REDOX, Disease & Evolution Part 2: Cancer on Clocks

    Are we facing a cancer epidemic?

The International Agency for Research on Cancer estimated that 18.1 million new cancer cases would be diagnosed in 2018 across twenty world regions. Worldwide cancer mortality rate was estimated to reach 9.6 million deaths in 2018. Lung cancer was the most commonly diagnosed cancer in both sexes combined, with lung cancer being the leading cause of death in men (18.4% of total cancer deaths) followed by breast cancer in women (11.6% of total cancer deaths).

In 2016, the Center for Disease Control & Prevention estimated that from 1969 to 2020, the number of deaths from cancer in the USA for men would increase 91.1% and 101.1% for women. Whereas deaths from heart disease would actually DECREASE 21.3% for men and 13.4% for women. These divergent paths between cancer and heart disease seem to indicate that improved medical care, diagnostic tools, and preventive strategies have had a positive impact on heart disease pathology but not in cancer development, despite unrelenting attempts to defeat cancer by doctors, scientists and researchers.

Why has there been such an explosive increase in cancer incidences? Many believe the modern sedentary, indoor lifestyle is to blame. Our food source is adulterated by synthetic carcinogens from chemical fertilizers and pesticides. The soil that nourishes our food source is depleted of essential micronutrients. Most of the air we breathe and the water we drink are contaminated by man-made pollutants. Most of all, the constant exposure to man-made electromagnetic radiation is believed to cause immeasurable damage to all biological systems in most living organisms on earth.

If these assumptions are correct, then if we travel back to prehistoric times where most humans needed to be active in order to survive, and where the soil was replete with micronutrients; food sources were natural and pristine; air and water were free from man-made pollutants, would we still find evidence of cancer?

    Cancer in Antiquity

The earliest evidence for cancer in hominins was found in the remains of the extinct hominin, Australopithecus sediba from Malapa, from 1.98 million years ago. Malapa is part of the famous paleoanthropological site within the Cradle of Humankind, northwest of Johannesburg in South Africa. Scientists believed that the affected individual suffered from a primary osteogenic tumor that affected the right lamina of his sixth thoracic vertebra. The cancer was believed to be chronic and active at the time of his death around the age of 12 to 13 years. Evidence of osteosarcoma was also found in a hominin dating back 1.8 to 1.6 million years ago from the Swartkrans cave at the same paleoanthropological site in South Africa.

In 2018, a study documented six cases of cancer from 1087 mummies buried between 3000 and 1500 BC at the Dakhleh Oasis in Egypt. The authors found evidence of adenocarcinoma of the rectum in one mummy; acute lymphocytic leukemia in a 3–5 year old child; an older female with metastatic carcinoma; and the possibility of uterine, cervix cancer in two other females; and testicular cancer in a male. Six cases out of 1087 mummies examined amounts to an incidence rate of about 0.6%. Whereas the lifetime risk for developing the most common lung cancer based on 2014-2016 data is estimated to be about 6.3% for both men and women. Are you surprised that there was only a ten-fold increase over a period of 3500 to 5000 years?

The Edwin Smith Surgical Papyrus, dated approximately 3,000–2,500 BC, offered the earliest documentation on breast cancer. According to the writings most likely attributable to the Egyptian physician-architect Imhotep, the patient was deemed incurable if the disease was “cool to touch, bulging and spread all over the breast”. The Iliad referenced the classic description of the six stages of breast by Hippocrates circa 400 B.C., where the imbalance of blood, phlegm and bile was believed to be the cause for the disease.

History showed that Greek physicians treated cancer of the skin, mouth, stomach and breast. Hippocrates (460-375 BCE) deemed breast cancer and cervical cancer with bloody discharge as life‐threatening tumors and untreatable. Superficial carcinomas were treated with lotions and cautery whereas deep tumors were usually removed with a knife or left untreated.

Today, many people believe that the modern indoor style of living that is devoid of adequate exposure to nature, including the sun, is one of the major reasons for the explosion in cancer growth rates. Why would the lack of sun be the cause of diseases like cancer? It is possible that the lack of sun disrupts an intricate timing system generally known as circadian rhythm.

    Circadian Clocks & The Sun

Circadian clocks that are responsible for maintaining timekeeping systems can be found in almost all living organisms from bacteria to humans. The circadian rhythms maintained by these clocks can regulate biochemical, physiological and behavioral processes. Mammalian circadian clocks coordinate physiology with environmental cycles through the regulation of daily oscillations of gene expression. The oscillations of clock genes are controlled via a negative feedback loop, where a gene like BMAL, PER, or CRY can suppress its own transcription during a rhythmic cycle.

For most living organisms on earth, this rhythmic cycle spans a period of about 24 hours. The ability to anticipate and adapt to changing environmental conditions like day and night, enhances efficiency and survival of organisms. Light cues from the sun has been responsible for the entrainment of circadian clocks in most living organisms. It is therefore not surprising that the disruption of circadian clocks is associated not only with cancer pathology, but many other health conditions including cardiovascular disease, Type 2 diabetes, Metabolic Syndrome and its main comorbidities including sleep disturbances, depression, steatohepatitis and cognitive dysfunction.

Sunlight is critical for ensuring the proper functioning of circadian clocks in humans. Yet scientists and researchers have shown convincing evidence that UV radiation from the sun can cause skin cancer, including the deadly melanoma. UV radiation was officially identified as a human carcinogen by the National Toxicology Program of the US Department of Health and Human Services in 2018.

Reports from more than two decades ago in 1996, showed that 90% of nonmelanoma skin cancers were associated with exposure to UV radiation from the sun. The diagnosis and treatment of nonmelanoma skin cancers in the U.S.A increased by 77% between 1994 and 2014. In the U.S.A. it is estimated that the number of new melanoma cases diagnosed in 2019 will increase by 7.7%. A paper published in 2011 showed that 86% of melanoma cases diagnosed in the United Kingdom in 2010 could be attributed to UV radiation from the sun. Melanoma is a form of skin cancer that is highly malignant and aggressive because it is able to metastasize at a very early disease stage.

Many believe that skin cancer, including melanoma, is caused not by UV radiation from the sun, but the improper use of sunscreens, and increased exposure to man-made electromagnetic radiation (EMR), including mobile phones, and light at night which can severely disrupt circadian rhythms. If this assumption is correct, then there should be a lack of evidence in skin cancers in antiquity, since most humans would lead lives entrained to the rise and fall of the sun, devoid of man-made EMR and sunscreens.

    Melanoma in Antiquity

The Greek roots of the word Melanoma are ‘melas’ (dark) and ‘oma’ (tumor). The earliest records of the word appeared in the writings of Hippocrates in the 5th century B.C. and later in the works by Greek physician Rufus of Eupheses (80 – 150 CE). The earliest physical evidence of melanoma were found in Pre-Colombian mummies who lived about 2,400 years ago in Chancay and Chingas in Peru. Egyptian mummies from the Dynastic period (3100 BC – 2686 BC) have also been identified with basal cell nevus syndrome, a genetic disorder presented as basal cell carcinoma, a type of skin cancer. Other mummies from Egypt and Peru have been found with histiocytoma, squamous papilloma, and possible malignant melanomas.

In European medical literature recorded between the years of 1650 -1760, numerous descriptions referred to melanoma as the ‘fatal black tumors with metastases and black fluid in the body’. The first documented surgical removal of a melanoma tumor was performed in Scotland in 1787 by the surgeon John Hunter. This tumor was preserved, and later diagnosed as melanoma in 1968. The specimen has been exhibited at the Hunterian Museum in London, UK. In 1858, Olivier Pemberton, a physician in London, documented precise clinical details and sites of metastases of 60 different melanoma cases.

In 1956, a mathematician from Australia, Henry Lancaster, was the first scientist to make the connection between melanoma and ultraviolet radiation from the sun. He noticed that the risk of melanoma development was directly associated with latitude or the intensity of sunlight. Lancaster also observed that the risk for developing melanoma was elevated in those of English/Celtic ancestry who have pale skin and a poor tanning response.

Why would sunlight, the driver behind the rhythm of life in all living organisms cause pathologies like skin cancer? Why would humans in antiquity with an active outdoor lifestyle, eating a diverse range of natural unadulterated foods, living in different geographical areas show signs of atherosclerosis? Isn’t the maintenance of a robust, well-functioning circadian rhythm key to good health? There were no man-made EMR, LED light at night to disturb circadian rhythm that could have caused cancer and/or atherosclerosis. What are we missing here?

    PEROXIREDOXINS, Your REDOX Circadian System

Circadian rhythms exist in almost all living organisms on earth. These self-sustained rhythmic cycles are approximately 24 hours in length because they are entrained to the 24-hour period of daily light and dark cycles. Most higher organisms use light-sensitive photoreceptors to entrain and regulate circadian systems. This also means that organisms that live in complete darkness may not have circadian clocks. The Mexican bind cavefish (Astyanax mexicanus) is the perfect example. This blind cavefish also known as Tetra, exhibits no circadian rhythm, and have not been identified with the presence of any circadian clocks.

Yet simple organisms like cyanobacteria or yeast, all demonstrate robust circadian functions, despite NOT having any light-sensitive photoreceptors. How do these simple organisms keep time if they cannot entrain light and dark cycles taken as cues from the presence and absence of light?

In the past several years, science has discovered an ‘alternate’ counterpart to the extensively studied transcriptional circadian system. This ‘alternate’ system is a family of proteins known as peroxiredoxins (PRDX) that scientists estimate to date back as far as 2.45 billion years ago at the dawn of the Great Oxygenation Event; or perhaps even further beyond to the time when the cyanobacteria first appeared about 3 billion years ago. Scientists now believe that this ancient system may actually pre-date most of the transcriptional circadian clocks genes in higher living organisms.

Peroxiredoxins (PRDX) were first discovered in 1989. Its enzymatic processes were definitively identified only in 2000. Remarkably, PRDX is conserved in all phyla – from archaea to prokaryotes like cyanobacteria, and all eukaryotes from plants to animals. The most exciting aspect of PRDX is that science recently discovered that peroxiredoxins are governed by the REDOX status of the organism. When PRDX is either oxidized or reduced, they generate oscillations that are COUPLED to the transcriptional circadian clock system. This is how simple organisms without light-sensitive photoreceptors entrain their circadian rhythms.

    PEROXIREDOXIN, REDOX Sensors of Light

Peroxiredoxins are transcript-independent circadian clocks. The regulation of their oscillations are determined by the REDOX status of the organism. The rhythm of their oxidation and reduction have been demonstrated to persist even in the absence of transcriptional circadian clock mechanisms (via mutation or pharmacological abrogation). Since peroxiredoxins may actually be more ancient than transcriptional circadian clocks, it is not surprising that the time-keeping mechanisms in peroxiredoxins were able to continue uninterrupted in mice, bacteria and fungi even when their circadian gene expression feedback loops were mutated.

The peroxiredoxin circadian system in the world’s smallest free-living eukaryote, Ostreococcus tauri, has been observed to maintain robust rhythmic cycles even when the bacteria were transferred into total darkness. The absence of light in these phototrophic unicellular organisms caused the termination of circadian gene transcription, but their REDOX based circadian clocks, peroxiredoxins remained persistent and active, maintaining biological time for the O. tauri kept in total darkness.

    How do peroxiredoxins keep time?

The simple yeast lacks photoreceptors, yet it is able to exhibit circadian transcriptional response when it is exposed to blue light. Yeast and all other simple organisms without photoreceptors maintain accurate time-keeping systems by relying on peroxiredoxins to translate light signals from reactive oxygen species like hydrogen peroxide that are generated by blue light.

Peroxiredoxins can reduce hydrogen peroxide (H2O2) to water. The subsequent cycle involves the regeneration of the enzyme by a reducing equivalent such as NADPH. This cycle of reduction and oxidation of peroxiredoxins is the basis of circadian rhythm in the REDOX state, and this system is tightly coupled to the transcriptional circadian clock system.

Recently, science has discovered that perturbations of the peroxiredoxin REDOX circadian system are associated with the development of cancer, inflammatory diseases, insulin secretion, insulin resistance, hyperglycemia, Type 2 diabetes, neurodegeneration, cataracts, infertility, and of course, atherosclerosis, to name just a few.

The influence of peroxiredoxins on cancer has been a major focus of scientists and researchers recently. The role of peroxiredoxin in cancer is extremely complex, as it is able to suppress or promote tumorigenesis. Once we understand how REDOX truly affects our health, the fact that ancient mummies were found with evidence of cancer and atherosclerosis is no longer an anomaly. Yet the question remains: Why would early humans have perturbed REDOX circadian rhythms?

The answer is again, quite simple. The key is what happened to hominids and hominins during evolution as explained in detail in my article, “Uric Acid & Vitamin C: Devolution of Evolution in a 5G World”.

    How much do you know about Peroxiredoxin, Vitamin C and Uric Acid?

Vitamin C and Uric Acid play critical roles in the modulation of peroxiredoxin oscillations in the past and present. Perhaps even more so in our 5G world because of increased oxidative stress induced by electromagnetic radiation. How peroxiredoxins oscillations affect our health and the understanding of the relevance of perturbations in our REDOX circadian system makes all the difference in whether one can attain optimal health in today’s 5G world. – To Be Continued –

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