Licorice compound kept aging mice leaner, steadier, and higher in Klotho

Four of the five untreated mice had fatty livers by the twelve-month mark. Not one of the five mice that had been swallowing a licorice extract did. That single line in a table from a Japanese pharmacology lab captures the shape of the whole experiment: a modest intervention, given over most of a mouse's adult life, with effects that showed up in the liver, the kidneys, the blood, and even in how long the animals could stay on a spinning rod.

Shiho Ohnishi and colleagues at Suzuka University of Medical Science worked with glycyrrhizin, the sweet-tasting compound that gives licorice root its flavor and much of its medicinal reputation. The team had reported earlier that glycyrrhizin dampens inflammation by blocking HMGB1, a protein that leaks out of damaged and aging cells and acts as an alarm signal, telling the immune system that something has gone wrong. Chronic, low-level alarm of exactly this kind is one of the leading explanations for why bodies decline with age.

The target this time was Klotho, a protein made mainly in the kidneys and brain. Mice bred without it age fast and die young, with stiff calcified blood vessels, shrinking muscle, and cognitive decline. Mice engineered to make extra live longer. Klotho levels fall as animals get older, and inflammatory cytokines are known to push them down further, so the authors reasoned that a drug that quiets inflammation might keep Klotho from slipping.

What the experiment looked like

Ten male ICR mice, split into two groups of five. Starting at eight weeks old, one group got glycyrrhizin dissolved in buffered saline by feeding needle, 15 mg per kilogram of body weight, three times a week for twelve months. The other group got water on the same schedule. The dose was deliberately set well below the toxicity threshold reported in earlier work. A separate handful of young mice, ten weeks old, served as a baseline for what youthful values look like.

Body weight told the first part of the story. From the seventh month onward, the treated mice weighed significantly less than the controls. When the researchers looked at the livers, the control organs were flecked with white spots of fat; the treated livers were not. Under the microscope, the fat droplets that had accumulated in control liver cells were largely absent in the glycyrrhizin group. Blood triglycerides and cholesterol had climbed in the older control mice and that climb was blunted by treatment.

The kidneys showed a similar pattern, though more subtly. Kidneys from all animals looked normal to the naked eye. In stained tissue sections, two independent investigators found that control kidneys had enlarged glomeruli (the tiny filtering units), swollen tubules, heavily stained basement membranes, and deposits consistent with advanced glycation end products, the sugar-damaged proteins that build up with age. Treated kidneys showed less of all of it. Cystatin C in the blood, a marker that rises when filtration falters, went up with age in controls and significantly less so with glycyrrhizin.

Then the behavior. Old control mice explored less in an open box, gripped a bar with less force, and fell off a rod turning at 10 rpm sooner than young mice did. Each of those declines was smaller in the treated animals. The authors describe this as the first demonstration that glycyrrhizin slows age-related loss of motor function.

In blood, IGF-1 and Klotho both fell with age and both held up better under treatment. IL-6 and TNF-alpha, two inflammatory signals, rose with age and rose less in treated mice. SOD2, an antioxidant enzyme that mops up reactive oxygen inside mitochondria, stained less strongly in old liver and kidney tissue, and the authors write that glycyrrhizin seemed to soften that loss. They are careful with the word: the SOD2 result comes from images rather than counts, and they present it as an appearance rather than a measurement.