This counterintuitive discovery by scientists at Vanderbilt University and in Germany has upended more than 100 years of conventional scientific wisdom and may provide new insights into the Western epidemics of obesity, diabetes, and heart disease.
Their findings, reported in two papers in this week’s Journal of Clinical Investigation, shed new light on the body’s response to high salt intake and could provide an entirely new approach to these three major killer diseases.
According to the textbooks, the excretion of dietary salt inevitably leads to water loss into the urine and thereby reduces body water content. But that’s not what Vanderbilt’s Jens Titze, MD, and his team found. On the contrary, he said, “we showed the biological principle of salt excretion is water conservation and water production.”
It takes a lot of energy to conserve water in the face of salt excretion. To do it, the body either must take in more fuel or utilize its own energy stores and break down muscle mass. “This predisposes to overeating,” Titze said. “The resulting metabolic response looks a lot like diabetes.”
Titze, associate professor of Medicine and of Molecular Physiology and Biophysics at Vanderbilt, has been probing the mysteries of salt and water metabolism since he was a medical student at Freie Universität Berlin (Free University of Berlin).
In the mid-1990s he began conducting long-term sodium balance studies in Russian cosmonauts who were participating in a human space flight simulation program at a research facility in Moscow in preparation for a potential manned spaceflight to Mars.
When the simulation program resumed a decade later, Titze—then a faculty member at the University of Erlangen-Nuremberg—continued his studies, this time carefully controlling what the men ate and measuring how much salt and water they excreted in their urine.
Between 2009 and 2011, his team studied four men during a 105-day pre-flight phase and six others during the first 205 days of a 520-day phase that simulated a full-length manned mission to Mars and back.
The amount of dietary salt varied between 6, 9, and 12 grams a day. Russian scientist Natalia Rakova, MD, PhD, first author of the clinical study, made sure the men ate every crumb of their meals and collected every drop of urine every day. Rakova is now at the Charité Medical Faculty and Max-Delbrück Center for Molecular Medicine in Berlin.
Titze came to Vanderbilt in 2011. In 2013 the scientists reported that sodium excretion occurred not on a daily basis but fluctuated with a weekly rhythm. That observation, which went against the prevailing dogma, suggested sodium was stored in the body.
Levels of the hormones aldosterone, which regulates sodium excretion, and cortisol, a glucocorticoid that helps break down glucose and fat for fuel, also fluctuated weekly.
Surprisingly, when dietary salt was increased from 6 to 12 grams a day, the men drank less water, not more. That suggested they must be conserving and producing water.
But how? In a subsequent study in mice, the researchers confirmed what they’d suspected in humans. High salt induces a catabolic state driven by glucocorticoids. Muscle protein is broken down and converted into urea by the liver.
Urea is usually thought of as a waste product that is eliminated into the urine. Titze’s group now shows this nitrogen-containing compound creates a driving force that brings the water back into the body instead of letting it follow the salt into the urine.
The kidneys thus act as a biological barrier for water conservation to prevent dehydration when salt intake is high.
Traditionally, salt and water balance has focused on the kidney. This study suggests the liver and skeletal muscle also play a role in regulating salt and water metabolism, said Kento Kitada, PhD, research fellow in Titze’s lab.
Muscle wasting is a high price to pay for avoiding dehydration, added Steffen Daub, MD, a visiting research fellow in the lab and co-first author with Kitada of the second paper. The alternative is bringing in more fuel—eating more. That may be why the men in the study complained they were hungry when their salt intake was high.
Water conservation in response to a high-salt diet may have pathological consequences. Increased levels of glucocorticoids are an independent risk factor for diabetes, obesity, osteoporosis, and cardiovascular disease.
“We have always focused on the role of salt in arterial hypertension. Our findings suggest that there is much more to know—a high salt intake may predispose to metabolic syndrome,” Titze said.
Contributing to the studies were scientists from the Max-Delbrück Center in Berlin and the German Aerospace Center in Cologne. Vanderbilt faculty members Friedrich C. Luft, MD, David G. Harrison, MD, David Wasserman, PhD, and Raymond Harris, MD, also contributed.
Support for the studies came largely from the German Federal Ministry for Economics and Technology, the Interdisciplinary Center for Clinical Research Junior Research Group in Erlangen, and from the American Heart Association and National Institutes of Health.