Dietary Ketone Supplementation as a Novel Strategy to Attenuate the Adverse Vascular and Renal Consequences of High Dietary Salt in Older Adults

PROJECT SUMMARY Excess dietary salt is associated with increased risk for hypertension and cardiovascular disease (CVD), the leading cause of death in the United States. High dietary salt is also associated with increased chronic kidney disease (CKD) risk, another leading cause of morbidity and mortality. Yet, 90% of adults consume excess dietary salt based on the Dietary Guidelines for Americans recommendation. Americans struggle to reduce their salt intake because the vast majority (~70%) of dietary salt comes from processed foods and meals prepared at restaurants, making it difficult to alter their dietary salt. As a result, there have been calls for alternative strategies to counteract excess consumption of dietary salt. We have identified Beta-hydroxybutyrate (β-OHB) as a promising tool to counteract the adverse cardiorenal health effects of high dietary salt. β-OHB is a ketone body typically produced during prolonged exercise, fasting, and ketogenic dieting. Alternatively, oral ketone monoesters are a type of ketone supplement that are metabolized into β-OHB. While most individuals are unable to adhere to strict ketogenic diets, oral ketone supplements are convenient, typically well tolerated, and increase β-OHB to a similar or greater extent. Recent rat data suggests that high dietary salt suppresses β-OHB production and that increasing β-OHB via ketone supplementation counteracts the adverse effects of high salt on cardiorenal function. Similar to the published rodent data, our pilot data also indicate that high dietary salt reduces fasting plasma β-OHB in humans. Recently published data also demonstrate that increasing β-OHB with ketone supplementation can improve blood pressure and vascular function in humans under certain contexts. However, it is unclear whether raising β-OHB via ketone supplementation can protect older humans against the adverse cardiorenal effects of high dietary salt. Therefore, we are proposing to examine whether taking a ketone monoester supplement concurrently with high salt for 10 days counteracts the adverse effects of short-term high dietary salt on blood pressure (Aim 1), vascular function (Aim 2), and kidney injury and blood flow (Aim 3). We will utilize a double masked, randomized, placebo-controlled crossover design pilot trial in 30 older adults who will also undergo a low salt control intervention and high salt alone. The PI (Dr. Austin Robinson) has a strong record of productivity investigating the cardiorenal consequences of short-term high dietary salt and has assembled an outstanding interdisciplinary team of co-investigators and consultants to help secure future R01 funding for this line of research. The public health impact of this innovative project is that establishing strategies (e.g., ketone supplementation) to attenuate the adverse cardiorenal effects of high dietary salt could lead to reductions in CVD and CKD risk and mortality.