Ketone Ester And Salt (KEAS) in Older Adults

NCT06868719 | Recruiting

• 2 other identifiers: 23207bR21AG087524
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Most Americans consume excess dietary salt based on the recommendations set by the American Heart Association and Dietary Guidelines for Americans. High dietary salt impairs blood pressure control by affecting systemic blood vessels and the kidneys. These changes contribute to excess salt consumption being associated with increased risk for chronic kidney disease and cardiovascular disease, the leading cause of death in America. Salt is particularly deleterious in older adults who are more likely to exhibit salt-sensitive hypertension. However, salt consumption remains high in the United States. Thus, there is a critical need for strategies to counteract the effects of high dietary salt as consumption is likely not going to decrease. One promising option is ketones, metabolites that are produced in the liver during prolonged exercise and very low-calorie diets. While exercise and low-calorie diets are beneficial, not many people engage in these activities. Limited evidence indicates that ketone supplements improve cardiovascular health in humans. Additionally, published rodent data indicates that ketone supplements prevent high salt-induced increases in blood pressure, blood vessel dysfunction, and kidney injury. Our human pilot data also indicates that high dietary salt reduces intrinsic ketone production, but it is unclear whether ketone supplementation confers humans' protection against high salt similar to rodents. Therefore, the investigators seek to conduct a short-term high-dietary salt study to determine whether ketone supplementation prevents high dietary salt from eliciting increased blood pressure, blood vessel dysfunction, and kidney injury/impaired blood flow. The investigators will also measure inflammatory markers in blood samples and isolate immune cells that control inflammation. Lastly, the investigators will also measure blood ketone concentration and other circulating metabolites that may be altered by high salt, which could facilitate novel therapeutic targets to combat high salt.

Conditions

Salt; Excess; Hypertension; Aging; Inflammation; Blood Pressure

Keywords

Blood Pressure; Salt; Aging; Inflammation; Cardiovascular Disease

Outcome Measures

Primary Outcomes (1)

• Blood pressure reactivity responses

  The investigators will measure systolic and diastolic pressure using photoplethysmography at the finger and manually measure brachial pressures. Systolic and diastolic blood pressure will be assessed at rest and during submaximal cycling exercise. Blood pressure reactivity will be expressed as a change in pressure (mmHg) from baseline to a predetermined time during the stressor.

  This measure is completed on day 10 of each 10-day intervention (low salt, high salt, high salt + ketone) over 3-4 months and values will be compared across interventions.

Secondary Outcomes (1)

• Flow mediated dilation (FMD)

  This measure is completed on day 10 of each 10-day intervention (low salt, high salt, high salt + ketone) over 3-4 months and values will be compared across interventions.

Other Outcomes (9)

• Pulse wave velocity

  This measure is completed on day 10 of each 10-day intervention (low salt, high salt, high salt + ketone) over 3-4 months and values will be compared across interventions.

• Pulse wave analysis

  This measure is completed on day 10 of each 10-day intervention (low salt, high salt, high salt + ketone) over 3-4 months and values will be compared across interventions.

• Passive Leg movement

  This measure is completed on day 10 of each 10-day intervention (low salt, high salt, high salt + ketone) over 3-4 months and values will be compared across interventions.

Study Arms (3)

Placebo/Placebo, then Salt/Placebo, then Salt/Ketone

ACTIVE COMPARATOR

Participants will consume each of the supplemental interventions for 10 days (in this assigned order). On Day 10 of each interventional condition, participants will arrive at the laboratory where the investigators will assess resting blood pressure, arterial stiffness, endothelial function, renal blood flow, and submaximal exercise blood pressure reactivity. Blood will be collected to investigate inflammatory and immune responses to the dietary conditions. After a washout period, participants will consume the next assigned supplemental intervention for 10 days, and repeat the Day 10 assessments. After another washout period, participants will consume the final assigned supplemental intervention for 10 days, and again repeat the Day 10 assessments.

Dietary Supplement: No Salt, No β-OHB; Dietary Supplement: High Salt, No β-OHB; Dietary Supplement: High Salt, High β-OHB

Salt/Placebo, then Salt/Ketone, then Placebo/Placebo

ACTIVE COMPARATOR

Participants will consume each of the supplemental interventions for 10 days (in this assigned order). On day 10 of each interventional condition, participants will arrive at the laboratory where the investigators will assess resting blood pressure, arterial stiffness, endothelial function, renal blood flow, and submaximal exercise blood pressure reactivity. Blood will be collected to investigate inflammatory and immune responses to the dietary conditions. After a washout period, participants will consume the next assigned supplemental intervention for 10 days, and repeat the Day 10 assessments. After another washout period, participants will consume the final assigned supplemental intervention for 10 days, and again repeat the Day 10 assessments.

Dietary Supplement: No Salt, No β-OHB; Dietary Supplement: High Salt, No β-OHB; Dietary Supplement: High Salt, High β-OHB

Salt/Ketone, then Placebo/Placebo, then Salt/Placebo

ACTIVE COMPARATOR

Participants will consume each of the supplemental interventions for 10 days (in this assigned order). On day 10 of each interventional condition, participants will arrive at the laboratory where the investigators will assess resting blood pressure, arterial stiffness, endothelial function, renal blood flow, and submaximal exercise blood pressure reactivity. Blood will be collected to investigate inflammatory and immune responses to the dietary conditions. After a washout period, participants will consume the next assigned supplemental intervention for 10 days, and repeat the Day 10 assessments. After another washout period, participants will consume the final assigned supplemental intervention for 10 days, and again repeat the Day 10 assessments.

Dietary Supplement: No Salt, No β-OHB; Dietary Supplement: High Salt, No β-OHB; Dietary Supplement: High Salt, High β-OHB

Interventions

No Salt, No β-OHB DIETARY_SUPPLEMENT

Participants will consume the following for ten days. Enteric capsules will be filled with a dextrose placebo. The placebo supplement will be a β-OHB-free, taste and viscosity-matched, beverage produced by KetoneAid.

Placebo/Placebo, then Salt/Placebo, then Salt/Ketone; Salt/Ketone, then Placebo/Placebo, then Salt/Placebo; Salt/Placebo, then Salt/Ketone, then Placebo/Placebo

High Salt, No β-OHB DIETARY_SUPPLEMENT

Participants will consume the following for ten days. Enteric capsules will be filled with Morton's table salt. Sodium consumption will be normalized to caloric intake (2 mg Sodium/Calorie). The placebo supplement will be a β-OHB-free, taste and viscosity-matched, beverage produced by KetoneAid.

Placebo/Placebo, then Salt/Placebo, then Salt/Ketone; Salt/Ketone, then Placebo/Placebo, then Salt/Placebo; Salt/Placebo, then Salt/Ketone, then Placebo/Placebo

High Salt, High β-OHB DIETARY_SUPPLEMENT

Participants will consume the following for ten days. Enteric capsules will be filled with Morton's table salt. Sodium consumption will be normalized to caloric intake (2 mg Sodium/Calorie). Ketone beverage will be the β-OHB supplement produced by KetoneAid. Participants will consume 24 mL (12 grams β-OHB) of the ketone beverage three times a day (total 36 grams β-OHB).

Placebo/Placebo, then Salt/Placebo, then Salt/Ketone; Salt/Ketone, then Placebo/Placebo, then Salt/Placebo; Salt/Placebo, then Salt/Ketone, then Placebo/Placebo

Eligibility Criteria

• Age: 60 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Between the ages of 60-85
• Resting blood pressure no higher than 150/90
• BMI below 35 kg/m2 (or otherwise healthy)
• Free of any metabolic disease (diabetes or renal), pulmonary disorders (COPD, severe asthma, or cystic fibrosis), cardiovascular disease (peripheral vascular, cardiac, or cerebrovascular)
• Do not have any precluding medical conditions that prevent participants from exercising (i.e., cardiovascular issues, or muscle/joint issues including painful arthritis) or giving blood (e.g., blood thinners)

You may not qualify if:

• High blood pressure - greater than150/90 mmHg
• Obesity (BMI \> 30 kg/m2)
• History of metabolic disease (diabetes or renal disease), pulmonary disorders (e.g., COPD, severe asthma, \& cystic fibrosis), and cardiovascular disease (peripheral vascular, cardiac, or cerebrovascular).
• Medical issues that prevent safe exercise (i.e., cardiovascular issues, or muscle/joint issues including painful arthritis)
• Medical issues that prevent giving blood (e.g., blood thinners).
• Current smoking, using smokeless tobacco, or vaping (within past 12 months)
• Current pregnancy

Sponsors & Collaborators

• Indiana University: lead
• University of Utah: collaborator
• University of Missouri-Columbia: collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (1)

School of Public Health

Bloomington, Indiana, 47405, United States

RECRUITING

Related Publications (6)

• Babcock MC, Robinson AT, Migdal KU, Watso JC, Martens CR, Edwards DG, Pescatello LS, Farquhar WB. High Salt Intake Augments Blood Pressure Responses During Submaximal Aerobic Exercise. J Am Heart Assoc. 2020 May 18;9(10):e015633. doi: 10.1161/JAHA.120.015633. Epub 2020 May 14.

  PMID: 32406312 BACKGROUND

• Costa TJ, Linder BA, Hester S, Fontes M, Pernomian L, Wenceslau CF, Robinson AT, McCarthy CG. The janus face of ketone bodies in hypertension. J Hypertens. 2022 Nov 1;40(11):2111-2119. doi: 10.1097/HJH.0000000000003243. Epub 2022 Aug 8.

  PMID: 35969209 BACKGROUND

• Barnett AM, Babcock MC, Watso JC, Migdal KU, Gutierrez OM, Farquhar WB, Robinson AT. High dietary salt intake increases urinary NGAL excretion and creatinine clearance in healthy young adults. Am J Physiol Renal Physiol. 2022 Apr 1;322(4):F392-F402. doi: 10.1152/ajprenal.00240.2021. Epub 2022 Feb 14.

  PMID: 35157527 BACKGROUND

• Chakraborty S, Galla S, Cheng X, Yeo JY, Mell B, Singh V, Yeoh B, Saha P, Mathew AV, Vijay-Kumar M, Joe B. Salt-Responsive Metabolite, beta-Hydroxybutyrate, Attenuates Hypertension. Cell Rep. 2018 Oct 16;25(3):677-689.e4. doi: 10.1016/j.celrep.2018.09.058.

  PMID: 30332647 BACKGROUND

• McCarthy CG, Chakraborty S, Singh G, Yeoh BS, Schreckenberger ZJ, Singh A, Mell B, Bearss NR, Yang T, Cheng X, Vijay-Kumar M, Wenceslau CF, Joe B. Ketone body beta-hydroxybutyrate is an autophagy-dependent vasodilator. JCI Insight. 2021 Oct 22;6(20):e149037. doi: 10.1172/jci.insight.149037.

  PMID: 34499623 BACKGROUND

• Wenstedt EF, Verberk SG, Kroon J, Neele AE, Baardman J, Claessen N, Pasaoglu OT, Rademaker E, Schrooten EM, Wouda RD, de Winther MP, Aten J, Vogt L, Van den Bossche J. Salt increases monocyte CCR2 expression and inflammatory responses in humans. JCI Insight. 2019 Nov 1;4(21):e130508. doi: 10.1172/jci.insight.130508.

  PMID: 31672939 BACKGROUND

MeSH Terms

Conditions

Hypertension; Inflammation; Cardiovascular Diseases

Condition Hierarchy (Ancestors)

Vascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Austin T Robinson, PhD

CONTACT

5745141034; ausrobin@iu.edu

Braxton A Linder, PhD

CONTACT

2568567599; balinder@iu.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Participants will be randomized to a condition order. A single lab member, not involved in data collection or analysis, will know condition order and contents and distribute them to participants.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Placebo-controlled, double-blinded, randomized

Study Record Dates

• First Submitted: February 27, 2025
• First Posted: March 11, 2025
• Study Start: March 6, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: October 30, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: One year after completion of the trial, indefinitely

Locations

US (1)