Ketone Ester And Salt (KEAS) in Older Adults

Overview

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.