Uric Acid and Evolution

Bonifacio Álvarez-Lario; Jesús Macarrón-Vicente


Rheumatology. 2010;49(11):2010-2015. 

In This Article

Abstract and Introduction


Uric acid (UA) is the end product of purine metabolism in humans due to the loss of uricase activity by various mutations of its gene during the Miocene epoch, which led to humans having higher UA levels than other mammals. Furthermore, 90% of UA filtered by the kidneys is reabsorbed, instead of being excreted. These facts suggest that evolution and physiology have not treated UA as a harmful waste product, but as something beneficial that has to be kept. This has led various researchers to think about the possible evolutionary advantages of the loss of uricase and the subsequent increase in UA levels. It has been argued that due to the powerful antioxidant activity of UA, the evolutionary benefit could be the increased life expectancy of hominids. For other authors, the loss of uricase and the increase in UA could be a mechanism to maintain blood pressure in times of very low salt ingestion. The oldest hypothesis associates the increase in UA with higher intelligence in humans. Finally, UA has protective effects against several neurodegenerative diseases, suggesting it could have interesting actions on neuronal development and function. These hypotheses are discussed from an evolutionary perspective and their clinical significance. UA has some obvious harmful effects, and some, not so well-known, beneficial effects as an antioxidant and neuroprotector.


Unlike the majority of mammals, uric acid (UA) is the end product of purine metabolism in humans, due to the loss of uricase activity during the evolution of hominids.[1,2] This loss, together with UA balance in the kidney, in which the majority of filtered UA is reabsorbed, and the lifestyle and eating habits of developed countries, has led to a high prevalence of hyperuricaemia and its consequences.[1–4] Hyperuricaemia is the primary risk factor for developing gout and this risk increases exponentially when the serum UA levels rise.[2,5,6] However, only a minority of those with high UA levels will develop gout.[1,3,7] Along with its association with gout, there is increasing evidence of a relationship between hyperuricaemia and hypertension, renal disease, metabolic syndrome, diabetes and cardiovascular disease.[1–6]

Regulation of serum UA levels is complex, with diet and various genetic polymorphisms of renal urate transporters being the main causal factors of hyperuricaemia and gout.[1,3,8] The importance of the interaction between genetic factors and lifestyle in the development of hyperuricaemia and gout has a clear example in the Maori of New Zealand.[3,9] This population has a marked predisposition to develop hyperuricaemia and gout, because of a genetic defect in renal urate handling.[10–12] However, there is no mention of gout among them before the 18th century. The lean and strong ancient Maori ate a diet of sweet potato, taro, fern root, birds and fish. After the introduction of a diet low in dairy products and high in fatty meats and carbohydrates in the early 1900s, an epidemic of obesity and gout developed [9]. The drastic changes in their diet and the adoption of the lifestyle of developed countries, has led them to have the highest gout prevalence in the world. This demonstrates that genetically predisposed people will develop hyperuricaemia and gout if they are exposed to other risk factors, such as a high-purine content diet, obesity, increased alcohol consumption or diuretic use.[3,13,14]