Uric Acid & Vitamin C: Devolution of Evolution in a 5G World



Uric acid is increasingly associated with metabolic diseases like insulin resistance, diabetes, hypertension, cardiovascular diseases, and even cancer.  Humans, unlike other animals, are unable to produce ascorbic acid, vitamin C.[1]   On top of that, humans have also lost the ability to degrade uric acid. [2]  It is believed that during evolution, increased uric acid as a result of genetic mutations, was instrumental in the survival of hominids as it offered not only antioxidant protection, but the ability to suppress insulin signaling, modulating insulin resistance and gluconeogenesis as adaptation to extended periods of food shortages during dramatic climate shifts.  In our world today, hyperuricemia, or excess serum uric acid can be the result of genetic polymorphisms, or diet modifications that rely on high levels of meat, seafood or even fat. The fact that hyperuricemia is often associated with various metabolic diseases and health disorders including gout, may be indications that it no longer serves the protective roles it once did millions of years ago.  In the attempt to recreate physiological responses that mirror our hominin hunter-gatherer ancestors, the reliance on low carbohydrate/zero carbohydrate, paleo, 100% carnivorous, or even ketogenic diets may encounter unexpected challenges from evolutionary adaptations that are contradictory in nature: that of insulin resistance and insulin sensitivity. This article will attempt to explain why uric acid was indispensable in the past; the roles uric acid play in insulin signaling, and how its limitations as an antioxidant and its inverse relationship with ascorbic acid are affected by our high technology world, ultimately changing the nature of its once protective features. 


Table of Contents


Best Diet for Metabolic Syndrome

   Your Diet Is Predetermined By Your Genes?

        The GCKR Gene

        The TBC1D4 Gene

Carnivores & Insulin Resistance

   Genetic adaptations to Carnivory: GCKR & AGT

        AGT & Oxalates

Insulin Resistance, Gluconeogenesis & Uric Acid: The Surprise Trio

   Insulin Resistance as Metabolic Adaptation: Blessing or Curse?

        You Cannot Survive Without Glucose

        Gluconeogenesis in the Human Brain

   Gluconeogenesis & Type 2 Diabetes

   Insulin Inhibits Gluconeogenesis

Hyperuricemia & Metabolic Syndrome: Devolution of Evolution?

   Xanthine Oxidoreductase as Double-Edged Sword: NADH or Reactive Oxygen Species?

   Hyperuricemia Induces Insulin Resistance & Reduces Insulin Sensitivity

        Uric Acid: An Intracellular Source of Reactive Oxygen Species

   Uric Acid Homeostasis

        Underexcretion of Urate: A Story of Genetic Mutations

GULO and UOX: A Tale of Two Pseudogenes

   Neotropical Forests & The Loss of GULO

        Ascorbic Acid Synthesis Generates Hydrogen Peroxide

   Savannas & The Loss of UOX

Uric Acid in The Ice Ages

   Fructose, Obesity & Insulin Resistance: The Uric Acid Connection

        Uric Acid Stimulates Fat Accumulation: The Superoxide Connection

   Uric Acid Increases Gluconeogenesis by Suppression of AMPK & Insulin Signaling

        Uricase Blunts Gluconeogenesis, Restores AMPK Function

   Hyperuricemia & Hypertension: The Sodium Connection

        Insulin Resistance & The Ability to Hibernate

Ascorbic Acid & Uric Acid: The Yin & Yang of REDOX

   UV Radiation Protection: AA or UA?


Redox Balancer versus Antioxidant-Prooxidant

Hyperuricemia & Cancer: The mTOR Connection

   Activation of mTOR by Uric Acid increases Stress Response

   Hyperuricemia Linked to Cancer

The Yin and Yang in Uric Acid

   UA & AA Protect Sperm Viability

Inverse Relationship between Ascorbic Acid and Uric Acid

   Ascorbic Acid Improves Insulin Sensitivity

Insulin Resistance & Insulin Sensitivity in a 5G World

   GLUT9 Polymorphisms Modulate Serum Uric Acid Levels

AA, UA & 5G – The REDOX Connection

   Uric Acid, Neurodegeneration & Cancer: The mTORC1 Connection

        Uric Acid Inhibits Nitric Oxide

        Nitric Oxide & Insulin Resistance

        Ascorbic Acid Regenerates BH4 to Produce Nitric Oxide

   Uric Acid & Cancer: The 8-oxoG Connection

       OGG1 Polymorphism & Insulin Resistance






Best Diet for Metabolic Syndrome

Metabolic Syndrome (MetS) is a combination of conditions that are composed of at least three out of five risk factors including: hypertension, hyperglycemia, obesity, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL).  MetS is now becoming an alarming growing epidemic because its impact is being observed in increased premature mortality.  MetS is associated with increased risk for various disorders such as fatty liver disease, type II diabetes, and cardiovascular diseases, all of which have common denominators of inflammation and oxidative stress. [3]

To combat dysregulation of blood sugar in hyperglycemia, many advocate the intake of low carbohydrates to improve glucose tolerance. [4]  Yet convincing evidence also points to the efficacy of using a high carbohydrate, low fat diet to improve insulin sensitivity and reverse other common symptom of MetS such as high fasting glucose levels.[5]  Does this make any sense to you? Diametrically opposed diets achieving similar effects. Is that even possible? Yes, if you understand how a high carb (or low carb) diet affects metabolism in people with different genetic variations.

Your Diet Is Predetermined By Your Genes?

Some scientists wanted to test the hypothesis that a high whole-grain diet is beneficial for lowering fasting blood glucose and insulin.  What they discovered was that higher whole-grain diets were able to reduce fasting glucose as well as insulin levels, INDEPENDENT of demographics and other dietary and lifestyle factors, including BMI (Body Mass Index)  However, for people with certain polymorphisms in their GCKR (glucokinase regulatory protein) gene that would lead to impaired insulin homeostasis, the benefits of a high whole-grain diet was greatly reduced. The authors found an inverse association between fasting insulin and variation in the GCKR polymorphism in the context of whole-grain diets where homozygous carriers, or people carrying two copies of the allele, had almost no reduction in insulin levels, whereas those who carried only one copy of the allele had partial reductions in their insulin levels compared to those who did not carry the risk allele. [6]

     The GCKR Gene

The glucokinase regulatory protein (GCKR) gene codes for a regulatory protein that inhibits glucokinase which regulates glucose metabolism. The authors believed that the allelic variation at GCKR diminished the beneficial effects on insulin homeostasis by whole-grain diets.  The influence of genetic factors in the development of insulin resistance and the metabolic syndrome is now being viewed as critical in the understanding of these health challenges. Large-scale genome-wide association studies are being done to identify common genetic variation associated with insulin resistance and the metabolic syndrome while exome sequencing now allows the identification of rare variants associated with the pathogenesis of these health conditions. [7] 

     The TBC1D4 Gene

During the past three decades, there has been a dramatic increase of over 10% in Type 2 diabetes among the historically isolated population of Inuit in Greenland [43]. The traditional carnivorous diets of Inuit typically consist of meat, fat and organs from marine mammals, including seals, whales and walruses; terrestrial species such as caribou, musk, birds, along with eggs and some berries [44], Scientists recently identified a common nonsense variant in the TBC1D4 gene of Inuit. This variant is associated with non-autoimmune diabetes, characterized by elevated circulating glucose and insulin after an oral glucose load, as well as decreased post-prandial glucose uptake. This variant in homozygous carriers causes insulin resistance in skeletal muscles. [45]

The TBC1D4 protein plays an important role in glucose homeostasis as it regulates the glucose transporter 4 (GLUT4), responsible for transporting glucose from the bloodstream into skeletal muscles and fat tissues. When exposed to insulin, the TBC1D4 protein is phosphorylated by protein kinase B (AKT), resulting in its dissociation from GLUT4 vesicles. The phosphorylation of TBC1D4 by AKT creates an increase of GLUT4 at the cell surface that facilitates increased glucose transport.[46]  Inhibition of the AKT insulin-signaling pathway by excess uric acid may also contribute to decreased functions of the TBC1D4 gene that regulates GLUT4.  [47]  

Did Nature make a mistake? Why would we have genes that are associated with insulin resistance?  Nature rarely makes mistakes, if you want my humble opinion. Everything that happened during evolution, happened for a reason. Let’s explore some of them now.

Carnivores & Insulin Resistance

The term insulin resistance was first used in 1936 to describe metabolic disturbances characterized by decreased cellular responsiveness to insulin signaling in insulin-dependent tissues such as skeletal muscle, liver, and adipose tissues. It is a state in which greater than normal insulin levels are required to elicit normal glucose responses in the body.  The term Insulin resistance is often used interchangeably with diminished insulin action or decreased insulin sensitivity. Is insulin resistance a disease state? The answer depends on context, because in carnivorous animals like cats, lions or even dolphins, insulin resistance is considered normal. 

Dolphins are hypercarnivores, whose diets are composed of over 70% meat, with plants, fungi, and other nutrients making up the rest of their food intake. Obligate carnivores can only subsist on meat because their bodies are unable to digest plants properly.  All cats, from small house cats to lions and tigers, are obligate carnivores. How carnivores metabolize their nutrients is substantially different from non-carnivores. First of all, carnivores do not taste sweetness. The gene responsible for the detection of sweetness is a pseudogene in carnivores. But the most interesting part about how carnivores process their food is that their normal glucose and protein metabolism affect serum glucose and insulin in ways that resemble diabetes pathology in humans. The hepatic glucokinase (GCK) pathway is actually absent in healthy carnivores yet GCK deficiency may result in diabetes in rodents and humans.  It is not uncommon to find glucose intolerance in healthy cats & dolphins. [12]

Genetic adaptations to Carnivory: GCKR & AGT

Healthy Bottlenose dolphins have been found to exhibit high fasting blood glucose similar to humans undertaking glucose challenges, and their fasting plasma insulin levels are comparable to those found in humans with insulin resistance. Obligate carnivores like cats, are also found to exhibit carbohydrate intolerance after glucose challenges, and they are prone to develop physiologic hyperglycemia. [8]

It has also been extensively demonstrated that the livers of domestic cats lack the glucokinase (GCK) enzyme and do not express the glucokinase regulatory protein (GCKR) gene; whereas GCKR is intact in most non-carnivore species, including humans. In addition, a variety of GCKR mutations have been found in the genomes of mammalian carnivores like cats and dolphins, [8] not dissimilar to the human subjects with GCKR polymorphisms who showed reduced benefits in insulin reduction when given high whole-grain diets. [6]

The consistent loss of GCKR and GCK in carnivore species suggests the change is adaptive, and that the GCKR mutations arose separately in different carnivorous species during evolution, with all mutations resulting in a common phenotype as adaptation to carnivory. Among genetic adaptations that arose to serve carnivore metabolism during evolution, none is more fascinating than the molecular adaptation of the intermediary metabolic enzyme alanine:glyoxylate aminotransferase (AGT), which tends to be mitochondrial in carnivores, peroxisomal in herbivores, and both mitochondrial and peroxisomal in omnivores. [9]

In humans, it seems that at one point during evolution, AGT was targeted to mitochondria instead of peroxisome in modern humans.  But in patients with hyperoxaluria type 1, this mitochondrial targeting sequence that was deleted from the human coding region by point mutation at the initiation codon is re-established, thereby producing an active mitochondrial targeting sequence. Mammals including humans, rabbits, and guinea pigs under normal conditions, do not target AGT to the mitochondrion, whereas cats and other carnivores do. [10]  Why is the targeting of AGT important? 

     AGT & Oxalates

The intermediary metabolic enzyme alanine:glyoxylate aminotransferase (AGT) catalyses the detoxification of the intermediary metabolite glyoxylate to glycine, preventing it from being oxidized to oxalate. The subcellular distribution of AGT has changed many times during the evolution of mammals as a result of dietary selection pressure. This is because in order for glyoxylate detoxification to be efficient, AGT must be concentrated at the site of glyoxylate synthesis. The site of glyoxylate synthesis is different in herbivores and carnivores because the dietary precursor of glyoxylate in herbivores is glycolate, which is metabolized to glyoxylate in the peroxisomes, whereas in carnivores, the dietary precursor would be hydroxyproline, which is converted to glyoxylate in the mitochondria. That is the main reason why AGT is targeted to mitochondria in carnivores, but peroxisomes in herbivores. In most humans, AGT is peroxisomal, but in many patients with hyperoxaluria type 1, AGT is mistargeted to the mitochondria. Although the mistargeted AGT remains active, it is unable to detoxify glyoxylate efficiently, leading to increased oxalate synthesis and the formation of oxalate crystals in the kidney and urinary tract. [11]   

It is understandable why genetic adaptations like the redistribution of AGT subcellular targeting makes sense in the evolution of carnivory, but I am sure you are wondering why insulin resistance also evolved as an adaptation to carnivory. Scientists now believe that insulin resistance evolved as a result of selection pressure that favored mechanisms that offered maximum protection against the conditions of regular food deprivation that was very much a part of life for our hominin ancestors during the Ice Ages over 2 million years ago.

Insulin Resistance, Gluconeogenesis & Uric Acid: The Surprise Trio 

How do our bodies respond to starvation or extended periods of food deprivation?  Generally speaking, when our bodies are deprived of food, metabolic changes start to happen after we deplete glucose and glycogen stores which normally could last for one day in the absence of food.  To maintain a steady level of glucose in plasma during food deprivation, insulin levels are decreased, and glucagon levels are increased in order to promote the production of glucose in the process of gluconeogenesis in liver, or even in kidneys during prolonged starvation. The decrease in insulin leads to a dramatic reduction in the uptake of glucose by muscles and adipose tissue, closely resembling what happens during insulin resistance. [13]  Why is it necessary to maintain a constant level of plasma glucose?  You can blame it on the high carbohydrate diets of our early primate ancestors who first appeared on earth over 55 million years ago. [14]

Insulin Resistance as Metabolic Adaptation: Blessing or Curse? 

The brain and reproductive organs of humans have developed specific requirements for glucose as source of fuel because our primate ancestors ate an extremely high-carbohydrate diet over 55 million years ago (MYA).  Starting around 2.5 MYA, the earth’s climate cooled drastically, and the ensuing glacial periods of the Quaternary brought about a low-carbohydrate, high-protein diet that is mainly carnivorous. Selection pressure during these glacial periods heavily favored those who could metabolically adapt to low glucose diets. Studies in both human and experimental animals have demonstrated that the phenotypic response to low-carbohydrate intake is insulin resistance. [15]  Insulin resistance allowed our early ancestors to survive and reproduce under restrictive cold and harsh conditions where food was scarce.  Insulin resistance is a critical metabolic adaptation, because it can help the body maintain a higher level of blood glucose during starvation or conditions of glucose deficiency despite amino acid surplus in carnivory.  Why is glucose so critical?

    You Cannot Survive Without Glucose

Red blood cells carry and deliver oxygen to cells and tissues. Without oxygen and the cells that transport it, life cannot be sustained. Erythrocytes (red blood cells) in our blood are completely GLUCOSE DEPENDENT. Surprisingly, red blood cells cannot utilize aerobic glycolysis, such as the Krebs cycle (TCA, or citric acid cycle), to extract energy from glucose. Instead, erythrocytes use the Embden-Meyerhof anaerobic glycolytic pathway to convert 90% of glucose into high-energy phosphates, which is critical for the maintenance of many of their vital functions. [16]  

The requirement of glucose is especially exaggerated during human pregnancy, which probably represents the most extreme example of physiologic insulin resistance. During human pregnancy, glucose requirement is increased because the fetus and placenta oxidize glucose as a source of energy. The average glucose used by the fetus during the third trimester is approximately 33 μmol/kg/min.  Accompanying this increased glucose demand by the fetal unit is the concomitant increase in peripheral insulin resistance as adaptation to the rising glucose demands. Maternal insulin resistance results in the utilization of fats for energy by the mother, sparing carbohydrates for fetal development thus ensuring an adequate source of glucose to supply the rapidly growing fetus. [17]   By the third trimester of pregnancy, it is common to find insulin sensitivity in normal pregnant women to be reduced by approximately two thirds relative to nonpregnant women of similar age and weight. [18]  As such, there remains yet another organ that consumes the highest amount of glucose in the human body, and we cannot survive without that organ – the human brain. 

  Gluconeogenesis in the Human Brain

The human brain has an unusually high glucose requirement. Even though the human brain accounts for only 2% of the body weight, it consumes about 20% of body energy that is derived from glucose. The brain is known to consume glucose at the rate of 5.6 mg per 100g per minute. [19]  During peak development in childhood, metabolic processes in the brain use glucose at a rate equivalent to 66% of the body’s resting metabolism and 43% of the body’s daily energy requirement. [20]  Glucose is the main source of energy for mammalian brains, and its tight regulation is critical for brain physiology. Brain disorders result from disruption of glucose metabolism. Neurons in adult brains require constant delivery of glucose from blood.  How do neurons cope with glucose deficiency during starvation or inadequate supply of carbohydrates? In 2016, neurons have been found to use glucose generated by astrocytes using the gluconeogenesis pathway in our brains. This gluconeogenesis pathway in the brain uses lactate produced by astrocytes via glycolysis as gluconeogenic precursors in neurons. Cerebral gluconeogenesis is now recognized to be an important pathway for alternative energy sources in the brain. [21]

Gluconeogenesis & Type 2 Diabetes

Gluconeogenesis is a highly conserved evolutionary pathway found in most living organisms, from microorganisms to vertebrates. Gluconeogenesis is an oxidative, anabolic pathway that produces glucose from pyruvate, the exact REVERSE of what happens during glycolysis. Gluconeogenesis consumes NADH to produce NAD+, whereas glycolysis consumes NAD+ to produce NADH [22]  During periods of starvation, extended food deprivation, or even carbohydrate deficiency, our bodies generate glucose using gluconeogenesis mainly in the liver, but also kidneys, intestines and muscles. 

    Insulin Inhibits Gluconeogenesis

In patients with Type 2 diabetes, increased gluconeogenesis in the liver is thought to be the major contributing factor to hyperglycemia and subsequent organ damage. Under normal physiology, insulin suppresses hepatic gluconeogenesis while facilitating glucose uptake into muscle. The major hallmark of Type 2 Diabetes is insulin resistance. [23]   As of 2018, the dominant mechanism of how insulin modulates hepatic gluconeogenesis is not yet fully understood. However, it has been shown that insulin exerts significant control over the transcriptional regulation in the expression of key hepatic gluconeogenic genes such as Pck1 and G6pc.  Insulin has also been found to activate signaling pathways that regulate gluconeogenesis. [23]  

The inhibition of insulin signaling leading to insulin resistance is now considered as key to the pathogenesis of type 2 diabetes.  Yet there exists a deep, ancient relationship, which most are unaware of, between insulin, insulin resistance and uric acid. This complex entanglement began over 20 million years ago when our primate ancestors lost the function of the uricase gene responsible for the degradation of uric acid. 

Hyperuricemia & Metabolic Syndrome: Devolution of Evolution? 

Hyperuricemia, or the excess accumulation of uric acid in the blood, always had a rather negative connotation from its ubiquitous association with metabolic disorders such as gout [24], hypertension, cardiovascular disease [25], chronic renal diseases [26], and metabolic syndrome [27].  Newer evidence now links hyperuricemia to the development of insulin resistance [28] and Type 2 diabetes [29].  

Xanthine Oxidoreductase as Double-Edged Sword: NADH or Reactive Oxygen Species?

Uric acid is the end product of the metabolism of purine compounds in humans and uricotelic primate species. Purines are the monomeric precursors of nucleic acids, DNA and RNA. In normal physiological pH, uric acid circulates plasma as the deprotonated urate anion. [30]  Uric acid is generated from the breakdown of DNA, RNA and ATP. The immediate precursor enzyme for this process is xanthine oxidoreductase (XOR).  The XOR enzyme exists in two forms, xanthine dehydrogenase (XDH), which prefers NAD+ as electron acceptor, and xanthine oxidase (XO), which prefers using oxygen as electron acceptor.  When XOR oxidizes xanthine to form uric acid, the XDH form will yield NADH and uric acid, whereas the XO form will yield superoxide, hydrogen peroxide and uric acid.[31]   It is under inflammatory conditions, that the XDH form of xanthine oxidoreductase is converted into xanthine oxidase, XO. In this XO oxidase form, affinity for NAD+ becomes greatly reduced while that for oxygen is significantly increased, resulting in electron transfers to oxygen that generate reactive oxygen species, superoxide and hydrogen peroxide [32]

Xanthine Oxidoreductase (XOR) has been studied for over a hundred years.  Only until recently, its main role as critical source of reactive oxygen species and nitrogen species contributing to negative clinical outcomes in many inflammatory disease processes where XOR activity is elevated, is being re-evaluated.  The nitrate/nitrite reductase capacity of XOR is now regarded as a source of beneficial nitric oxide under ischemic/hypoxic/acidic conditions. XOR is therefore, a double-edged sword, capable of generating both positive and negative biological effects of reactive oxygen species and reactive nitrogen species derived from its activities. [33] 

The association of hyperuricemia to the pathogenesis of atherosclerosis is perhaps one of the effects of XOR in endothelial cells as XOR activity has been found to induce inflammatory response and cause dysfunction in endothelial cells.  Not only that, the role of XOR products in the formation of foam cells and adipogenesis has been implicated in the development of insulin resistance and obesity, the two hallmarks of Type 2 diabetes. [34]  This association brings us back full circle to the final oxidation product of xanthine oxidoreductase (XOR), uric acid. 

Hyperuricemia Induces Insulin Resistance & Reduces Insulin Sensitivity

In humans, hyperuricemia is a condition where the level of serum uric acid (SUA) is greater than 6.8 mg/dL. In a survey conducted between 2007 and 2008, up to 21.4% of adults surveyed in the USA exceeded 7 mg/dL. [35]   Hyperuricemia can be the result of overproduction of urate, underexcretion caused by abnormal renal urate transport activity, or a combination of both.  More than 90% of patients with hyperuricemia are associated with the underexcretion of urate. [36]  Most mammals other than primates and carnivorous dipteras are able to metabolize uric acid into allantoin, which is water soluble and is excreted in urine easily.  Depending on the species, allantoin may be further degraded into ammonia.  In most amphibians and fish, purine is degraded to urea and glyoxylate as final products. [37]  The accumulation of excess uric acid in the human body is now associated with suppression of insulin signaling and secretion, reduction of insulin sensitivity, and increased gluconeogenesis.  How does uric acid suppress insulin signaling?   

    Uric Acid: An Intracellular Source of Reactive Oxygen Species

Uric acid has been found to be a potent extracellular antioxidant (primarily in plasma), but a dangerous pro-oxidant within cells.[38]  Science has identified pro-oxidant evidence that links uric acid to the suppression of insulin, and reduction of insulin sensitivity. Hyperuricemia is now linked to the direct inhibition of insulin receptor substrate 1 (IRS1) and protein kinase B (Akt) insulin signaling. Increased uric acid induces insulin resistance by a mechanism mediated by reactive oxygen species. [39]

The hormone Insulin regulates energy uptake by inhibiting hepatic gluconeogenesis, and by increasing glucose uptake in peripheral tissues.[40]  Binding of the insulin hormone to its receptors initiates signaling cascades that result in glucose transport activation and other metabolic effects. Insulin Receptor substrate 1 (IRS1)  is one of the main complexes that process these transmitted signals. The formation of reactive oxygen species as a result of high intracellular uric acid, leads to the serine phosphorylation of insulin receptor substrate-1 (IRS1), inhibiting insulin signal transduction downstream by further reducing phosphorylation of Akt (Ser473). [40,41,42]   

Uric Acid Homeostasis

The amount of circulating uric acid in humans is determined by the production and the net balance of reabsorption and secretion in the kidneys and intestines.  About 10% of patients with hyperuricemia are believed to have overproduction of uric acid; where most of the time, more than 90% of hyperuricemic patients have underexcretion of uric acid. Deficiency of enzymes involved in purine metabolism can result in overproduction of uric acid.  The type of diet you follow can also affect the level of uric acid production. 

A diet rich in purines from meat or seafood is a key element in the increase of uric acid precursors. However, meat eaters do not necessarily have the highest level of serum uric acid. Vegans who do not eat meat, fish, dairy nor eggs, are found to have the HIGHEST levels of uric acid, followed by meat eaters and fish eaters. Whereas vegetarians who do not eat meat nor fish, have the lowest serum uric acid concentrations. [48]  Vegans abstain from milk. Milk has been found to exert an acute uric acid lowering effect.[49] Female subjects on dairy-free diets are found to have elevated serum uric acid levels. [50]  The urate-lowering effect of dairy could be attributed to orotic acid, lactalbumin and casein content in milk. [51]

    Underexcretion of Urate: A Story of Genetic Mutations

Most of the uric acid produced in the body is reabsorbed. Only 8-12% of the uric acid produced in the body is excreted. Two thirds of the excretion of urate, the deprotonated form of uric acid under normal physiology, occurs in the kidneys while the remaining is excreted through the gastrointestinal tract.  The kidney is now recognized as the primary modulator of serum uric acid and renal urate excretion. The process of renal urate excretion is a combination of reabsorption and secretion of urate. 

Renal urate reabsorption is mainly regulated by two urate transporters:  urate transporter 1 (URAT1, also known as SLC22A12), and glucose transporter 9 (GLUT9, also known as SLC2A9).  In 2009, scientists identified the ABCG2 gene that mediates the secretion of urate.  A common polymorphism in this gene results in a 53% reduction in urate transport rate compared to wild-type ABCG2.[52]  The discovery of this gene and the effects of its common variants led scientists to re-evaluate the condition of ‘overproduction’ in hyperuricemic patients.  The decrease in extra-renal urate excretion via the dysfunctional ABCG2 is now recognized as a common mechanism of hyperuricemia. The traditional interpretation of ‘overproduction’ obtained from high urinary uric acid excretion values does not accurately reflect the correct pathophysiological condition where renal overload from dysfunction of common ABCG2 is the real cause of ‘extra-renal urate underexcretion’. [53]

Since the discovery of the common polymorphism in ABCG2, more genomic loci associated with serum uric acid increasing alleles have been identified.  In April of 2019, scientists identified eight novel loci, bringing the total to 8948 variants at 36 genomic loci that are part of transport-related genes important to serum uric acid regulation. All of these loci are tied to key cellular processes which contribute to elevated serum uric acid levels.  The most current understanding of uric acid homeostasis is that serum uric acid is regulated by not only by multiple transport-related genes, but also non-transport related genes. [54]

Nature has obviously undertaken great efforts to regulate uric acid levels in humans since unlike most other mammals, humans have lost the ability to degrade urate. There is no doubt that uric acid played a critical role in facilitating the adaptation to conditions of starvation and low food sources during the Ice Ages over 2 million years ago. The REAL question that remains unanswered is why humans and primates lost the function of uricase while other mammals retained functional uricases despite having to deal with the exact same environmental changes in temperature and food supply shortages during evolution. 

GULO and UOX: A Tale of Two Pseudogenes

Urate Oxidase (UOX), or uricase, is an enzyme responsible for purine catabolism and is found in all prokaryotes and eukaryotes.  Uricase coxidizes the highly insoluble uric acid and converts it into soluble allantoin. Unlike other animals with functional uricases, primates and humans have exaggerated elevation of serum uric acid due to the fact that they cannot oxidize uric acid as a result of evolutionary events that led to the silencing or pseudogenization of the uricase gene (UOX) in ancestral primates. [55]   Compared to other mammals with functional UOX genes, humans and primates not only have higher levels of uric acid, but lower levels of ascorbic acid.  As it turns out, most mammals that have functional UOX genes which degrades uric acid, also have functional GULO genes that produce ascorbic acid. [56]

Neotropical Forests & The Loss of GULO

L-gulonolactone oxidase (GULO) is the final enzyme in the pathway of ascorbic acid (Vitamin C) biosynthesis. Humans, primates, some guinea pigs, teleost fish, bats and certain birds have lost the ability to produce ascorbic acid as a result of mutations in the GLO gene that codes for the L-gulonolactone oxidase. [57]  It is generally believed that primates lost the ability to produce ascorbic acid sometime between 55-35 million years ago (MYA).  However, a robust analysis of available GLO gene sequences, their substitution record and transposable element distribution yielded an estimate date of inactivation to be around 61 MYA. [57]  What happened 61 million years ago?  Take a look at this record of global temperature fluctuations on earth [58]:



The Paleocene Epoch from 66 to 56 MYA was preceded by the mass extinction event, and was followed by the Paleocene-Eocene Thermal Maximum at 56 MYA, that led to extreme climate changes.  Temperatures rose sharply during the Paleocene–Eocene Thermal Maximum when extremely warm and humid conditions resulted in an abundance of neotropical rainforests. [59]  During this period, plants grew rapidly in over-extended growing seasons with minimal dry or cold periods.  Subtropical vegetation was found in Greenland and Patagonia; extensive tropical palm forests in northern Wyoming and other areas would have supported the evolution of early primates that took to the trees and subsisted on a diet based mainly on abundantly available fruits. [60]  From about 56 MYA to 49 MYA in the Eocene, temperatures continued to rise, and the warm, humid environments further fostered the spread of forests throughout the Earth from the North to South Poles. [61]  It is believed that during this period, the Earth was entirely covered in forests except for the driest deserts, and there was little to no ice, with only minor variations in temperature from the equator to the poles. 

It is believed that this unusual abundance of readily available fruits, ultimately led to the pseudogenization of the GLO gene in early primates. 

    Ascorbic Acid Synthesis Generates Hydrogen Peroxide

When Albert Szent-Györgyi discovered ascorbic acid  in 1928, he named it hexuronic acid because the molecule can be synthesized in the hexuronic acid pathway of the liver or kidneys.  Since glycogen is the main source of de novo ascorbate synthesis, it is not surprising to find gulonolactone oxidase expressed in glycogen-storing organs of animals with functional GULO.  During synthesis of ascorbic acid in animals, an equivalent amount of ascorbate and hydrogen peroxide is formed. Hydrogen peroxide can be metabolized by either catalase or glutathione peroxidase at the expense of glutathione (GSH). [62]

The uninterrupted supply of abundant fruits replete with ascorbic acid during the early Eocene became a reliable source of exogenous ascorbate for early primates. The loss of the gulonolactone oxidase enzyme could not have been an accident because the genetic alteration was wide-spread, resulting in the complete pseudogenization of the GLO gene around 42 MYA. [63]  The most likely reason for this advantageous genetic adaptation was to conserve glutathione consumption during ascorbate synthesis. [62] 

The pseudogenization of GULO in the evolution of early primates is an excellent example demonstrating Nature’s frugality and ability to capitalize on changing environments. If only Nature had the ability to foresee changes that happened 20 million years later, she might not have made the same decision. 

Savannas & The Loss of UOX 

Take a look again at the chart showing temperature fluctuations on Earth during the various epochs. The early Eocene marked the height of the warmest temperatures ever recorded in history. The subsequent progressive cooling that is the signature event of early Miocene (23.03 to 5.3 MYA) led to drastic environmental changes resulting in drier. more seasonal climates. Instead of flourishing in lush neotropical rainforests, early primates found themselves foraging for limited food sources in open grassy savannas with few trees, interspersed with tropical and subtropical forests. Wet and wooded habitats were found only in some areas in East Africa as rainforests receded to the equatorial zone during this time.  This period of change also witnessed the extinction of many Miocene apes, especially in Europe. [64]  

It is no coincidence that the progressive loss of uricase (UOX) activity in early primates began in the late Eocene, resulting in the complete loss of function by the early Miocene (∼15–20 MYA). [55]  It would appear that this time, Nature made the right decision in the pseudogenization of UOX, as the loss of uricase function prepared early primates for even more drastic changes to come. The loss of UOX was instrumental in the protection of early primates during the Messinian Salinity Crisis from 5.96 to 5.33 MYA when global oceans probably saw a 6% reduction in salinity.  Lower salinity also resulted in greater sea ice formation due to higher freezing point in seawater. [65] 

Uric Acid in The Ice Ages

The periods with freezing temperatures became more frequent as time passed. When the evolutionary lines of hominins were clearly identified [66] during the early Pleistocene (2.58 – 11,700 MYA), also commonly referred to as the Ice Ages, the Earth was covered in kilometers of thick glaciers in the northern and southern regions.  Early hominins quickly adapted to diverse food sources in wooded savanna environments in the relatively short interglacial periods. [67] The significant increase of serum uric acid as a result of UOX pseudogenization selectively enhanced their survival advantage during the longer, harsher glacial periods.  How did uric acid protect early primates in the Miocene and Ice Ages? 

Fructose, Obesity & Insulin Resistance: The Uric Acid Connection

The consumption of excess fructose in the modern diet is associated with obesity and the development of Metabolic Syndrome. [68]  Yet fructose, heavily ostracized and regarded with much disdain, was responsible for the survival of early primates in the Miocene when the lost of uricase function actually provided a survival advantage, because increased uric acid enhanced the effects of fructose to raise fat stores.  A higher fat reserve allowed early primates to forage longer distances during periods of food shortage. [55]

Diets of early primates in the Miocene consisted mainly of fruits that contained fructose as well as ascorbic acid. Unlike glucose, fructose is able to increase plasma triglycerides, visceral fat, as well as storage of fat in liver. [69]  In addition, fructose effectively increases intracellular and circulating uric acid levels as a result of increased purine nucleotide turnover and nucleotide synthesis in fructose metabolism.[70,  71]  By increasing uric acid, fructose is able to enhance fat storage. The discovery as to how uric acid increases fat storage in liver provided the answer to the paradox involving the lipogenic effect of fructose, and people with genetic fructose intolerance who can develop fatty liver in response to fructose intake despite having dysfunctional fructose metabolism. [72]

Although fructose is associated with increased triglycerides and other lipids, there are contradictory indications that only a small percent (1-3%) of fructose ingested is directly converted into triglycerides. [73]  So why is fructose able to increase fat storage, especially in people with impaired fructose metabolism who are not able to absorb fructose?  

     Uric Acid Stimulates Fat Accumulation: The Superoxide Connection

Fructokinase (KHK) is the first step in fructose metabolism that involves the transient depletion of ATP in a reaction that generates intracellular uric acid as consequence. Intracellular uric acid can further stimulate the expression of KHK, accelerating fructose metabolism that is characterized by increased lipogenesis and decreased beta-oxidation of fatty acids. [74]  Uric acid has been observed to increase fat synthesis in liver cells by enhancing mitochondrial translocation of NOX4 (NADPH oxidase isoform) that leads to increased generation of mitochondrial superoxide. This excess oxidative stress in mitochondria inhibits the Krebs (TCA cycle). The resulting accumulation of citrate as well as increased ATP citrate and fatty-acid synthase is the cause for de novo lipogenesis. [75]  That is the reason why when uric acid production is inhibited, fructose-induced triglyceride accumulation in liver cells can be substantially blocked, in vitro and in vivo. [76] 

Uric Acid Increases Gluconeogenesis by Suppression of AMPK & Insulin Signaling

One of the hallmarks of diabetes is increased hepatic gluconeogenesis.  Metformin, a drug used to treat diabetes, inhibits gluconeogenesis by activating the energy sensor protein AMPK (AMP activated kinase). [77]  AMPK is an essential cellular energy sensor that regulates metabolic energy balance throughout the body. AMPK modulates both catabolic and anabolic pathways. Catabolic processes that are activated by AMPK include glucose uptake, glycolysis, fatty acid uptake, fatty acid oxidation, mitochondrial biogenesis and autophagy; whereas anabolic pathways inhibited by AMPK include fatty acid and triglyceride synthesis, cholesterol synthesis, transcription of lipogenic and gluconeogenic enzymes, glycogen synthesis, protein and ribosomal RNA synthesis. [78]

During drastic climate cooling in the early Miocene, as a result of the successful pseudogenization of uricase, our primate ancestors were able to survive constant conditions of near starvation as a result of periodic famine. One of the key anabolic pathways inhibited by AMPK is hepatic gluconeogenesis. [79]  Reduced AMPK activity has been shown to increase hepatic gluconeogenesis in diabetes. During extended periods of food shortage, a steady supply of blood glucose from gluconeogenesis is critical for survival and reproduction. Both insulin and AMPK suppress gluconeogenesis. Uric acid not only can inhibit insulin signaling and induce insulin resistance [39], it is also extremely effective in down-regulating AMPK via AMP deaminase (AMPD). 

Insulin is critical in the tight regulation of intracellular phosphate levels. Phosphate is a natural inhibitor of AMPD activity. Lower intracellular phosphate as a result of insulin resistance activates AMPD, inhibiting AMPK and increasing gluconeogenesis. Upon activation of AMPD, increased uric acid is produced as a downstream metabolite. When AMPK activity is down-regulated by uric acid, the reduced TORC2 phosphorylation at SER171 by AMPK as well as the up-regulation of the rate-limiting enzymes PEPCK and G6Pc all contribute to heightened gluconeogenesis. [80]  Why is the role of uric acid in the suppression of AMPK important for gluconeogenesis?

AMPK is activated by calorie restriction. When there is a decrease in nutrient availability, the AMP/ATP ratio is increased and AMPK is activated.  Upon activation, AMPK initiates CATABOLIC pathways including glycolysis and fatty acid oxidation to restore ATP levels. [81]  However, when an animal needs to conserve fat storage to face extended famine, the role of AMPK needs to be suppressed by AMPD and uric acid.[82]  The pseudogenization of UOX in early primates allowed for maximum production of fat stores while fructose containing food sources were available. 

    Uricase Blunts Gluconeogenesis, Restores AMPK Function 

To prove that the pseudogenization of UOX allowed for increased fat storage that provided the distinct survival advantage of maintaining glucose levels under famine conditions, scientists resurrected ancestral uricase from early hominids and showed that their expression in liver cells not only blunted gluconeogenesis but also UP-REGULATED AMPK activity! [80]  The pseudogenization of UOX proved to be even more critical during the Messinian Salinity Crisis (5.96 to 5.33 MYA) when there was a possible 6% reduction in global oceanic salinity.

Hyperuricemia & Hypertension: The Sodium Connection

Hyperuricemia is increasingly associated with hypertension.  Elevated serum uric acid is consistently found to predict the development of hypertension, with a 13% higher risk per 1 mg/dL increment in serum uric acid.[83]  A study released in April 2019 found hyperuricemia independently increased the risk for the onset of hypertension in adolescents with type 2 diabetes. [84]  What was once an essential survival mechanism millions of years ago has inevitably morphed into a trigger for disease in the world we live in today.

Data as of 2010 suggest that the average global intake of salt is around 10 g daily (equivalent to approximately 4 g/day of sodium). [85]  High sodium intake is often associated with hypertension, [86] whereas sodium deficiency can cause not only hypotension, but aversive psychological states including anhedonia, impaired cognition, and fatigue. [87]  Science believes that increased uric acid had the important role of conserving sodium in order to maintain blood pressure in early primates. 

A frugivorous diet consisting primarily of fruit would have delivered only 225 mg sodium per day to early hominids adapting to climatic shifts during Miocene ( 24 to 6 MYA). During the Ice Ages in mid to late Pleistocene (2.58 – 11,700 MYA), the sodium intake of our hunter-gatherer hominin ancestors was about 690 mg per day. Hyperuricemia can be regarded as the result of selection pressure to maintain blood pressure under low-salt dietary conditions. [88]  

I am sure you are now thinking, if hyperuricemia is a critical survival mechanism during evolution, why did primates and humans lose the ability to degrade uric acid for easy elimination while other animals retained the ability even though they all faced the same challenges in climatic shifts and food shortages?

Insulin Resistance & The Ability to Hibernate

One of the biggest challenges for carnivores that were able to find food sources during seasonal changes, is the maintenance of a steady blood glucose supply due to lack of carbohydrates in their diet. Cats and other obligate carnivores like lions solved this problem by becoming genetically insulin resistant. These carnivores adapted by genetically altering important glucose-sensing pathways like GCK.  The glucose-sensing glucokinase (GCK) molecular pathway is COMPLETELY absent in livers of healthy carnivores. Proper GCK genetic expression in non-carnivores is essential for the maintenance of glucose homeostasis because the GCK enzyme that is coded by the GCK gene regulates metabolism via its glucose-sensing abilities.  [12]  In humans, polymorphisms of the GCK promoter is associated with insulin resistance and diabetes, whereas healthy carnivores do not have functional GCK pathways as a result of genetic adaptation to an all-meat diet. [89]  

Due to limited food supply during  cold seasons, some animals that are not carnivorous adapt by hibernating. Omnivores like brown bears and hedgehogs conserve their energy during cold seasons where food is scarce by entering a state of torpor characterized by inactivity, depressed metabolic functions, and lowered body temperatures. [90]  

Bears that live in temperate and arctic climates show remarkable physiological and metabolic flexibility that allow adaptation to dramatic seasonal changes.  Brown bears (Ursus arctos) can alternate flexibly between being insulin sensitive when they are active and insulin resistant when they are hibernating. Brown bears, unlike humans, do not rely on uric acid to modulate insulin resistance during hibernation. In fact, uric acid levels in hibernating brown bears were found to be two-fold lower during hibernation than during the active period. [91]  So if animals don’t have to rely on uric acid to modulate and maintain insulin resistance as adaptation to starvation or lack of carbohydrates, then why did early primates and humans lose the function of uricase?  The answer can be found in the hibernating arctic ground squirrel. 

Arctic ground squirrels (Spermophilus parryii) have been found to rapidly decrease their uric acid levels in the liver during hibernation. Concurrent with the decrease in uric acid, a decrease in AMP deaminase (AMPD) activity was also detected in hibernating arctic squirrels. [92] As discussed earlier, lower AMPD activity allows activation of AMPK, which is essential for fat oxidation during hibernation. [93]  However, the truly fascinating observation is that during hibernation, plasma concentration of ascorbate in arctic ground squirrels increased THREE to FIVE-FOLD while that of uric acid decreased!  [94]  Is there an inverse relationship between uric acid and ascorbic acid? 

If you examine all the animals that lost the function of the UOX uricase gene, including humans, higher primates, perching birds (Passeriformes), and bats, these animals have also lost the function of the GULO gene that produce ascorbic acid.  [37]   Most mammals have low circulating uric acid levels that is around 0.5 to 2.9 mg/dL, compared to around 2.0 mg – 7.0 mg/dL in humans. Scientists believe that one of the primary reasons for the pseudogenization in early primates was due to the loss of function in the GULO gene.  Unable to synthesize ascorbic acid, early primates faced additional challenges when food sources containing ascorbic acid were unavailable for extended periods. Scientists believed that the increase in uric acid achieved through pseudogenization of uricase provided early primates with enhanced antioxidant capacity, resulting in positive selection during evolution.  [95]

Ascorbic Acid & Uric Acid: The Yin & Yang of REDOX

In humans, gulonolactone (L-) oxidase (GULO), an enzyme that produces the precursor to ascorbic acid (AA), and urate oxidase (UOX, uricase), an enzyme that catalyzes the oxidation of uric acid (UA) to allantoin, are unitary pseudogenes. Unitary pseudogenes are unprocessed pseudogenes with NO FUNCTIONAL COUNTERPARTS, representing unequivocal losses of biological functions. [63]

Even though the GLO gene is non-functional in humans, our reliance on ascorbic acid as primary REDOX Balancer has not changed over time. [96]  The association of diseases with ascorbic acid deficiency is ubiquitous. The inability to produce ascorbic acid leaves humans at a great disadvantage unless adequate amounts are obtained from diet. It is also clear that the pseudogenization of UOX allowed humans and primates to survive the various challenges presented during periodic starvation caused by dramatic climatic changes, especially during the harshest cold climates in the Ice Ages where ascorbic acid from diet was reduced to a bare minimum. Is it reasonable to assume that humans today can safely depend on uric acid (UA) to compensate for low ascorbic acid (AA) availability as they had in the past?  

UV Radiation Protection: AA or UA?

If you maintain a 100% carnivorous diet, you may notice an increased resilience to sunburns, not dissimilar to the way ascorbic acid protects the skin from erythema during prolonged sun exposure. [97]  A meat-based diet high in purines can increase the level of uric acid in blood. It has been observed that the amount of uric acid in human skin is increased by two-fold when exposed to sunlight! [128]   

Diurnal mammals that can synthesize ascorbic acid have a significantly higher concentration of ascorbate in the aqueous humor and corneal epithelium. It is believed that ascorbate, being extremely effective in the absorption of UV radiation, is used as a UV filter for the eye. Perching birds, passeriforms, or more than half of all birds, cannot synthesize ascorbic acid [98] , they also do not have functional UOX. Like humans, these birds also have high circulating uric acid.  Diurnal perching birds are found to have especially high concentrations of uric acid in the aqueous humor of their eyes. [99] 

Uric acid, like ascorbic acid, is able to absorb UV radiation. The absorption peak of uric acid observed in the aqueous humor of diurnal birds is at 292 nm. [100]  Ascorbic acid is most effective in absorbing UV-B photons and suppressing fluorescence (or fluorescence quenching) of radiation below 310 nm. The absorption maximum of ascorbate is below 270 nm, with some studies showing a peak at 220 nm. [101]  The corneal epithelium probably has the highest concentration of ascorbate of all tissues in the human body.  The concentration of ascorbate in human corneal epithelium is about 14 times of that in the aqueous humor. The aqueous humor has 20 times the ascorbate in plasma. By this calculation, corneal epithelium will have close to 300 times the amount of ascorbate compared to plasma! [102]  So why do birds use uric acid to absorb UV radiation whereas humans use ascorbic acid in their eyes for protection even though both do not have functional genes that degrade uric acid? [103]   What is the difference between uric acid and ascorbic acid?


Urate exhibits negative birefringence [104], whereas ascorbate is the opposite. [105]  On the quantum level, this difference is significant. When light enters a birefringent material like urate or ascorbate, it will be split into two rays, one is called the ordinary wave, and the other, extraordinary wave.  The manner in which these rays emerge after passing through positive and negative birefringent crystals are reversed. [106]  Could this significant distinction account for the variations between these two molecules with seemingly similar attributes?  

Redox Balancer versus Antioxidant-Prooxidant

Ascorbic acid as a REDOX balancer, readily donates and accepts electrons and protons in important biological processes in our bodies. [96]  Uric acid can also donate and accept electrons, but the context is quite different. Uric acid donates electrons as an antioxidant only in extracellular plasma, and quickly becomes an acceptor of electrons, or pro-oxidant, in intracellular environments. Even though uric acid is recognized as an important antioxidant in human plasma, it is also highly correlated with oxidative stress associated with the development of obesity, hypertension, insulin resistance, dyslipidemia, Type 2 diabetes, kidney disease, and cardiovascular diseases. Increasing evidence show uric acid may act as a pro-oxidant within cells, resulting in oxidative modification of proteins and lipids. [107]  

The most important distinction that distinguishes ascorbic acid from uric acid, is the recycling of ascorbate by our bodies during biochemical processes.  The ascorbate/semidehydroascorbate redox couple is constantly renewed and regenerated by our plasma membrane redox system enzymes. [96]  Uric acid, on the other hand, is NOT regenerated after it is oxidized, and degrades into different metabolites as it reacts with different free radicals in the body. Some of these metabolites that are produced may actually be cytotoxic. [108] 

Uric acid is most effective as a free radical scavenger in plasma because its antioxidant features are limited to hydrophilic environments. [109]  One of the most damaging effects by free radicals is the damages caused by membrane lipid peroxidationPeroxynitrite, formed by superoxide and nitric oxide, induces membrane lipid peroxidation. Even though uric acid is capable of scavenging peroxynitrites, uric acid actually is incapable of scavenging superoxide, whereas ascorbic acid is an excellent scavenger of superoxide. [110]  Therefore, the presence of ascorbate or thiols, which are five times less effective than ascorbate, in the plasma is absolutely essential for the COMPLETE scavenging of peroxynitrite by uric acid. [111]  In addition, uric acid loses its ability to scavenge lipophilic radicals and becomes ineffective within lipid membranes where oxidized lipids can convert uric acid into dangerous oxidants. [112]  Ascorbate, as a Redox Balancer, is recognized for its ability to protect membranes from lipid peroxidation via its electron/proton tunneling reactions with plasma membrane redox enzymes. [113,114]  

Hyperuricemia & Cancer: The mTOR Connection

As adaptation to constant stress of food deprivation and climatic shifts, uric acid modulates insulin resistance and gluconeogenesis through the direct inhibition of insulin receptor substrate 1 (IRS1).  [39]  Adaptation to cold and stress often requires increased synthesis of catecholamines including norepinephrine and epinephrine. [115, 116]  Synthesis of all catecholamines depend upon adequate supply of ascorbic acid for the conversion of dopamine to norepinephrine by dopamine beta-hydroxylase. [117]  Norepinephrine and adrenaline levels in adrenal glands of mice are decreased when they are deficient in ascorbic acid. [118]

During catecholamine synthesis of dopamine, norepinephrine and epinephrine, our bodies use ascorbate as an electron donor to regenerate dopamine beta-hydroxylase almost exclusively as other electron donors like reduced glutathione and cysteine were found to be less effective. [119]  Ascorbate is shown to enhance the expression of tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. By increasing tyrosine hydroxylase proteins, ascorbate functions to increase and sustain catecholamine synthesis. [120]  The effects of norepinephrine has been found to be enhanced by the presence of ascorbate, [121] and it is recognized that ascorbate can protect and extend the viability of norepinephrine both in vivo and in vitro. [122]

Humans and primates do not produce ascorbic acid. During extended periods of food shortage where adequate ascorbic acid cannot be obtained from diet, what did hominids and hominins use instead of ascorbate to cope with increased stress? 

Activation of mTOR by Uric Acid increases Stress Response 

The kinase mammalian target of rapamycin, mTOR, is a stress response pathway. When our bodies are under duress, adaptive mechanisms are activated for survival and maintaining important biological functions  [123]   When uric acid inhibits the activity of AMPK, it also induces the activation of mTOR. [124]  The activation of mTORC1 by uric acid is important for the suppression of insulin signaling because mTORC1 inhibits insulin receptor substrate (IRS) by phosphorylating serine residues. [125]  mTOR is well-known for its functions in stimulating protein translations. Under stress, mTOR is now discovered to activate multiple stress-responsive transcription factors, including the amplification of the proapoptotic functions of the tumor suppressor p53. [123] 

Although mTORC1 protects us by activating stress responses like p53, sustained increases in mTORC1 activity can sensitize cells to stress, or induce irreversible damages when mTORC1 or p53 becomes dysregulated. [123]  Cancer cells are known to harbor proliferation of mutant p53 proteins that not only have lost the ability to suppress tumorigenesis, but also inhibits functional p53 genes. Cancer cells retain these mutant p53 proteins to subvert the activities of the p53 pathway by promoting invasion, metastasis and chemoresistance. [126]   

    Hyperuricemia Linked to Cancer

In 2017, results of the largest study ever conducted on the correlation between hyperuricemia and carcinogenesis in both men and women were published. The authors found higher cancer risks with increasing levels of serum uric acid. Of the 493,281 cancer free persons aged 20 years and older who participated in the study, 72,349 persons developed cancer during the following 19.47 years. Males had a higher incidence rate of cancer (56.96%).  Serum uric acid levels were higher in the group who developed cancer, compared to the cancer-free group. The authors also believed uric acid to play an important pro-oxidant role at relevant cancer sites, increasing potential risks in the development of colon, liver, kidney, non-melanoma, and other cancers in men, and for head, neck and other cancers in women. [127]

The fact that hyperuricemia may affect cancer development differently in men and women supports other observations showing specific differences in gender responses to excess uric acid in humans and animals. These observations also highlighted the primary objective of Nature: the survival of species through reproduction.  Nature really is not interested in prolonging life once it has served its functional role in the production of viable offspring. 

The Yin and Yang in Uric Acid

Genetically altered mice that do not express uricase, or UOX-knockout -/- mice, spontaneously develop hyperuricemia with about a 40% chance of surviving up to 62 weeks.  Male Uox-knockout -/- mice developed glycol-metabolic disorders associated with compromised insulin secretion, whereas female mice developed hypertension accompanied by dysfunctional lipid metabolism. [134]  Yet higher levels of uric acid have been proposed to be an evolutionary survival-advantage of long-lived species such as humans. [135]

Mice have functional uricase (UOX) that convert uric acid to the soluble allantoin.  Scientists discovered that the levels of uric acid in homozygous wildtype UOX+/+, and genetically altered heterozygous UOX+/−, and homozygous knockout UOX −/− mice produced dramatically different behavioral and physiological changes in male and female rodents.[129]   It is also important to point out that mice have functional gulonolactone (L-) oxidase (GULO) that produce ascorbic acid. Hence the following impressive results obtained must be considered in that specific context. 

Homozygous knockout UOX −/− mice with extreme elevations of serum uric acid displayed heightened exploratory and novelty-seeking behavior compared to wild-type UOX+/+ mice with intact, functional uricase.  UOX −/− mice with the highest levels of serum uric acid compared to the two other types also covered longer running distances. At the end of a five-month experiment period, UOX knockout mice ran five times further than wild-type counterparts. [129] 

Heterozygous UOX+/− mice with elevated serum uric acid levels showed significant increase in endurance during treadmill exercise when compared to wild-type mice. These  UOX+/− mice had increased brain-derived neurotrophic factor (BDNF) and showed significant reduction in brain damage and improved functional outcome in ischemic stroke models.  Under conditions of metabolic stress in muscle induced by running, and oxidative stress in brain induced by ischemia, these heterozygous UOX+/− mice were found to exhibit reduced levels of oxidative protein nitration as well as lipid peroxidation. [129] 

The most impressive and critical observation made by this study is that life spans of FEMALE heterozygous UOX+/− mice was significantly increased compared to wild-type mice, but not that of male UOX+/− mice. [129]  Both male and female rodents express functional GULO that produce ascorbic acid. However, female rodents have much higher concentrations of ascorbate in plasma and tissues compared to their male counterparts. [130]  The plasma content of ascorbate in male rats is an abysmal 1.6 mg per 100 g. [131] Female rats on the other hand, have extremely high levels of ascorbate in their plasma, ranging from 150 mg per 100 g to 165 mg per 100 g. [132] That is almost a 100-fold increase of plasma ascorbate content over males!  What do you think would happen when scientists knock out the GULO gene functions in male and female rodents?  The results were quite shocking, yet they offered a better understanding of how Nature prioritizes biological functions differently in male and females. 

UA & AA Protect Sperm Viability

The GULO gene has been observed to regulate oxidative genes and their relevant pathways in mice. Uricase (UOX) is a GULO partner oxidative gene. The deletion of the GULO gene in knockout -/- mice produced different results in male and female mice.[133]  Take a look at the following chart:

[Data source: Yan Jiao, Hong Chen et al. Genome-Wide Gene Expression Profiles in Antioxidant Pathways and Their Potential Sex Differences and Connections to Vitamin C in Mice Int’l Journal of Molecular Sciences 2013, 14 (5), 10042-10062; https://doi.org/10.3390/ijms140510042 ]

GULO knockout -/- males DECREASED their UOX expression as compared to wild-type males. That means they INCREASED their capacity to produce uric acid.  GULO knockout -/- females actually INCREASED the expression of UOX significantly, as compared to wild-type females. This means females had to dramatically REDUCE the level of uric acid in their bodies to compensate for the loss of ascorbic acid. [133]  Why would female mice and male mice who lost their ability to produce ascorbic acid control the levels of uric acid differently in their bodies?

Ascorbic acid is recognized for its ability to enhance human sperm fertility, [136] motility, viability, and DNA integrity [137] via its ability to limit excess lipid peroxidation and oxidative DNA damage in human seminal plasma. [138]

Uric acid is ALSO able to protect sperm viability, motility, morphology and DNA integrity mainly through its antioxidant capacities. Sperm generate small amounts of free radicals like peroxynitrite and hydroxyl radicals.  These free radicals, if not neutralized, have been found to reduce sperm motility [139], viability and morphology. [140]  Normal men are found to have higher average levels of uric acid than those with azoospermia and oligozoospermia [141]  However, due to the pro-oxidant effects of uric acid, an excess of uric acid in the presence of magnesium have been known to increase oxidative stress, damaging sperm viability and function. [142]  This is probably the main reason why GULO knockout -/- male mice had to increase their uric acid levels in the absence of ascorbic acid. However, the roles of ascorbic acid and uric acid during pregnancy in humans and rodents are quite a different story.

Hyperuricemia has been found to increase risk of preterm birth in humans. High serum uric acid concentration is associated with increased risks of neonatal mortality by over sevenfold. [143]  Serum uric acid is now recognized as an effective clinical indicator in predicting maternal complications in women with pre-eclampsia. [144]  It is now very clear why female GULO -/- mice more than doubled the expression of uricase to lower uric acid in the absence of ascorbic acid. 

Since both uric acid and ascorbic acid offers protection against oxidative stress, would it be correct to assume there is a natural inverse relationship between UA and AA, as observed in the male GULO -/- mice that increased their uric acid levels when their ascorbate production became non-functional?  

Inverse Relationship between Ascorbic Acid and Uric Acid

The supplementation of ascorbic acid has been found to affect serum uric acid levels, where an inverse dose-response association was observed through vitamin C intake of 400 to 500 mg per day in men with hypertension and without hypertension. [145 ,146,147]   It has been shown that supplementation with 500 mg/day of ascorbic acid is effective in the prevention and management of hyperuricemia, gout and other urate-related diseases. [148]  The uricosuric action of ascorbic acid is believed to be the competition for reabsorption in the kidneys, resulting in increased uric acid excretion in urine. [149, 150]  

Excess uric acid suppresses insulin signaling and increases insulin resistance.  Is ascorbic acid able to reduce insulin resistance, since there is an inverse relationship between ascorbic acid and uric acid?

Ascorbic Acid Improves Insulin Sensitivity

Since ascorbic acid can decrease hyperuricemia, [148]  it is reasonable to assume it should be able to reduce insulin resistance.  Scientists recently discovered that chronic supplementation of high dosage ascorbic acid (500 mg x 2 daily) could significantly increase peripheral insulin sensitivity, and decrease oxidative stress in muscles during hyperinsulinemia in people with Type 2 diabetes. [151]  Acting as Redox Balancer, ascorbic acid enhanced insulin sensitivity by improving oxidative stress levels in muscle. Ascorbic acid was also observed to double the protein expression of sodium-dependent vitamin C transporter 2 (SVCT2) in skeletal muscle, to facilitate increased utilization of ascorbic acid. Increased ascorbic acid also lowers the pressure on other antioxidants, as ascorbic acid supplementation was observed to significantly reduce the activities of superoxide dismutase (SOD) in skeletal muscles. [151]

A study released at the end of 2018 revealed that individuals diagnosed with Type 2 diabetes who supplemented with 500 mg x 2/day of ascorbic acid for 4 months showed significant reductions in daily postprandial glucose levels, as well as marked reduction in 24-hour hyperglycemia states. In addition, blood pressure was also decreased in individuals receiving ascorbic acid versus placebo. [171]

Understanding the inverse relationship between ascorbic acid and uric acid now brings us back to the original question raised at the beginning of this article. Which diet is best for metabolic syndrome. The answer is not a straightforward one, as it depends on your genetic disposition.  There is no doubt that our hominin ancestors thrived in harsh arctic environments by adopting a hunter-gatherer lifestyle that relied on big game species as a major source of food, and survived the extended periods of food shortages in between big game kills via the development of insulin resistance. [152]  Uric acid was the hero during those times, providing antioxidant protection, and stabilizing blood sugar in times of low glucose intake and periodic famine. Many today probably still carry the genetic traits that allowed our hominin ancestors to thrive during the Ice Ages as Nature tends to favor positive selection adaptations.  We are currently in an unusually warm interglacial period known as the Holocene epoch that began 11,650 years before present. Some regard the Holocene as part of the Pleistocene that began 2.58 MYA. Despite incessant fluctuations in conditions that affect the survival of our species, Nature emerged as the winner because she had been extremely skillful in hedging her bets.  

Insulin Resistance & Insulin Sensitivity in a 5G World

During the Ices Ages, our hominin ancestors survived mainly by hunting large game animals instead of gathering a variety of plant and animal based foods as they once did before the dramatic cooling of temperatures.  Recent discoveries showed that carbohydrates were reintroduced in hominin diets in the form of wild grains about 22000 years ago. [153]  The successful cultivation of crops in various cultures led to an intensification of agriculture in civilizations such as Mesopotamian Sumer, ancient Egypt, the Indus Valley Civilisation of South Asia, ancient China (where rice was domesticated by 6,200 BC), and ancient Greece, the selection pressure for insulin resistance as adaptation to low-carbohydrate diets became significantly relaxed, theoretically resulting in the reduction of genes that enhance insulin resistance.[15]

Diets with ample carbohydrates provide the body with glucose, reducing the need for uric acid to enhance insulin resistance. As humans adapt to higher levels of carbohydrates, insulin sensitivity is increased [6] and genes that regulate uric acid homeostasis began to adapt also.

GLUT9 Polymorphisms Modulate Serum Uric Acid Levels   

The recently discovered facilitative glucose transporter isoform GLUT9 (SLC2A9), expressed in liver and kidney, has a large capacity to transport urate or hexose sugars including glucose, galactose, and fructose. [154]  GLUT9 is able to exchange urate for glucose or fructose. Increased urate uptake have been observed in cells overexpressing human GLUT9 and diminished uptake could be achieved by knocking down GLUT9 expression. [155]  As GLUT9 controls glucose uptake, variations in uptake results in modulation of glucose-6-phosphate, which affects uric acid production through the pentose phosphate shunt. GLUT9 variants in the kidney have also been found to be able to regulate the concentration of organic anions. Anions are exchanged for urate by the uric acid transporter URAT1, changes in anion levels can therefore affect urate reabsorption in kidneys as well as circulating urate levels. [156]  

Variants of GLUT9 have been found to modulate serum urate acid levels in humans where homozygotes for allelic variants show differentiation in serum uric acid by 10% of average levels. [156]  Pathogenic inactivating mutations of GLUT9 is associated with idiopathic renal hypouricemia with high renal urate fractional excretion. [157,  161]  Whereas other polymorphisms of GLUT9 and URAT1 are associated with hyperuricemia and hypouricemia [158], as well as increased or decreased risks in the development of gout in various ethnicities. [159]

Despite the presence of polymorphisms in urate transporters, healthy human subjects who are insulin sensitive have been found to be able to significantly raise uric acid levels by more than two-fold in order to maintain blood glucose levels when adjusting to a ketogenic diet providing less than 20 g of carbohydrates. [160]  Even though uric acid is a time-tested reliable mechanism for maintaining glucose homeostasis when challenged with reduced carbohydrates from food sources, the current oxidative environment created by excess electromagnetic radiation in which uric acid finds itself is nothing short of catastrophic. 

AA, UA & 5G – The REDOX Connection

Electromagnetic radiation (EMR) from manmade sources has been linked to the rise in diseases including the proliferation of cancer [162], cardiovascular diseases [163], neurodegenerative disorders [164], and even infertility [165].  In 2008, a contemporary sample of adults in the USA found that cell-phone usage was inversely associated with self-reported hypertension independent of age, sex, race/ethnicity and other variables. [166]  A disturbing study released in late 2018 linked electromagnetic radiation from 2.4 GHz Wi-Fi to hyperglycemia, impaired insulin secretion in rodent pancreatic islets. Wi-fi generated electromagnetic radiation was observed to cause excess oxidative stress by dramatically increasing lipid peroxidation, significantly decreasing levels of antioxidants such as glutathione and superoxide dismutase in pancreas. [167]  The results of this 2018 study validated the findings of a 2015 study where students exposed to high levels of EMR from mobile phone base stations  had significantly higher levels of HbA1c, as well as higher proportion of diabetes mellitus than students who were exposed to lower EMR from mobile phone base stations. [168]

The rats used in the 2018 Wi-fi study were MALE Sprague-Dawley rats.  Male rats have significantly less ascorbic acid in their plasma compared to female rats. [130]  It is entirely plausible that without adequate ascorbate, uric acid becomes pro-oxidant, creating oxidative stress that suppresses insulin signaling, causing insulin resistance and hyperglycemia. [39]   Lack of adequate ascorbic acid in uncontrolled oxidative stress caused by electromagnetic radiation will result in reduced levels of antioxidants like glutathione since ascorbate as REDOX Balancer can maintain and enhance antioxidant protection capacity in blood. [169]  

It is important to remember that although uric acid is recognized as an effective antioxidant in plasma, the presence of ascorbate or thiols, which are actually five times less effective than ascorbate, in the plasma is absolutely essential for the COMPLETE scavenging of peroxynitrite by uric acid. [111]  Peroxynitrites can cause lipid peroxidation if not neutralized.[170]  Increased lipid peroxidation was one of the observed effects induced by EMR from 2.45 GHz Wi-fi. [167]   In addition, uric acid loses its ability to scavenge lipophilic radicals and becomes ineffective within lipid membranes where oxidized lipids can further convert uric acid into dangerous oxidants. [112] 

Uric Acid, Neurodegeneration & Cancer: The mTORC1 Connection

When uric acid inhibits the activity of AMPK, it also induces the activation of mTOR. [124]  The activation of mTORC1 by uric acid is important for the suppression of insulin signaling because mTORC1 inhibits insulin receptor substrate (IRS) by phosphorylating serine residues. [125]  The increased association between oxidative stress as a result of exposure to electromagnetic radiation, cancer, neurodegenerative diseases, as well as autoimmune and metabolic diseases is deeply related to mTORC1 and uric acid.  Why? mTORC1 is also activated by oxidative stress, and uric acid loses its antioxidant potential in oxidative environments, becoming pro-oxidant, further compounding the cascade of free radical production. 

Oxidative stress activation of mTORC1 is now recognized as a central pathway for the pathogenesis of systemic lupus erythematosus and other autoimmune diseases. mTORC1 has also been identified as chief mediator of the Warburg effect that allows cancer cells to survive under hypoxic conditions. [172]  More recent discoveries have identified the overexpression of mTOR as driving force behind pathogenesis for Alzheimer’s Disease as well as diabetes, autoimmune diseases and cancer. 

Overexpression of mTOR leads to hyperphosphorylation of tau protein and promotion of Aβ (amyloid beta) aggregation in brains. People suffering from diabetes exhibit enhanced mTOR activation, and insulin resistance is now implicated as one of the primary causes for the severity of AD (Alzheimer’s Disease). [173]   mTOR activation causes dysfunction of autophagy, which results in aggregation of Aβ (amyloid beta). Increased Aβ in turn stimulates tau hyperphosphorylation.

The blockade of mTOR activation, on the other hand  has been found to successfully inhibit tauopathy. [174]   mTOR activity has been shown to be a critical mediator in the breakdown of the blood-brain barrier.  Inhibition of mTOR has recently been found to promote integrity in the BBB (blood-brian barrier), dramatically limiting infiltration of proinflammatory and neurotoxic elements. Protecting integrity of BBB controls progression of AD (Alzheimer’s Disease). Inhibition of mTOR yielded significant improvement in cerebrovascular and cognitive function in mouse models of AD. [175]

Reduced cerebral blood flow (CBF) precedes the development of cognitive impairments, brain atrophy, amyloid β (Aβ) accumulation in AD pathology. [176]  Decreases in regional and global vascular density is believed to be the reason for reduction of CBF  in AD. mTOR is now regarded as the major cause for cerebromicrovascular density loss, resulting in CBF deficits. mTOR has been found to inhibit Nitric Oxide synthase (NOS) activity, significantly reducing microvascular nitric oxide (NO) bioavailability in AD model mouse brains.  Chronic reduction of mTOR activity can halt the progression of cognitive decline by preserving brain vascular integrity and function. [177] 

  Uric Acid Inhibits Nitric Oxide

It is no coincidence that uric acid, being the activator of mTOR, also inhibits nitric oxide.  Nitric oxide (NO) was first discovered in 1980 as an endothelial cell-derived relaxing factor. Since then, NO has been regarded as one of the most important regulators of cardiovascular, nervous and immune systems. A deficit in endothelial cell nitric oxide levels is often the major pathogenic event preceding the development of neurological, cardiovascular and metabolic diseases.  [178]

Uric acid reacts irreversibly with nitric oxide (NO) to form 6-aminouracil. This reaction could result in the depletion of NO.  Even in the presence of oxidants like peroxynitrite and hydrogen peroxide, uric acid will PREFERENTIALLY react with nitric oxide, depleting NO and causing endothelial dysfunction. Although this reaction can be partially blocked by glutathione, under oxidative stress conditions (as a result of excess exposure to electromagnetic radiation leading to the depletion of endogenous antioxidants like ascorbic acid and/or glutathione), high concentrations of uric acid can ostensibly inhibit endothelial function by depleting NO, in the absence of adequate glutathione. [178]   Why does uric acid preferentially select to inhibit nitric oxide? 

    Nitric Oxide & Insulin Resistance

It is now widely accepted that dysfunction of insulin signaling in Alzheimer’s Disease (AD) and diabetes are inextricably associated. Since the brain is an insulin-sensitive organ, insulin signaling is now regarded as neutrophic and neuroprotective. Brains of patients with AD are often found to have impaired insulin signaling. [179]  Patients with Type 2 diabetes and obese individuals also show a higher prevalence in the development of AD. [180]  

One of the main functions of uric acid is to suppress insulin signaling in order to induce insulin resistance. That is why it inhibits AMPK, and activates mTOR.  AMPK knockout mice show prominent levels of amyloid beta. But Aβ production was dramatically reduced when the mice were treated with AMPK activators. [181]  Whereas the genetic removal of one copy of the mTOR gene from the forebrain of mice with Alzheimer’s Disease rescued impaired insulin signaling resulting in improved cognition as well as reduced tau and amyloid beta. [182]  The preferential selection by uric acid to react only with nitric oxide even in the presence of peroxynitrite and superoxide in plasma is deeply tied to the REDOX environment. The consequences of nitric oxide depletion as a result of these selective reaction with uric acid severely affects the pathology of AD. 

The development of insulin resistance is now understood to be modulated by nitric oxide (NO) bioavailability.  Insulin resistance is ALWAYS associated with impaired NO bioavailability.  Nitric oxide bioavailability is found to be highly decreased in animal models of obesity and diabetes [183] and in obese and diabetic humans [184]. eNOS knockout animal models exhibit a number of features of insulin resistance and hypertension even in the absence of obesity as nitric oxide plays an important role in modulating insulin sensitivity as well as carbohydrate metabolism. [185]  

The balance between nitric oxide production and degradation determines its bioavailability.  The reduction in expression of nitric oxide synthase (NOS), as well as impaired NOS enzymatic activities can lower NO production. The reaction of NO with reactive species like superoxide can also decrease bioavailability. [186]  

The complex entanglement between ascorbic acid and uric acid is further highlighted by how these two elements react with nitric oxide, especially in a highly oxidative environment that may be caused by excessive exposure to electromagnetic radiation.

    Ascorbic Acid Regenerates BH4 to Produce Nitric Oxide

Nitric Oxide Synthase (NOS) produce nitric oxide from combining l-arginine and oxygen in a reaction that requires several cofactors.   Tetrahydrobiopterin (BH4) is the most important cofactor because without BH4, electrons cannot flow to oxygen and the entire process becomes ‘uncoupled’ from l-arginine oxidation and nitric oxide production. [187]  Without adequate BH4, NOS will produce the dangerous free radical superoxide, instead of nitric oxide.  The problem with superoxide if it is not quenched, is that superoxide will react with nitric oxide to form the even more toxic peroxynitrite.  If Peroxynitrite is not neutralized, the detrimental free radical cascade will continue on its destructive path to inhibit the binding of BH4 to NOS, further suppressing nitric oxide production. [188] 

In plasma, uric acid is regarded as an effective antioxidant, capable of scavenging peroxynitrite.  However, uric acid actually is incapable of scavenging superoxide, whereas ascorbic acid is an excellent scavenger of superoxide. [110]  Even though thiols are capable of neutralizing superoxide, it is five times less effective than ascorbate. [111]  Superoxide if not neutralized will react with nitric oxide to form peroxynitrite.  In the absence of ascorbate, uric acid will not be able to completely scavenging peroxynitrite properly. [111]  Peroxynitrite is then free to oxidize BH4 into dihydrobiopterin (BH2).  BH2, unlike BH4, is NOT a cofactor for nitric oxide synthase.  In fact, the presence of BH2 will competitively inhibit the binding of BH4 to NOS, further preventing nitric oxide production. 

The presence of elevated oxidative stress in plasma acts to deplete ascorbate. The depletion of ascorbate in plasma is perhaps the primary reason why uric acid seeks to react with nitric oxide to form 6-aminouracil, a process that eventually could result in the depletion of NO in plasma.  [178]   Ascorbate not only is highly effective in completely quenching superoxide, thus stopping the initial free radical cascade that could lead to inactivation of BH4 by peroxynitrite, it is also a requisite factor in the production of nitric oxide because ascorbate is used exclusively by our bodies as electron donor to regenerate BH4. 

The recycling of BH4 by ascorbate is especially critical in the function of endothelial nitric oxide synthase (eNOS). During the production of nitric oxide by endothelial nitric oxide synthase (eNOS), BH4 is constantly recycled, where BH4 donates an electron to eNOS and becomes a free radical (BH3•) as a result. If ascorbate is present, ascorbate will donate an electron to turn BH3• back into BH4. The focal point to pay attention to is that science has demonstrated that other antioxidants like thiols are totally INEFFECTIVE in this regeneration process.  If the BH3• free radical is not properly reduced back into BH4 by ascorbate, it will quickly degrade into the inactive BH2. BH2 will then bind to NOS and actually inhibit nitric oxide production. Increased BH2 and lack of BH4 uncouples eNOS, causing the enzyme to generate superoxide free radicals instead of nitric oxide. The cascade of damage continues, when superoxide reacts with whatever nitric oxide that has already been generated, forming more deadly peroxynitrite free radicals. [189]  

Early hominids lost the function of uricase when the availability of ascorbic acid from food sources became dramatically reduced due to climatic changes.  The loss of adequate ascorbic acid can be detrimental during the generation of nitric oxide by NOS, as nitric oxide will form peroxynitrite with superoxide, and BH4 will degrade into BH2, which will also lead to increased generation of dangerous free radicals. That is why it is possible that in highly oxidized environments, uric acid preferentially reacts with nitric oxide regardless of the presence of peroxynitrite so as to effectively stop the initiation of potential deadly free radical cascades.  The functions of uric acid also explain the observed inverse relationship with ascorbic acid.  

A perfect, but somewhat troubling example of this inverse association, can be found in the relationship between uric acid and 8-oxoG. There is a deep reason why scientists were able to find a high correlation between hyperuricemia and elevated risks in cancer development. [127]  

Uric Acid & Cancer: The 8-oxoG Connection

Guanine, a purine derivative, is one of the four constituent bases of nucleic acids. It is paired with cytosine in double-stranded DNA.  Guanine has an extremely low redox potential, and as such, is most vulnerable to oxidative stress. The low redox potential of guanine renders it extremely reactive, resulting in its ability to readily react under oxidative environments, resulting in genomic instability that could lead to cell death.  When guanine is oxidized by reactive species, it will form DNA lesions, and 8-oxoguanine (8-oxoG or 8-oxo-7,8-dihydroguanine) is the most common lesion. When 8-oxoG is inserted during DNA replication, it could generate double-strand breaks, leading to deleterious consequences. [190]  That is why 8-oxoG and 8-oxodG are often used as cellular biomarkers to indicate the extent of oxidative stress in the body, as well as the early detection for the development of cancer. [191]

One of the main characteristics of 8-oxoG is that after it is oxidized, it can further react with nitric oxide to form oxidation products like xanthosine and oxanosine.  The interesting part about the oxidation pathways of 8-oxoG is that they share great similarities with the oxidation pathways of uric acid. In fact, it is believed that the oxidation products of uric acid may actually be mutagenic lesions derived from 8-oxoG under oxidative conditions that include deamination. [192]  This is probably the reason why uric acid is observed to increase by two-fold in human skin when exposed to sunlight. [128]  

Chronic UVB exposure increases the formation of 8-oxoG in epidermal cells.[193]  Human epidermal cells also has the ability to produce nitric oxide when exposed to UV-A or UV-B radiation.  Studies have shown that keratinocytes can produce a threefold amount of nitric oxide when exposed to UVA, and FOURFOLD when exposed to UV-B. [194]  The production of nitric oxide with inadequate levels of ascorbate can result in increased reactive oxygen species like superoxide and peroxynitrite. The observed increase of uric acid from sunlight exposure may be the protective mechanism of 8-oxoG oxidation as uric acid is able to absorb UV radiation. [100]  So when you are eating a high purine diet without adequate ascorbic acid, and find yourself more resilient against sunburns, it is most probably due to the increased level of uric acid that is offering protection from UV radiation.  But have you considered the cost of that protection?    

    OGG1 Polymorphism & Insulin Resistance

8-oxoguanine DNA glycosylase (OGG1) is the primary repair mechanism for DNA damage from oxidative stress. When exposed to UVB radiation three times a week for 40 weeks, OGG1 knockout mice developed 3.7 times more skin tumors than wildtype and heterozygous mice. The age of onset of developing skin tumors in the OGG1 -/- mice was also earlier than in other types of mice. [195]  Even though these results are alarming, it is important to remember that mice have both intact GULO and UOX. So these results must be interpreted in the right context.  What most people are not aware about OGG1 functions in HUMANS, is that global deletions of OGG1 and common OGG1 polymorphisms render mice and humans highly susceptible to metabolic diseases such as insulin resistance and Type 2 diabetes. It is now widely accepted that OGG1 deficiency leads to alterations in cellular substrate metabolism, favoring a fat sparing phenotype, with increased susceptibility to obesity and metabolic dysfunctions. [196] [197]


It may appear from the evidence presented so far, that our high technology world today has turned an unmistakable hero of the past into a villain of little redemption value. But it is important to remember that our understanding of how Nature truly works is rather limited. What we can see is but a fraction of what happens on a quantum level.  A very good example is how perching birds accumulate uric acid in their corneal epithelium. If the purpose is only for protection from UV radiation, why do perching birds not use ascorbic acid like other diurnal animals including humans, who like perching birds, have also lost the ability to produce ascorbic acid? Afterall, ascorbic acid is just as effective, if not more effective, than uric acid in the absorption of UV radiation. [101]

A recent paper published on the findings of magnetoreception mechanisms in the zebra finch revealed that their magnetic compasses that facilitate the detection of the Earth’s magnetic field in the navigation of short and long distances are actually LIGHT DEPENDENT.  The most intriguing and relevant finding in this paper is that the magnetic compass orientation in these zebra finches are modulated by overhead polarized light, and that their magnetoreceptors are selective for polarized light. [198]  Urate, unlike ascorbate, exhibits negative birefringence. That means the manner in which ordinary wave and the extraordinary wave emerge after passing through the negative birefringent urate crystals is reversed from those that pass through ascorbate. [106]  Is this distinction significant for magnetoreception in zebra finches? 

There are still many unanswered questions regarding uric acid. Things we do know is that uric acid served a decidedly positive function in the survival of hominids throughout evolution. What we also know is our world today is drastically different than that in the past. Uric acid is simply not meant to protect our species from uncontrolled oxidative stress created by excess electromagnetic radiation in our environment.  To ensure the survival of our species in this brave new world humans created, uric acid must be recoupled with its long lost partner, ascorbic acid. Everything in Nature serves a multitude of purposes. I believe Nature has already given us all the tools we need to navigate these treacherous waters. To succeed, all we have to do is to properly decipher her messages and follow her deftly coded instructions. 






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[2] Evolutionary history and metabolic insights of ancient mammalian uricases https://www.pnas.org/content/pnas/111/10/3763.full.pdf 

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[4] Retrospective study on the efficacy of a low-carbohydrate diet for impaired glucose tolerance


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[7] Genetics of Insulin Resistance and the Metabolic Syndrome  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911377/ 

[8] Dolphins as animal models for type 2 diabetes: sustained, post-prandial hyperglycemia and hyperinsulinemia.


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[10] Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC53039/

[11] Differential Enzyme Targeting As an Evolutionary Adaptation to Herbivory in Carnivora


[12] Normal glucose metabolism in carnivores overlaps with diabetes pathology in non-carnivores  https://www.frontiersin.org/articles/10.3389/fendo.2013.00188/full#B1

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[82] Opposing Activity Changes in AMP Deaminase and AMP-Activated Protein Kinase in the Hibernating Ground Squirrel


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[92] Ascorbate dynamics and oxygen consumption during arousal from hibernation in Arctic ground squirrelshttps://www.physiology.org/doi/full/10.1152/ajpregu.2001.281.2.R572?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed 

[93] Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liverhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494720/ 

[94] Role of the antioxidant ascorbate in hibernation and warming from hibernation https://www.ncbi.nlm.nih.gov/pubmed/12458177

[95] Uric acid and evolution  https://academic.oup.com/rheumatology/article/49/11/2010/1785765

[96] Vitamin C & Mitochondria Part 1 Redox in a 5G World  https://www.linkedin.com/pulse/vitamin-c-mitochondria-part-1-redox-5g-world-doris-loh/

[97] Vitamin C in dermatology https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673383/

[98] L-ascorbic acid synthesis in birds: phylogenetic trendhttps://www.ncbi.nlm.nih.gov/pubmed/5777214

[99] UV Absorption by Uric Acid in Diurnal Bird Aqueous Humor https://iovs.arvojournals.org/article.aspx?articleid=2123591

[100] UV Absorption by Uric Acid in Diurnal Bird Aqueous Humor https://iovs.arvojournals.org/article.aspx?articleid=2123591

[101] The significance of ascorbate in the aqueous humour protection against UV-A and UV-B https://www.ncbi.nlm.nih.gov/pubmed/8690035 

[102] Ascorbic Acid Content of Human Corneal Epithelium https://iovs.arvojournals.org/article.aspx?articleid=2123569

[103] Uric acid and life on earth  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512146/

[104] Wide-field imaging of birefringent synovial fluid crystals using lens-free polarized microscopy for gout diagnosis  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928089/

[105] Polarized Microscopy  https://fpnotebook.com/rheum/lab/PlrzdMcrscpy.htm 

[106] Principles of Birefringence https://fpnotebook.com/rheum/lab/PlrzdMcrscpy.htm 

[107] URIC ACID: THE OXIDANT–ANTIOXIDANT PARADOX  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895915/

[108] Peroxynitrite-mediated formation of free radicals in human plasma: EPR detection of ascorbyl, albumin-thiyl and uric acid-derived free radicals.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1217137/

[109] Antioxidant defenses and lipid peroxidation in human blood plasma  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC282858/

[110] Scavenging of superoxide radical by ascorbic acid   https://link.springer.com/article/10.1007/BF02704692

[111] Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase. https://www.ncbi.nlm.nih.gov/pubmed/15963955

[112] When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1220232/

[113] Role of cytochrome b5 reductase on the antioxidant function of coenzyme Q in the plasma membrane.


[114] Solvent-induced hydrogen tunnelling in ascorbate proton-coupled electron transfershttps://www.sciencedirect.com/science/article/pii/S0040403911001912?fbclid=IwAR266nMmx29oFefCSnclDuAzYdG0vxzb6ThmQN3OuAwY6B73OKGJS5MXBF4 

[115] Catecholamines in stress: molecular mechanisms of gene expression https://www.ncbi.nlm.nih.gov/pubmed/18257649

[116] Stress stimulates production of catecholamines in rat adipocytes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419009/

[117] Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2)https://www.ncbi.nlm.nih.gov/pubmed/12897061 

[118] Effect of ascorbic acid deficiency on catecholamine synthesis in adrenal glands of SMP30/GNL knockout mice.


[119] Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase.  https://www.ncbi.nlm.nih.gov/pubmed/12692136/

[120] Mechanisms of Ascorbic Acid Stimulation of Norepinephrine Synthesis in Neuronal Cellshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3449284/

[121] Antioxidant-independent ascorbate enhancement of catecholamine-induced contractions of vascular smooth musclehttps://www.physiology.org/doi/full/10.1152/ajpheart.00968.2003?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed 

[122] Fostering venture research: A case study of the discovery that ascorbate enhances adrenergic drug activityhttps://www.researchgate.net/publication/229457240_Fostering_venture_research_A_case_study_of_the_discovery_that_ascorbate_enhances_adrenergic_drug_activity

[123] Transcriptional regulation of the stress response by mTOR. https://www.ncbi.nlm.nih.gov/pubmed/24985347 

[124] Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathwayhttps://www.pnas.org/content/114/21/5485#ref-27

[125] The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707648/ 

[126] Mutant p53 as a guardian of the cancer cell  https://www.nature.com/articles/s41418-018-0246-9 

[127] Circulating uric acid levels and subsequent development of cancer in 493,281 individuals: findings from the AMORIS Sthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522070/ 

[128] Effect of sunlight exposure and aging on skin surface lipids and urate  https://www.ncbi.nlm.nih.gov/pubmed/14756518

[129] Uric acid enhances longevity and endurance and protects the brain against ischemiahttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410356/

[130] Gender and sodium-ascorbate transporter isoforms determine ascorbate concentrations in micehttps://www.ncbi.nlm.nih.gov/pubmed/15333707 

[131] DISTRIBUTION OF ASCORBIC ACID, METABOLITES AND ANALOGUES IN MAN AND ANIMALShttps://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1749-6632.1975.tb29271.x 

[132] Evaluation of tissue ascorbic acid status in different hormonal states of female rat https://www.sciencedirect.com/science/article/abs/pii/002432059390111F

[133] Genome-Wide Gene Expression Profiles in Antioxidant Pathways and Their Potential Sex Differences and Connections to Vitamin C in Mice https://www.mdpi.com/1422-0067/14/5/10042/htm#b1-ijms-14-10042

[134] Knockout of the urate oxidase gene provides a stable mouse model of hyperuricemia associated with metabolic disordershttps://www.kidney-international.org/article/S0085-2538(17)30331-9/fulltext

[135] Family History of Exceptional Longevity is Associated with Lower Serum Uric Acid Levels in Ashkenazi Jews https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325371/#R7


[137] Effects of ascorbic acid on sperm motility, viability, acrosome reaction and DNA integrity in teratozoospermic samples https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009562/

[138] Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC53061/

[139] Total oxyradical scavenging capacity toward different reactive oxygen species in seminal plasma and sperm cells https://www.ncbi.nlm.nih.gov/pubmed/12636043

[140] Effects of reactive oxygen species from activated leucocytes on human sperm motility, viability and morphologyhttps://www.ncbi.nlm.nih.gov/pubmed/22097888

[141] Biochemical analysis of human seminal plasma. II. Protein, non-protein nitrogen, urea, uric acid and creatine https://www.ncbi.nlm.nih.gov/pubmed/6465552

[142] Magnesium and selected parameters of the non-enzymatic antioxidant and immune systems and oxidative stress intensity in the seminal plasma of fertile males  https://www.ncbi.nlm.nih.gov/pubmed/25967880/

[143] Maternal serum uric acid concentration and pregnancy outcomes in women with pre‐eclampsia/eclampsia


[144] Accuracy of serum uric acid as a predictive test for maternal complications in pre-eclampsia: Bivariate meta-analysis and decision analysis https://www.researchgate.net/publication/38957403_Accuracy_of_serum_uric_acid_as_a_predictive_test_for_maternal_complications_in_pre-eclampsia_Bivariate_meta-analysis_and_decision_analysis

[145] Vitamin C Intake and Serum Uric Acid Concentration in Men https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853937/

[146] The effects of vitamin C supplementation on serum concentrations of uric acid: Results of a randomized controlled trialhttps://onlinelibrary.wiley.com/doi/full/10.1002/art.21105

[148] Vitamin C supplementation and serum uric acid: A reaction to hyperuricemia and gout diseasehttps://www.sciencedirect.com/science/article/pii/S221343441630072X

[149] The effect of ascorbic acid on uric acid excretion with a commentary on the renal handling of ascorbic acid https://www.ncbi.nlm.nih.gov/pubmed/835593

[150] Effect of large doses of ascorbic acid in man on some nitrogenous components of urine https://www.ncbi.nlm.nih.gov/pubmed/6863023

[151] Ascorbic acid supplementation improves skeletal muscle oxidative stress and insulin sensitivity in people with type 2 diabetes: Findings of a randomized controlled study   https://www.sciencedirect.com/science/article/pii/S0891584916000071

[152] Archaeology of NIDDM. Excavation of the “thrifty” genotype https://www.ncbi.nlm.nih.gov/pubmed/1991567

[153] Ice Age Cereal  https://www.sciencemag.org/news/2004/08/ice-age-cereal 

[154] Facilitative glucose transporter 9, a unique hexose and urate transporter https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763791/ 

[155] SLC2A9 Is a High-Capacity Urate Transporter in Humans https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561076/

[156] The GLUT9 Gene Is Associated with Serum Uric Acid Levels in Sardinia and Chianti Cohorts https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2065883/

[157] Plasma Urate Level Is Directly Regulated by a Voltage-driven Urate Efflux Transporter URATv1 (SLC2A9) in Humans http://www.jbc.org/content/283/40/26834.full

[158] P107 Polymorphisms in SLC2A9 and SLC22A12 genes are related to hyperuricemia, gout and also to hypouricemia https://ard.bmj.com/content/78/Suppl_1/A47.1

[159] Associations of gout with polymorphisms in SLC2A9, WDR1, CLNK, PKD2, and ABCG2 in Chinese Han and Tibetan populations http://www.ijcep.com/files/ijcep0027265.pdf

[160] The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation https://www.ncbi.nlm.nih.gov/pubmed/6865775?dopt=Abstract

[161] Pathogenic GLUT9 mutations causing renal hypouricemia type 2 (RHUC2).  https://www.ncbi.nlm.nih.gov/pubmed/22132964

[162] Extremely low frequency electromagnetic fields affect proliferation and mitochondrial activity of human cancer cell lines https://www.tandfonline.com/doi/abs/10.3109/09553002.2015.1101648?src=recsys&journalCode=irab20 

[163] Exposure to electromagnetic fields induces oxidative stress and pathophysiological changes in the cardiovascular system https://medcraveonline.com/JABB/JABB-04-00096

[164] Effect of electromagnetic radiations on neurodegenerative diseases- technological revolution as a curse in disguise. https://www.ncbi.nlm.nih.gov/pubmed/25345513 

[165] Effect of electromagnetic field exposure on the reproductive system https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341445/

[166] Cell-Phone Use and Self-Reported Hypertension: National Health Interview Survey 2008 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095917/

[167] Radiofrequency radiation emitted from Wi-Fi (2.4 GHz) causes impaired insulin secretion and increased oxidative stress in rat pancreatic islets  https://www.ncbi.nlm.nih.gov/pubmed/29913098

[168] Association of Exposure to Radio-Frequency Electromagnetic Field Radiation (RF-EMFR) Generated by Mobile Phone Base Stations with Glycated Hemoglobin (HbA1c) and Risk of Type 2 Diabetes Mellitus https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661664/

[169] Vitamin C elevates red blood cell glutathione in healthy adults https://www.ncbi.nlm.nih.gov/pubmed/8317379?fbclid=IwAR0ilnWleqxNk0jMVgsh1pjxLqE7tpMsWfNSpLMiaQzX1VMIiDnp7aPTl2U

[170] Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide https://www.ncbi.nlm.nih.gov/pubmed/1654835 

[171] Ascorbic acid supplementation improves postprandial glycaemic control and blood pressure in individuals with type 2 diabetes: Findings of a randomized cross‐over trial   https://onlinelibrary.wiley.com/doi/full/10.1111/dom.13571

[172] mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480196/ 

[173] Tau and mTOR: The Hotspots for Multifarious Diseases in Alzheimer’s Development https://www.frontiersin.org/articles/10.3389/fnins.2018.01017/full

[174] Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies  https://www.tandfonline.com/doi/abs/10.1080/14737175.2017.1244482?journalCode=iern20

[175] Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairmen  https://www.physiology.org/doi/full/10.1152/ajpheart.00570.2017

[176] Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919512/

[177] Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764385/ 

[178] Inactivation of Nitric Oxide by Uric Acid  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701227/

[179] The effect of insulin and glucose on the plasma concentration of Alzheimer’s amyloid precursor protein https://www.sciencedirect.com/science/article/abs/pii/S0306452299004583?via%3Dihub

[180] Insulin Resistance and Alzheimer-like Reductions in Regional Cerebral Glucose Metabolism for Cognitively Normal Adults With Prediabetes or Early Type 2 Diabetes  https://jamanetwork.com/journals/jamaneurology/fullarticle/802106

[181]Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis https://www.sciencedirect.com/science/article/pii/S0006291X10014014?via%3Dihub

[182] Genetically reducing mTOR signaling rescues central insulin dysregulation in a mouse model of Alzheimer’s disease https://www.ncbi.nlm.nih.gov/pubmed/29729422 

[183] Vascular Inflammation, Insulin Resistance and Reduced Nitric Oxide Production Precede the Onset of Peripheral Insulin Resistance  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577575/

[184] Effect of obesity on endothelium-dependent, nitric oxide-mediated vasodilation in normotensive individuals and patients with essential hypertension  https://www.ncbi.nlm.nih.gov/pubmed/11710783/

[185] REGULATION OF OBESITY AND INSULIN RESISTANCE BY NITRIC OXIDE https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112002/

[186] Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. https://www.ncbi.nlm.nih.gov/pubmed/11457755

[187] Oxidative stress induces BH4 deficiency in male, but not female, SHR http://www.bioscirep.org/content/38/4/BSR20180111 

[188] Vascular Superoxide Production by NAD(P)H Oxidase  https://www.ahajournals.org/doi/full/10.1161/01.RES.86.9.e85 

[189] Role of Vitamin C in the Function of the Vascular Endothelium  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869438/?fbclid=IwAR1mQpleErhjXBuisO3jnNGOsTKmFm9kkDX54c-d6N8EyHT63YYN9Y2Ly4c

[190] Oxidative Stress and DNA Lesions: The Role of 8-Oxoguanine Lesions in Trypanosoma cruzi Cell Viabilityhttps://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002279

[191] Oxidative damage DNA: 8-oxoGua and 8-oxodG as molecular markers of cancer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539537/

[192] Oxidation of 9-β-d-ribofuranosyl uric acid by one-electron oxidants versus singlet oxygen and its implications for the oxidation of 8-oxo-7,8-dihydroguanosine  https://www.sciencedirect.com/science/article/pii/S0040403910021544 

[193] Cellular Levels of 8-Oxoguanine in either DNA or the Nucleotide Pool Play Pivotal Roles in Carcinogenesis and Survival of Cancer Cells  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139859/

[194] Nitric Oxide Produced by Ultraviolet-irradiated Keratinocytes Stimulates Melanogenesis http://content-assets.jci.org/manuscripts/119000/119206/JCI97119206.pdf

[195] 8-Oxoguanine Formation Induced by Chronic UVB Exposure Makes Ogg1 Knockout Mice Susceptible to Skin Carcinogenesis http://cancerres.aacrjournals.org/content/65/14/6006?ijkey=5070d347ebb8e1a859f3d020a443483df241c179&keytype2=tf_ipsecsha

[196] 8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Increases Susceptibility to Obesity and Metabolic Dysfunctionhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051697

[197] Association between polymorphisms of the DNA repair gene (OGG1) in Iraqi patients with type2 diabetes mellitus  https://pdfs.semanticscholar.org/fc18/52321251e1c92f7d6fc72f187d9a3f24e9d2.pdf

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