Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations

Abstract

All human beings are uricase knockouts; we lost the uricase gene as a result of a mutation that occurred in the mid-Miocene epoch approximately 15 million years ago. The consequence of being a uricase knockout is that we have higher serum uric acid levels that are less regulatable and can be readily influenced by diet. This increases our risk for gout and kidney stones, but there is also increasing evidence that uric acid increases our risk for hypertension, kidney disease, obesity, and diabetes. This raises the question of why this mutation occurred. In this article we review current hypotheses. We suggest that uric acid is a danger and survival signal carried over from the RNA world. The mutation of uricase that occurred during the food shortage and global cooling that occurred in the Miocene epoch resulted in a survival advantage for early primates, particularly in Europe. Today, the loss of uricase functions as a thrifty gene, increasing our risk for obesity and cardiorenal disease.

Figure 1. Hypotheses for Evolutionary Benefit of Uricase Mutation

The parallel mutations that occurred in early hominoid evolution in both ancestral humans and great apes, and in lesser apes, suggests a natural selection advantage with the mutation. The primary hypotheses proposed for this mutation are shown. These include the possible role of uric acid as an extracellular antioxidant that would combat oxidative stress associated with aging, cancer and cardiovascular disease, a role for uric acid in increasing intelligence and reaction time, and finally a potential role as a danger and survival signal to protect against starvation, but which in today’s society translates into increased risk for obesity, diabetes, and cardiorenal disease.