Bioarchaeological studies reveal unsettling evidence that cardiovascular diseases in the form of atherosclerosis was not uncommon thousands of years ago. Most people believe the decline of heart health is associated with the modern way of life. So why would a man from the Alps who lived 5,300 years ago, and a princess from Thebes who lived 3,500 years ago both develop atherosclerosis eating two drastically different diets in the ABSENCE of artificial LED lights, cell phones and electricity?
The right way to rephrase this question should be: what has not changed in human biology since the first identification of hominins some 2.5 million years ago?
Over the past 2.5 million years, the human genome has undergone quite a makeover. There appeared to have been an extreme burst of action in the human genome about 15,000 to 2000 years ago. A close examination of 15,336 genes in 6,515 individuals of European American and African American ancestry indicated that most human mutations happened within the past 5,000-10,000 years. The spectrum of protein-coding variation in modern humans has been found to differ considerably compared to those as recent as 200 to 400 generations ago. Yet diseases like atherosclerosis and cancer remained persistent and constant for close to 2 million years.
If one cannot attribute the development of atherosclerosis and cancer to genetic mutations, then is there a common thread that spanned this entire time? Is this factor intrinsic to the pathological development of diseases like atherosclerosis and cancer? What did hominids, hominins and humans all have in common since 61 million years ago?
Humans and our great ape ancestors all have pseudogenes in L-gulonolactone oxidase (GULO) and Urate Oxidase (UOX). We cannot produce ascorbic acid, and we produce relatively high amounts of uric acid compared to other animals with functional UOX.
The evolutionary pressure to eliminate the function of urate oxidase has been clearly elucidated in “Uric Acid & Vitamin C: Devolution of Evolution in a 5G World” However, the relatively exorbitant price paid for this necessary genetic adaptation that facilitated the survival of our species has not been truly defined.
Hyperuricemia: Cancer Past and Present
Hyperuricemia is a condition where the level of serum uric acid (SUA) is greater than 6.8 mg/dL. Hyperuricemia has been definitively correlated to carcinogenesis in the largest study ever conducted that involved close to half a million cancer free participants aged 20 years or older. 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.
My article “Cancer on Clocks” presented scientific documentations of cancer recorded from samples as far back as 1.98 million years ago. The archeological discovery of metastatic carcinoma in a young man from Ancient Nubia around 1200 BC provided scientists with further irrefutable evidence that cancer is not a product of modern living. The remains of the young man from over 3000 years ago showed multiple osteolytic lesions on the vertebrae, ribs, sternum, clavicles, scapula, pelvis, and humeral and femoral heads. The inferred metastatic malignant soft-tissue carcinoma that had spread across large regions of the body represented the first complete example in the world of a human who suffered metastatic tissue cancer.
In my paper on “Uric Acid & Vitamin C: Evolution of Devolution in a 5G World”, I connected the evolutionary need for Uric acid to activate mTOR as a stress response. Unfortunately, mTOR activation can also be carcinogenic, as sustained increases in mTORC1 activity can sensitize cells to stress, and even induce irreversible damages when mTORC1 or p53 becomes dysregulated.
The strong correlation between hyperuricemia and cancer may indicate that uric acid’s role in carcinogenesis may not be limited to the activation of mTOR only.
Hyperuricemia: Heart Disease, Past and Present
Uric acid is now accepted to be an accurate biochemical marker of endothelial function and atherosclerosis. It has also been used to assess risk factors for the development of cardiovascular diseases, as well as predicting the occurrence of cardiovascular events. Even though there has been considerable controversy regarding the association of coronary heart disease (CHD), a systematic review and dose-dependent meta-analysis of a total of 29 prospective cohort studies representing data from 958,410 participants showed that hyperuricemia was associated with increased risk of CHD morbidity. This 2016 study revealed that for each increase of 1 mg/dl in uric acid level, the pooled multivariate risk ratio of CHD mortality was 1.13, with a higher risk ratio being observed in females.
Hyperuricemia has been correlated to higher medium and long-term mortality rates as well as major cardiovascular event rates in patients following acute coronary syndrome. It has been determined that patients exhibiting gout, who show no sign of hyperuricemia, and lack clinical evidence of cardiovascular disease actually have a high prevalence of SUBCLINICAL atherosclerosis. The outstanding question remains- how do we know humans in antiquity had hyperuricemia?
Hyperuricemia in Antiquity
Science now believes humans evolved genetic mutations that favored insulin resistance as a result of selection pressure during the course of evolution in the past 2 million years. The fact that these polymorphisms are still retained in many humans indicate the tremendous survival edge conferred by these genetic adaptations in the past. However, a person who is genetically insulin resistant needs to follow the path of hominins who lived during the Ice Ages, and adopt a low carbohydrate diet. Cold temperatures together with periodic starvation during the Ice Ages created the necessity to maintain steady blood glucose via insulin resistance. Eating a diet rich in carbohydrates will result in hyperglycemia, and increase the risk for developing metabolic syndrome, including diabetes and cardiovascular dysfunction.
Princess Ahmose-Meryet-Amon who developed atherosclerosis lived in Thebes some 3,500 years ago. Thebes was an ancient Egyptian city located along the Nile about 500 miles south of the Mediterranean. Being close to the Nile meant that controlled irrigation would have yielded surplus crops. Ancient Egypt is well known for its irrigation systems and agricultural production techniques. Might the princess be genetically insulin resistant, and her high carbohydrate intake caused her to become diabetic?
The development of cardiovascular disease (CVD) is intimately related to diabetes
Science has now established that hyperglycemia, coronary artery calcification, and diagnostic HbA1c are predictive indicators for cardiovascular disease (CVD). For every 1% increase in HbA1c, the risk associated with atherosclerotic coronary vascular disease has been observed to increase by 11% to 16%. If hominins were genetically insulin resistant, did humans in antiquity also suffer from diabetes like modern humans?
Diabetes in Antiquity
Diabetes was first documented around 5th century BC by the famous Indian surgeon Sushruta. In his famous work Samhita, Sushruta referred to diabetes by the term ‘madhumeha’ or honey-like urine, and indicated that the urine had the ability to attract ants due to its sweetness and the texture of the liquid was sticky to the touch. Sushruta noted that diabetes mostly affected the rich castes who were able to afford high consumption of carbohydrates such as rice, cereals and sweets.
Diabetes was frequently mentioned in ancient Egyptian papyri, as well as ancient Indian and Chinese medical literature. Ancient Greek physician Aretaeus of Cappadocia who lived in the 2nd century AD provided the first accurate description of diabetes. He was the first to use the term “diabetes”. The term “mellitus” was added in the 17th century by Thomas Willis, in order to emphasize the extreme sweet taste of the urine.
It is understandable that high carbohydrate diets caused metabolic syndrome in humans thousands of years ago, resulting in the possible development of atherosclerosis. But how do we explain the evidence of major calcifications in the carotid arteries, distal aorta and right iliac artery of the Tyrolean Iceman named Ötzi who grew up and lived in different valleys in the southern region of the Alps 5,300 years ago? If he were insulin resistant, surely his diet that was high in animal products as supported by evidence of degenerative arthritis, and gallbladder stones, would have prevented the development of hyperglycemia and diabetic complications.
A diet high in animal products would also be high in purines. Uric acid is the end product of the metabolism of purine compounds in humans. A diet high in purines would have naturally resulted in high serum uric acid for our Tyrolean Iceman. Princess Ahmose-Meryet-Amon, if she were insulin-resistant, would also have a high level of serum uric acid. How does uric acid cause atherosclerosis and cancer? For that answer, we will have to understand the roles of the ancient circadian clocks, peroxiredoxins.
Peroxiredoxin are REDOX Circadian Regulators
The previous chapter, “Cancer on Clocks”, introduced peroxiredoxins as ancient transcript-independent circadian time-keepers from perhaps 3 billion years ago that functioned in concert with transcriptional circadian clocks. Peroxiredoxins also serve pivotal roles as antioxidant enzymes and REDOX signaling regulators. As important regulators of cellular homeostasis, peroxiredoxins can have a wide range of influence on different stages of growth and development in cells and tissues, as well as disease and cancer progression. How do peroxiredoxins regulate REDOX?
Peroxiredoxin Binds Hydrogen Peroxide
The reactive oxygen species hydrogen peroxide has been known for its important role as secondary messenger in REDOX signaling. Yet the mechanism involved has never been fully elucidated. Recent understanding of peroxiredoxin (PRX) show that they participate in the DIRECT regulation of intracellular signal transduction pathways that involve H2O2.
Mammalian cells have various means to eliminate H2O2, including enzymes like catalase and glutathione peroxidase (GPx). Yet peroxiredoxins, known for their antioxidant capacity in the catalytic reduction of hydrogen peroxide and other reactive oxygen species like peroxynitrite, possess a high-affinity binding site for H2O2 that is lacking in catalase and GPx. The target for H2O2 in Prx is actually the cysteine component, which is highly susceptible to oxidation by H2O2.
Mammals have six different isoforms of peroxiredoxins, PRDX1-6, and are distributed at sites of ROS production, such as the cytosol, mitochondria, as well as peroxisomes. Structurally, PRX enzymes belong to either the 1-cys or 2-cys groups. These two groups have the same mechanism of activity, but the way the Prx enzymes are recycled back from the oxidized to the reduced states are different.
Prx6 is the only mammalian peroxiredoxin that belong to the 1-cys group. Prx 2-5 in mammals are unique in that they undergo an additional step of oxidation called hyperoxidation that can reversibly, or irreversibly inactivate the enzyme.
It is the inactivation of peroxiredoxins in the hyperoxidized state that allows for circadian REDOX regulation.
Hyperoxidation: REDOX Circadian Regulation
If peroxiredoxins are not recycled back into their reduced state after the cysteine component is oxidized by H2O2, they can be reversibly, or irreversibly INACTIVATED when they are further oxidized by H2O2 into a hyperoxidized state. This oxidative inactivation of PRXs is now recognized as the key mechanism that allows local H2O2 levels to accumulate and initiate redox-signaling events.
The continuous cycle of hyperoxidation and reduction of peroxiredoxins is the basis of REDOX circadian regulation that oversees many cellular pathways. Most 2-cys Prx that are hyperoxidzed can be regenerated by an ATP-consuming process involving another molecule called sulfiredoxin (Srx).
Prx3 is a 2-cys peroxiredoxin. Its hyperoxidation and subsequent regeneration generates a REDOX circadian rhythm that regulates cellular functions like steroid biosynthesis. In the adrenal steroidogenesis of corticosterone, the extent of the hyperoxidation of Prx3 is proportional to the number of H2O2 molecules removed by Prx3, which in turn affects the number of corticosterone molecules synthesized. Signals generated from H2O2 buildup in the hyperoxidation of Prx3 will reflect to the organism that sufficient corticosterone has been produced.
Different isoforms of peroxiredoxins are found to exert different effects on signaling in humans. Hyperoxidized Prx2 levels are found to be higher in patients with sleep apnea compared to those who only snored. Human keratinocytes redox balance has been found to be regulated by the circadian oscillations of Prx2. Prx2 is now recognized as a potent suppressor of melanoma.
Uric Acid and the Hyperoxidation of Peroxiredoxins
The formation of hydrogen peroxide begins with the generation of superoxide, the one-electron reduction of molecular oxygen. Superoxide is easily generated in the human body, such as during the autooxidation of hemoglobin; during the production of ATP in mitochondria electron transport chain; as well as by exposure to ultraviolet radiation.
In the absence of adequate ascorbic acid, uric acid is one of the major antioxidants in plasma. The plasma level of urate in humans is about 300 microM. This level is considerably higher than that of ascorbate. Yet uric acid will preferentially react with nitric oxide instead of neutralizing superoxide, leaving superoxide to produce hydrogen peroxide under inadequate reducing environments.
Xanthine oxidoreductase, responsible for the production of uric acid in the human body, generates superoxide and hydrogen peroxide instead of NADH under oxidative inflammatory environments.
Most interesting of all, is that when urate, the anionic form of uric acid, has been found to cause hyperoxidation of peroxiredoxins. Urate can accumulate in plasma at levels ranging from 50 to 420 microM in health individuals. When the urate free radical combines with superoxide, it becomes a strong oxidant called urate hydroperoxide.
A study in 2017 showed that urate hyrdoperoxide can cause hyperoxidation of Prx 1 and Prx2. Prx2, which is abundant in plasma, is as sensitive to urate hydroperoxide as hydrogen peroxide.
It is entirely possible that uric acid affects the proper functioning of peroxiredoxins, leading to pathogenesis of disease in ancient humans. The question we need to ask is why. Why did nature fashion the reactions of uric acid to hyperoxidize peroxiredoxins? How do peroxiredoxins affect pathogenesis of atherosclerosis and cancer? The last, but most important question: what role does Ascorbic acid, Vitamin C, play in the regulation of peroxiredoxins? —- To Be Continued —-