Researchers here describe one very thin slice of the sweeping metabolic changes produced by exercise and calorie restriction. Both interventions act to reduce blood pressure, most likely through numerous distinct mechanisms. One of those mechanisms involves raised levels of β-hydroxybutyrate, an effect that can in principle be mimicked or enhanced via carefully designed therapies. The raised blood pressure that occurs with age is one of the more destructive changes that take place with aging; it is in effect a way to translate accumulating damage and dysfunction at the cellular level into a physical bludgeon that destroys delicate structures throughout the body. Blood pressure is so influential in aging that current pharmacological methods that force a lowered blood pressure result in sizable reductions in disease incidence and mortality even though they fail to address the underlying damage of aging in any way.
Hypertension is a modifiable risk factor for cardiovascular disease and exercise is widely recommended for hypertensive patients as a lifestyle modification because of the well-documented beneficial effect of exercise on lowering blood pressure (BP). Similarly, calorie restriction, although not widely recommended for patients, is also documented to lower hypertension. Interestingly, both exercise and calorie-restriction are associated with increased circulating levels of ketone bodies such as β-hydroxybutyrate (βOHB). βOHB is produced predominantly in the liver, transported to other tissues, and traditionally recognized as a vital alternative metabolic fuel during times of starvation. However, contemporary evidence indicates that apart from serving as energy fuels, ketone bodies such as βOHB block inflammasome-mediated inflammatory diseases and thereby play a prominent role in maintaining physiological homeostasis.
In contrast to exercise and calorie-restriction, consumption of high salt promotes hypertension. Studies on the effects of dietary salt have focused mainly on organs and tissues relevant to BP regulation such as kidney, vasculature, heart, and brain. A recent report suggests that a reduction in salt intake serves as an additional interventional approach for reducing the risk for developing metabolic syndrome, of which, hypertension is one of the hallmark features. Taken together, these studies point to an intriguing possibility that a high salt diet induced a deleterious effect on hypertension and could mechanistically represent the opposite scenario to that of the protective effects of exercise and calorie-restriction on hypertension by altering the levels of metabolites such as ketone bodies.
Here, we examined this possibility, first by an untargeted mass spectrometry-based plasma metabolomics study and discovered altered ketogenesis and over-activation of renal Nlrp3 as a key mechanistic link between high salt and hypertension. These results indicated that a high salt diet has mechanistically opposite effects of exercise and calorie-restriction on BP. Next, we demonstrated that nutritional intervention with 1,3-butanediol, a precursor of the endogenous ketone body, βOHB, reversed the adverse effects of high salt induced renal Nlrp3-mediated inflammation, fibrosis, and hypertension. Based on these observations in the Dahl S rat, which is a salt-sensitive pre-clinical model of hypertension, we propose dietary intervention with 1,3-butanediol as an intriguing strategy for the clinical management of salt-sensitive hypertension.