Potential targets for developing drugs to reduce the risk of gout, kidney stones, heart disease, stroke and Type 2 diabetes have been identified in new research by the Buck Institute for Research on Aging.
The research was recently published online in the scientific journal, PLOS Genetics.
It is well established that high levels of uric acid in humans increases the risk of gout, kidney stones and a condition known as metabolic syndrome, a cluster of conditions that increase the risk of heart disease, stroke and Type 2 diabetes. The new research by the Buck Institute identifies drug targets for preventing uric acid levels from building up.
Few people get the level of uric acid measured in their blood when they get their annual checkup, and Pankaj Kapahi, a Buck professor and senior author of the study, says that may be a mistake.
“Medical practitioners haven’t been paying sufficient attention to uric acid,” Kapahi said. “People can be at genetic risk for high uric acid and not know it.”
Kaphi believes uric acid should be included in routine check-ups similar to those done for cholesterol and blood glucose.
“Gout is associated with premature aging in humans,” Kapahi said. “Uric acid levels often go up with age.”
Uric acid is produced when the body breaks down substances called purines. Purines are normally produced in the body and are found in some foods and drinks. A high-purine diet is linked to excessive consumption of red meat, sugary beverages and alcohol.
“Uric acid was known as the disease of the kings because only rich people used to get this increased uric acid-induced gout,” Kapahi said.
Most species have a gene for metabolizing uric acid that humans lost about 15 million years ago. In the Buck Institute study, researchers inhibited this gene in a group of fruit flies. Once this gene was inhibited, the flies began reacting like humans when fed a diet high in purines. Their uric acid levels increased and they experienced shortened life spans.
The researchers discovered that a biochemical process, similar to the one by which insulin processes glucose into fat and muscle cells, plays a role in regulating uric acid levels in the flies. They found that when they suppressed this process the uric acid levels in the flies decreased.
Sven Lang, a former postdoctoral fellow in the Kapahi lab, who led the research, said a high-purine diet shortened the lifespan of the flies by 48%, but after the insulin-like process was suppressed uric acid levels remained stable even when the flies were fed a high-yeast diet.
Kapahi said the identification of the regulatory role played by this insulin-like process points to previously unrecognized potential drug targets to treat elevated uric acid levels.
Even though the experiments were conducted on flies not humans, Kapahi said, “We think what we have created is very translatable.”
In addition, the study found that the formation of kidney stones could be reduced by inhibiting an enzyme that increases free radicals in the body. Free radicals are unstable molecules that cause damage to DNA in cells.
“We were able to inhibit the increase in free radicals using the common antioxidant vitamin C, which reduced the burden of kidney stones and improved survival in the animals,” said Lang, who now has his own laboratory at the Department of Medical Biochemistry and Molecular Biology at Saarland University in Homburg, Germany.
Kapahi said one way for people to reduce their uric acid levels is to eat a healthier diet.
But the study’s co-author, Marshall Stoller, head of the urinary stone division at the University of California at San Francisco Department of Urology, said, “Changes in diet are not always sufficient to bring down levels of uric acid, so it’s important to track it and make sure that patients who need preventive drug treatment get it. It’s our hope that we’ll be able to utilize these targets to develop new drugs for the many diseases linked to uric acid accumulation.”
