The Evolutionary Role of Urate in Humans Revisited: Relevance to Gout and Metabolic Syndrome

Humans and other great apes are unique among animals in lacking functional uricase, an enzyme that breaks down urate and allows its excretion. Modern-day humans have elevated serum urate, which is associated with various chronic health issues, including gout, metabolic syndrome, and hypertension. This prompts the question: what is the evolutionary benefit of the loss of uricase function, given that it may confer an increased risk of these chronic diseases? In this review, we explore numerous possible advantages, including some less commonly discussed, such as urate’s function as an antioxidant, its roles in ancestral survival, and its metabolic role in the context of our evolutionary history and the environmental pressures that have shaped human biology. We go on to examine the tradeoffs of urate’s evolutionary advantages, and how these features may be a double-edged sword for our health in our modern environment characterized by a caloric abundance of key nutrients, such as fructose, which are intimately linked with urate production and/or metabolism. Moving forward, we suggest that future work should explore the role of our evolutionary history in the rising prevalence of gout and other modern-day metabolic diseases. We further recommend that drugs and therapeutic strategies for diseases such as gout be informed by an understanding of the rich evolutionary context from which these maladies emerged and the unifying role of serum urate across these disease states.