The planetary biology of ascorbate and uric acid and their relationship with the epidemic of obesity and cardiovascular disease

Abstract

Humans have relatively low plasma ascorbate levels and high serum uric acid levels compared to most mammals due to the presence of genetic mutations in L-gulonolactone oxidase and uricase, respectively. We review the major hypotheses for why these mutations may have occurred. In particular, we suggest that both mutations may have provided a survival advantage to early primates by helping maintain blood pressure during periods of dietary change and environmental stress. We further propose that these mutations have the inadvertent disadvantage of increasing our risk for hypertension and cardiovascular disease in today's society characterized by Western diet and increasing physical inactivity. Finally, we suggest that a "planetary biology" approach in which genetic changes are analyzed in relation to their biologic action and historical context may provide the ideal approach towards understanding the biology of the past, present and future.The reductionist paradigm for human biology has, over the past century, been remarkably successful. It has, in one sense, reached its apotheosis through the complete sequencing of the human genome [ 1 ]. This, together with analyses of the transcriptome, the metabolome, and their higher organization has provided a "parts list" for a living organism.As these parts lists have become more complete, it has become increasingly clear that they do not provide anything approaching an understanding of human biology [ 2 ]. Additional approaches are needed if that understanding is to emerge and, with it, the opportunity to manipulate the biological parts to manage, treat, and cure human disease.One approach is to exploit the axiom that a system can be fully understood only if we understand both its structure and its history. This is certainly true for the terrestrial living systems, which are the products of four billion years of random variation and natural selection, all constrained by physical and chemical law. Without understanding this history, we are no more likely to © 2008 Elsevier Ltd. All rights reserved.Send correspondence to: Richard J Johnson MD FACP, J. Robert Cade Professor of Nephrology, Chief of Nephrology, Hypertension and Transplantation, University of Florida, Room CG98, PO Box 100224, 1600 SW Archer Rd, Gainesville FL 32610-0224, phone 352-392-4007, Fax 352-392-5465, email E-mail: johnsrj@medicine.ufl.edu. Disclaimers: Dr Johnson is listed as an inventor on several patent applications related to lowering of uric acid in cardiovascular disease and also is author on a book on fructose that will be published in 2008 by Rodale press. Dr. Benner and Dr. Gaucher are listed as inventors on several patent applications to apply evolutionary analysis to understand protein evolution.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is...

Evolutionary history and metabolic insights of ancient mammalian uricases

“…More recently, uric acid has been implicated in metabolic syndrome and fat accumulation (2,(11)(12)(13). Mammals possessing a functional uricase typically display serum uric acid levels in the 1-to 2-mg/dL range (0.06-0.12 mM).…”

Evolution of the Human Brain: the key roles of DHA (omega-3 fatty acid) and Δ6-desaturase gene

“…Although the concentration of L-ascorbic acid in the blood is low, the levels in other body fluids, and in intracellular spaces in particular, are comparable to those of other mammals (Johnson et al, 2008). Nerve endings in the brain contain the highest concentrations of L-ascorbic acid in the human body after the suprarenal and pituitary glands (Bourre, 2006).…”

“…It is synthesized from xanthine by the xanthine oxidase enzyme in the liver (Johnson et al, 2008). In almost all mammals, urate oxidase (or uricase) catalyzes the oxidation of uric acid to allantoin (Wu et al, 1989), but in humans and most great apes (chimpanzees, gorillas, and orangutans), the urate oxidase gene is non-functional, such that uric acid is not decomposed (Wu et al, 1989).…”

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“…Low serum urate levels are a risk factor for amyotrophic lateral sclerosis (ALS), likely due to insufficient protection from oxidative damage in muscle cells [22]. In fact, it has been argued that human evolution has led to favouring urate over ascorbate as a major serum antioxidant, as evidenced by the loss of the gene for uricase, the enzyme that metabolizes urate, and the concurrent loss of L-glucuronate oxidase, the enzyme that synthesizes vitamin C [23].…”