An interventional study of No Salt, No β-OHB and High Salt, No β-OHB in Salt; Excess, Hypertension and Aging, sponsored by Indiana University. Recruiting at 1 site in United States. Open to participants aged 50 Years to 85 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-08-19.
Sponsored by Indiana University · Not applicable, Interventional, and Basic science
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.
Excess salt consumption is widespread across the United States and remains a leading risk factor for developing hypertension and cardiovascular disease (CVD). The well-documented relation between HS, hypertension, and CVD risk along with the ubiquitous HS intake in the United States demonstrate a critical need for investigation into mechanisms of salt-induced CVD; and the development of therapeutic strategies to combat the consequences of HS, particularly in at-risk populations, such as older adults. The investigators have identified the liver-derived ketone body β-hydroxybutyrate (β-OHB) as a potential target to combat the negative cardiovascular health effects of HS. Circulating β-OHB concentration typically increases in response to endurance exercise or calorie restriction, both of which also reduce blood pressure (BP) and lower CVD risk. Interestingly, chronic HS consumption suppressed endogenous hepatic β-OHB production in rats, but nutritionally upregulated hepatic β-OHB production attenuated the adverse effects of HS in the rats. Specifically, using 1,3-butanediol to increase β-OHB counteracts the adverse effects of HS on resting BP, in part by acting as a vasodilator, and attenuating inflammation. The investigators' human pilot data also indicates that HS suppresses circulating β-OHB concentration in healthy young adults. However, there is a knowledge gap regarding whether increasing β-OHB during HS intake can counteract the negative effects of HS on BP and cardiovascular health in humans. Therefore, the investigators will measure resting BP (in the lab and ambulatory), endothelial function, kidney blood flow, BP responses during and after submaximal aerobic exercise and inflammatory markers in blood and isolated immune cells (i.e., monocytes). Recognizing that HS does not increase BP in everyone, several studies consistently indicate that short-term HS ingestion (days to weeks) leads to endothelial dysfunction and exaggerated BP reactivity during submaximal exercise in humans. Importantly, endothelial dysfunction contributes to atherosclerotic cardiovascular disease. Exaggerated BP responses during aerobic exercise (i.e., BP reactivity) have prognostic value for future hypertension, coronary disease risk, and cardiovascular mortality. Apart from leading to exaggerated exercise BP reactivity, the investigators have found that HS also reduces the magnitude of post-exercise hypotension (PEH) after an acute bout of submaximal aerobic exercise in healthy adults. Importantly, the reductions in BP observed after a single bout of exercise are associated with longer-term exercise reductions in BP, suggesting that some of the benefits of aerobic exercise on BP status are the result of transient reductions in BP resulting from an acute bout of exercise. Regarding the effects of HS on the immune system and inflammation, microenvironments with elevated concentrations of sodium increase the prevalence of proinflammatory phenotypes within specific immune cell subsets. For example, HS conditions activate monocytes to produce pro-inflammatory cytokines. Thus, HS-induced immune system dysregulation may further amplify BP dysregulation and CVD risk. The investigators hypothesize that increasing circulating β-OHB concentration via ketone supplementation will counteract the negative effects of HS on these measures of cardiovascular health in older adults. Interestingly, elevating β-OHB leads to greater sodium excretion under HS conditions (indicative of restoration of plasma volume homeostasis) and restores nitric oxide-dependent vasodilation in rodents. Thus, the investigators hypothesize that ketone supplementation will improve endothelial function and BP regulation during and after exercise. Though exploratory, the investigators hypothesize that β-OHB supplementation blunts the HS-induced proinflammatory alterations in monocytes and blood samples using parallel in vitro and applied approaches.
Participants will report to the laboratory for four visits. At the first visit, consent for study participation will be obtained and participants will be screened for eligibility. Participants will then be randomly assigned to a crossover schedule for exposure to salt and ketone supplementation. Supplementation conditions include [A] Placebo capsules and Placebo beverage, [B] Salt capsules and Placebo beverage, and [C] Salt capsules and Ketone beverage. Each participant will be exposed to all three conditions, however, the order of exposure will be randomly assigned. Participants will consume their placebo/salt capsules three times per day and their placebo/ketone beverage three times per day.
Participants will consume the first assigned supplement combination for nine days prior to their first scheduled experiment visit (i.e., first experimental visit is day 10 of supplement combination #1). After a washout period, participants will consume the next randomly assigned supplement combination for nine days prior to the second scheduled experiment visit (i.e., day 10 of supplement combination #2). After another washout period, participants will consume the final randomly assigned supplement combination for nine days prior to the third scheduled experiment visit (i.e., day 10 of supplement combination #3). Participation will end after the third experimental visit has been completed.
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Exclusion Criteria:
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
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
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
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.
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.
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).
Resting blood pressure
The investigators will measure systolic and diastolic pressure using a validated oscillometric device (Suntech CT40)
Time frame: 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.
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.
Time frame: 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.
Flow mediated dilation (FMD)
Flow-mediated vasodilation will be assessed using continuous measures of brachial artery diameter and velocity via duplex Doppler ultrasound (Hitachi Arietta 70). The brachial artery will be imaged in the longitudinal plane proximal to the medial epicondyle using a high-frequency (10-12 MHz) linear-array probe. The ultrasound probe will be stabilized using a custom-built clamp. Shear rate (sec-1) will be calculated as \[(blood flow velocity (cm\*s-1) \*4)/blood vessel diameter (mm)\] The image will be recorded throughout a 60-s baseline, a 300-s ischemic stimulus (250 mmHg), and 180 seconds post deflation. FMD will be expressed as % dilation (final diameter-baseline diameter/baseline diameter x 100) and also normalized to the shear stimulus. Allometric scaling will be used if appropriate, including if there are baseline differences in artery diameter by race or condition.
Time frame: 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.
Post-exercise resting blood pressure
Resting systolic and diastolic blood pressure will be assessed via brachial oscillometric device immediately following the submaximal cycling exercise bout and at standardized intervals every five minutes after exercise cessation for 30 minutes and averaged. Post-exercise hypotension will be expressed as the change in blood pressure (mmHg) from a pre-exercise resting baseline to the post-exercise resting value.
Time frame: 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.
Post-exercise ambulatory blood pressure
Following the laboratory exercise bout on each Day 10 visit, participants will be fitted with an ambulatory blood pressure monitor (SunTech Oscar 2) to record systolic and diastolic blood pressure at regular intervals over the subsequent 24-hour period during normal daily activity. Ambulatory blood pressure will be expressed as mean awake, asleep, and 24-hour systolic and diastolic blood pressure (mmHg).
Time frame: 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.
Kidney blood velocity
The investigators will measure renal and segmental artery blood velocity using ultrasound-based imaging at 3.5 to 5 MHz. Blood velocity will be assessed at rest and during a cold pressor test (hand in ice-cold water for 3 minutes). Renal blood flow reactivity will be expressed as a change in velocity (cm/s) from baseline to a predetermined time during the stressor.
Time frame: 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
Passive leg movement will be used assessed blood flow responses to movement. The investigators will usie continuous measures of femoral artery diameter and velocity via duplex Doppler ultrasound (Hitachi Arietta 70) to calculate blood flow at rest and with the passive lelg movement. The femoral artery will be imaged in the longitudinal plane distal to the inguinal crease using a high-frequency (10-12 MHz) linear-array probe. Participants will be in a seated, reclined position with the lower leg free hanging. The ultrasound probe will be positioned by a lab member and the image will be recorded throughout triplicate 60-s measurements. Another lab member will independently move the lower leg through 90º range of motion at a rate of 1 Hz.
Time frame: 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 velocity
The investigators will use the SphygmoCor XCEL system to assess pulse wave velocity (PWV). A high-fidelity transducer is used to obtain the pressure waveform at the carotid pulse. Distances from the carotid artery sampling site to the femoral artery (upper leg instrumented with a thigh cuff for oscillometric sphygmomanometry), and from the carotid artery to the suprasternal notch will be recorded. PWV will be expressed as cm/s.
Time frame: 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
The investigators will use the SphygmoCor XCEL system to assess pulse wave analysis (PWA) The sampling site is the brachial artery (upper alarm instrumented with a cuff for oscillometric sphygmomanometer). PWA will be expressed as % (calculated as augmentation pressure divided by the pulse pressure).
Time frame: 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.
Inflammatory cell responses to Conditions
Participants' blood will be used to isolate peripheral blood mononuclear cells (PBMCs) for quantification of immune cell subsets specifically counts of monocytes and t cells.
Time frame: 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.
Inflammatory cytokine responses to Conditions
Plasma will be used for a multiplex to measure inflammatory cytokines.
Time frame: 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.
Changes in blood biomarkers of plasma metabolome
The investigators will measure changes in the plasma metabolome, including metabolites related to energy metabolism, inflammation, and oxidative stress. Plasma samples will be collected at rest.
Time frame: 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.
Plan to share: Yes — Data with all HIPAA identifiers removed may be shared in future collaborative efforts pending appropriate DMDA approvals
Supporting information: Study protocol, Sap, Icf, Analytic code
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