycles. Data will be expressed as m/s. Change in CFPWV from baseline to end-intervention will be determined. | 12 weeks | |
Secondary | Change in Casual (seated, resting) systolic blood pressure | Casual (resting, seated) measures of blood pressure (mmHg) will be measured according to American Heart Association/American College of Cardiology guidelines. Briefly, blood pressure will be measured in triplicate over the brachial artery of the non-dominant arm after 5 minutes of quiet rest, with 1 minute of recovery between each measure. Subjects will be seated quietly with their back supported, feet flat on the floor, and arm at heart level. Casual systolic blood pressure (SBP) will be defined as the average of the three measures. Change in casual SBP from baseline to end-intervention will be determined. | 12 weeks |
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