Acetate Supplements for Age-Related Vascular Stiffness

Overseen By Jill Herch, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: Calcium supplements

Disqualifiers: Cardiovascular disease, Diabetes, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

Duration: 12 weeks

66 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking calcium acetate or any other calcium supplements.

What data supports the effectiveness of the treatment Acetate, Sodium acetate, Acetic acid for age-related vascular stiffness?

While there is no direct evidence for acetate supplements, studies show that sodium nitrite, which also affects nitric oxide levels, can improve vascular function and reduce arterial stiffness in older adults. This suggests that treatments influencing nitric oxide pathways may help with age-related vascular issues. ^{1 2 3 4 5}

How does the treatment acetate differ from other treatments for age-related vascular stiffness?

Acetate supplements are unique because they may work by providing a source of acetic acid, which could influence metabolic pathways differently than other treatments like sodium nitrite or apigenin that focus on increasing nitric oxide availability or reducing oxidative stress. This approach might offer a novel way to address vascular stiffness by potentially altering metabolic processes rather than directly targeting oxidative stress or nitric oxide pathways. ^{1 6 7 8 9}

Research Team

Vienna E Brunt, PhD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

This trial is for adults aged 50+ with low fiber intake, stable weight, and normal serum phosphorus levels. They must not be pregnant or planning pregnancy, have a BMI over 40, take calcium supplements, or suffer from serious chronic diseases like heart disease or diabetes.

Inclusion Criteria

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

I can avoid dietary supplements for 2 days and alcohol, tobacco, and cannabis for 1 day before visits.

Exclusion Criteria

Your weight is very high for your height, with a body mass index (BMI) over 40.

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.

I am currently taking calcium supplements.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive 12 weeks of oral acetate or placebo supplementation to assess arterial function improvement

12 weeks

4 visits (in-person) at weeks 0, 2, 4, and 8; additional phone check-ins at weeks 1, 6, and 10

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

2 visits (in-person) for post-testing

Treatment Details

Interventions

• Acetate

Trial Overview The study tests if a 12-week oral acetate supplement can improve arterial function in older adults by reducing oxidative stress and increasing nitric oxide. It compares the effects of Calcium Acetate Oral Solution to Calcium Carbonate Oral Suspension.

Participant Groups

Group I: Acetate Experimental Treatment 1 Intervention

Subjects will be orally supplemented with calcium acetate for 12 weeks. Subjects will be instructed to take a volume of the oral liquid solution that contains 1,334 mg of calcium acetate 3x per day with meals, for a total dose of 4,000 mg/day. Calcium acetate will be compounded by the CU Anschutz Medical Campus Research Pharmacy and dispensed to subjects in 4-week supplies.

Group II: Placebo Placebo Group 1 Intervention

Subjects will be orally supplemented with calcium carbonate for 12 weeks. This placebo has been selected to match any potential effects of calcium and phosphate binding of the calcium acetate, i.e., we will isolate the effects of acetate. Subjects will be instructed to take a volume of the oral liquid solution equal to that of the calcium acetate group 3x per day with meals. To match the amount of elemental calcium between calcium acetate and calcium carbonate, this dose of calcium carbonate will contain 833 mg of calcium carbonate, for a total dose of 2,500 mg/day. Calcium carbonate will be compounded by the CU Anschutz Medical Campus Research Pharmacy, visually identical to calcium acetate including the packaging, and dispensed to subjects in 4-week supplies.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Findings from Research

Oral sodium nitrite supplementation (80 or 160 mg/day) for 10 weeks was found to be safe and well tolerated in middle-aged and older adults, significantly increasing plasma nitrite levels and improving endothelial function by 45-60%.

The treatment also led to improvements in carotid artery elasticity, indicating reduced arterial stiffness, without causing significant changes in blood pressure or adverse effects, suggesting potential benefits for vascular health in aging populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults. DeVan, AE., Johnson, LC., Brooks, FA., et al.[2018]

In a pilot study involving 14 men (8 older and 6 young), acute oral ingestion of tetrahydrobiopterin (BH(4)) significantly improved carotid artery compliance and reduced stiffness in older men, suggesting it may help counteract age-related vascular stiffness.

The study found that BH(4) increased its own circulating levels by 17-19 times and also lowered systolic blood pressure in older participants, indicating potential therapeutic benefits for vascular health in aging individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tetrahydrobiopterin supplementation enhances carotid artery compliance in healthy older men: a pilot study. Pierce, GL., Jablonski, KL., Walker, AE., et al.[2023]

Short-term sodium nitrite therapy significantly reverses age-related vascular endothelial dysfunction and arterial stiffness in older mice, restoring nitric oxide bioavailability and improving blood vessel dilation.

Nitrite treatment also reduces oxidative stress and inflammation markers in older mice, suggesting it could be a promising therapy for addressing arterial aging in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. Sindler, AL., Fleenor, BS., Calvert, JW., et al.[2023]

In a study involving 12 healthy elderly participants (average age 73.8 years), oral L-arginine supplementation significantly improved flow-mediated dilation (FMD) of the brachial artery, indicating enhanced endothelial function.

The improvement in FMD was likely due to L-arginine normalizing the ratio of L-arginine to its inhibitor, asymmetric dimethyl L-arginine (ADMA), suggesting a potential mechanism for restoring nitric oxide bioavailability in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Bode-Böger, SM., Muke, J., Surdacki, A., et al.[2022]

This study will evaluate the safety and efficacy of nicotinamide riboside supplementation over 3 months in 94 midlife and older adults with above-normal systolic blood pressure, aiming to reduce blood pressure and arterial stiffness.

The trial is designed to assess not only blood pressure changes but also the impact on oxidative stress and inflammation, which are key factors in cardiovascular health as people age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults. Freeberg, KA., Craighead, DH., Martens, CR., et al.[2022]

Oral supplementation with apigenin significantly improved arterial function in aging mice by restoring endothelial-dependent dilation and increasing nitric oxide bioavailability, demonstrating its potential as a therapeutic for arterial aging.

Apigenin also mitigated age-related aortic stiffness and prevented foam cell formation, indicating its role in reversing key indicators of arterial dysfunction and reducing cardiovascular disease risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. Clayton, ZS., Hutton, DA., Brunt, VE., et al.[2022]

Chronic administration of L-arginine significantly improved vascular function recovery after ischemia in male Sprague-Dawley rats aged 4 and 8 months, indicating its potential efficacy in enhancing heart health during young adulthood.

The study found that L-arginine did not show the same benefits in younger (1 month) or older (16 months) rats, suggesting that its effectiveness may be age-dependent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age-related changes in the protective effect of chronic administration of L-arginine on post-ischemic recovery of endothelial function. Nakamura, K., Al-Ruzzeh, S., Chester, AH., et al.[2019]

Fisetin, a natural compound, effectively reduces cellular senescence and inflammation in old mice, leading to improved arterial function and increased nitric oxide bioavailability.

The study demonstrated that fisetin lowers arterial stiffness and promotes favorable arterial wall remodeling, suggesting its potential as a therapy for age-related arterial dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence. Mahoney, SA., Venkatasubramanian, R., Darrah, MA., et al.[2023]

The renin-angiotensin-aldosterone system (RAAS) is a key target for treating cardiovascular diseases due to its role in promoting arterial stiffness and vascular aging, which are linked to conditions like hypertension and chronic kidney disease.

New components of the RAAS have been identified that possess antioxidant and anti-inflammatory properties, which can help improve arterial compliance and endothelial function, suggesting that RAAS inhibition may be an effective strategy to combat vascular aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Renin-Angiotensin-Aldosterone System and Its New Components in Arterial Stiffness and Vascular Aging. Neves, MF., Cunha, AR., Cunha, MR., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Tetrahydrobiopterin supplementation enhances carotid artery compliance in healthy older men: a pilot study. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Oral L-arginine improves endothelial function in healthy individuals older than 70 years. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Age-related changes in the protective effect of chronic administration of L-arginine on post-ischemic recovery of endothelial function. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

The Role of Renin-Angiotensin-Aldosterone System and Its New Components in Arterial Stiffness and Vascular Aging. [2018]