About this trial

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.

Eligibility criteria

This trial accepts healthy volunteers

Qualifiers

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)

Disqualifiers

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)

Trial design

Design model

Crossover

Treatments tested in this trial

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.
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.
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).

Treatment groups

35 Participants

are divided into 3 treatment groups

Group A: Placebo/Placebo, then Salt/Placebo, then Salt/KetoneActive comparator 3 interventions

Group B: Salt/Placebo, then Salt/Ketone, then Placebo/PlaceboActive comparator 3 interventions

Group C: Salt/Ketone, then Placebo/Placebo, then Salt/PlaceboActive comparator 3 interventions

Trial outcomes

Primary outcomes

1

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.

2

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.

Secondary outcomes

1

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.

2

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.

3

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.

4

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.

Other outcomes

1

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.

2

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.

3

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.

4

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.

Ketone Ester And Salt (KEAS) in Older Adults

About this trial

Eligibility criteria

Qualifiers

Disqualifiers

Trial design

Treatments tested in this trial

Treatment groups

Trial outcomes

Primary outcomes

Secondary outcomes

Other outcomes

Sponsors and contacts