Was There an Evolutionary Advantage To Losing Uricase?
Uric acid is a powerful radical scavenger and a chelator of metal ions, accounting for greater than 50% of the antioxidant activity present in human biological fluids. Thus, it was assumed that hyperuricemia would be associated with an increased antioxidant capacity and a greater life expectancy for the affected individual. In fact, the reverse holds true: hyperuricemia is a marker for worsening renal function, heart disease, and the metabolic syndrome. (For more information on this subject please see “Gout Complicates Comorbid Conditions”)
So we are left with the paradox: Why was uricase function lost? The evolutionary benefits of losing uricase function and the corresponding rise in serum urate have generated many hypotheses. Some of the early theories suggested that raised serum urate levels may have spurred an evolutionary leap in the intellectual capacity of hominids.7 This theory was based on the finding that uric acid and brain stimulants such as caffeine share structural homologies. Over the years, a number of studies emerged, claiming that mean higher intelligence scores based on IQ testing were noted in patients with gout. In fact, a study of the male faculty at the University of Michigan (such a highly accomplished and intelligent cohort), found that their mean serum urate concentrations were statistically greater than controls (no, they were not Ohio Buckeyes). Several subsequent larger studies failed to find the link between serum uric acid levels and intelligence.
A final blow to the theory linking urate to intelligence came after a careful study of the evolutionary time period when accelerated brain development occurred in hominids. The large increase in cerebral volume of hominid brains probably occurred 10 million years following the loss of the uricase enzyme. Thus, it is highly unlikely that these two events were linked.
Yet there still may be a gout–brain association. For example, gout has never been reported in patients with multiple sclerosis. Additionally, the very low incidence of other neurologic diseases, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, in patients with gout adds some credence to the theory that elevated urate levels may confer some form of a neuroprotective effect.
There is a third hypothesis. The mutations affecting the uricase enzyme occurred at a time when hominids were woodland quadrupeds that inhabited subtropical forests and survived on a diet consisting mainly of fruit and leaves. The salt content of the diet was extremely low; some estimates place it at a paltry 200 mg per day, a far cry from today’s average consumption of 4,000 mg daily. During times of low salt ingestion, increasing serum urate levels may have served to maintain an adequate blood pressure acutely through stimulation of the renin–angiotensin pathway and chronically by inducing sensitivity to salt through the development of microvascular and interstitial renal disease. Thus, having an elevated serum urate would confer upon the host the evolutionary advantage of being able to walk upright.
