Astaxanthin, Mitochondria, Oxidative Radicals and the Interacting Variables in our Nutrition, Health and Disease

By John Carberry

In many corridors of scientific leadership in scholarship and research many diseases are being traced to the roles of oxidation associated with the mitochondria and long-term mitochondrial decline. These are becoming a leading and even dominating theme.

While there are things, we can do to mitigate the amount of ROS the mitochondria generate, there is no way to eliminate this production, only we can use anti-oxidants to do this task.

Much is made of the antioxidant powers of COQ10, taurine, selenium and arachidonic acid and CBD. But the fact is they have special, discrete and necessary functions that oxidation precludes and limits. For instance, if COQ10 is burned up in the mitochondria as an antioxidant, then the mitochondrial production of ROS increases and less energy is created.

A highly bioavailable astaxanthin had been a key component in our evolutionary diet for many millions of years which mitigated the larger part of these dangers. About 10,000 years ago we industrialized food production and removed most all the bioavailable astaxanthin from our diet.

Astaxanthin is the most powerful and natural antioxidant in our evolutionary diet. It is probably a necessary ingredient in our diet to optimize healthy and healthful function. With an ORAC value of 2.9 million units, compared to 3000 for COQ 10, and with a molecular structure that lends a strong presence in the membranes of the cell and mitochondria it is likely that it was always a factor in controlling the unavoidable excess of oxygen radicals created by the mitochondria in using sugar and glucose on COQ10 to convert adenosine di phosphate to adenosine tri phosphate.

We will show how the mitochondria make ROS and cannot avoid doing so, and how, uncontrolled or mitigated, it is a primal candidate for many or our diseases.

We will describe in detail the mitochondrial functions,

The role and activity of astaxanthin, and how our nano emulsified astaxanthin, Adjuvia, presents a revolutionary solution to these problems and challenges.

How the mitochondria makes Reactive Oxidative Species (ROS) and where and how bioavailable astaxanthin resides.

We will explore much of the current peer reviewed leadership connecting oxidation and mitigation of mitochondrial expression with aging, diminished cognitive function and many diseases.

We will explore the role and function and history of the mitochondria

We will review work done with astaxanthin and justification for its benefits

We will conclude that a health diet for all should include a daily intake of 12 mg of highly bioavailable 3S, 3’S astaxanthin as well as a few grams of vitamin C. (The vitamin C is water loving and does not easily get through the cell plasma membrane. The astaxanthin likes the hydrophobic neighborhood of the cell plasma membrane, rich in lipids. But when an ROS shows up, the astaxanthin shakes hands with the vitamin C at the outer membrane and the Vitamin C goes to the liver and has it removed from our bodies.)

While my brain is 2% of my body mass it uses 20% of the oxygen and 20% of the calories and about 15-20% of my cardiac resources. So if there is a place where we would expect to find evidence of disease caused by oxidative decay in the mitochondria, it would be the brain!

How the mitochondria generates Reactive Oxidative Species (ROS) and where and how bioavailable astaxanthin resides.

In his review Article How mitochondria produce reactive oxygen species Michael P. Murphy (Biochem. J. (2009)417,1–13(Printed in Great Britain) doi:10.1042/BJ20081386) summarizes his review:

The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signaling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The ﬂux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria resultant in signiﬁcantO2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high p (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix.

He introduces his review:

Mitochondria are an important source of ROS (reactive oxygen species) within most mammalian cells [1–8]. This ROS production contributes to mitochondrial damage in a range of pathologies and is also important in redox signaling from the organelle to the rest of the cell [3,9]. Consequently, knowledge of how mitochondria produce ROS is vital to understand a range of currently important biomedical topics (Figure 1). The first report that the respiratory chain produced ROS came in 1966 [10], followed by the pioneering work of Chance and colleagues who showed that isolated mitochondria produce H₂O₂[4,11,12]. Later, it was confirmed that this H₂O₂arose from the dismutation of superoxide (O₂^•−) generated within mitochondria [13,14]. The parallel discovery that mitochondria contain their own SOD (superoxide dismutase), MnSOD, confirmed the biological significance of mitochondrial O₂^•−production [15]. Since then, a huge literature has developed on the sources and consequences of mitochondrial ROS production…

Dr. Murphy describes this process graphically:

Figure 1 overview of mitochondrial ROS production

ROS production by mitochondria can lead to oxidative damage to mitochondrial proteins, membranes and DNA, impairing the ability of mitochondria to synthesize ATP and to carry out their wide range of metabolic functions, including the tricarboxylic acid cycle, fatty acid oxidation, the urea cycle, amino acid metabolism, haem synthesis and FeS centre assembly that are central to the normal operation of most cells. Mitochondrial oxidative damage can also increase the tendency of mitochondria to release intermembrane space proteins such as cytochrome c (cyt c) to the cytosol by mitochondrial outer membrane permeabilization (MOMP) and thereby activate the cell’s apoptotic machinery. In addition, mitochondrial ROS production leads to induction of the mitochondrial permeability transition pore (PTP), which renders the inner membrane permeable to small molecules in situations such as ischaemia/reperfusion injury. Consequently, it is unsurprising that mitochondrial oxidative damage contributes to a wide range of pathologies. In addition, mitochondrial ROS may act as a modulatable redox signal, reversibly affecting the activity of a range of functions in the mitochondria, cytosol and nucleus.

The Mitochondria’s production of ROS cause harm in several ways:

ROS consume COQ 10, which reduces Adenosine Tri Phosphate production (ATP)
This reduces available energy
This also increases production of ROS in a kind of cascade
The ROS damages the mitochondria in several ways, causing long term diminishment of capacity and function;
The ROS migrate out of the mitochondria and interfere with essential molecular biological functions and damage cellular and endocrinal structures and functions.

The mitochondria is understood to be evolutionary descendants of the first form of life on earth, the Archaea, which lived on earth from about 3.9 billion years ago. In the great oxidative event, about 2.5 billion years ago, the archaea, who abhor oxygen retreated to places which had little oxygen, salt, acidity and often heat. Through endosymbiosis some of these archaea found refuge in cellular structures containing a cell membrane, a nucleus and a need for an energy source.

The process of making adenosine tri phosphate (ATP) from adenosine di phosphate (ADP) involves breaking an O₂ molecule in half, which is best done two ATP from two ADP at a time. There is a normal yield loss, about 10% but if there is not enough COQ10, then there will be too much fuel, not enough ADP/ATP conversions and too many ROS.

In his review, Astaxanthin, Cell Membrane Nutrient with Diverse Clinical Benefits and Anti-Aging Potential Parris M. Kidd, PhD Cell biology; University of California, Berkeley; contributing editor, Alternative Medicine Review; health educator (Alternative Medicine Review Volume 16, Number 4) writes:

Effect on Mitochondrial Function The mitochondria have double membranes crammed with catalytic proteins that utilize oxygen to generate energy;16 however, a small proportion of this oxygen escapes catalytic control and is transformed into electronically excited reactive oxygen species (ROS). Some of these are neutralized by the antioxidant defenses, but others evade neutralization and pose a threat to the mitochondrial membranes.49 Mitochondrial decline due to cumulative ROS damage has been suggested as contributing to the aging process.50 In a series of experiments with various cultured cell lines,3 astaxanthin improved cell survival under oxidative stress (from the addition of antimycin A, which increases mitochondrial ROS generation). By adding an oxidant-sensitive molecular probe into the mitochondria, the researchers found that astaxanthin reduced the mitochondria’s endogenous production of oxygen radicals and protected the mitochondria against a decline of membrane function that typically occurs over time in these cultures. Astaxanthin’s positive activity went even further; it increased mitochondrial activity in these cells by increasing oxygen consumption without increasing generation of ROS. The researchers then inserted into the mitochondria another molecular probe that measured their reducing or redox activity, which mirrors their capacity to conserve glutathione and re-reduce oxidized biomolecules.3 The mitochondria were then challenged with hydrogen peroxide (H2O2), an ROS that should normally oxidize and reverse this redox state. Astaxanthin was found to protect against the H2O2 oxidant effect. The concentrations of astaxanthin required for these in vitro effects (100-800 nM/L) are achievable in humans by dietary supplementation.30,51 Its capacities both to protect mitochondria and to boost their energy efficiency should stimulate further research into this nutrient’s potential for possible anti-aging effects.

Several investigators reveal that as much as 50% of bioavailable astaxanthin takes residence in the mitochondrial membranes. (Park JS et al. (2010) Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans. Nutrition & Metabolism 7:18)

It is noteworthy that the length of the astaxanthin molecule is about 30 nm, which is the approximate thickness of our cellular and mitochondrial membranes, allowing the astaxanthin molecule to put its hydrophobic backbones in the hydrophobic lipid inner membrane and hang the hydroxl and esther groups on the rings on either end at the other side of the cell plasma membranes, therefor acting as a barrier and agent of denaturing of ROS.

Chapter 2: We will explore much of the current peer reviewed leadership connecting oxidation and mitigation of mitochondrial expression with aging, diminished cognitive function and many diseases.

In recent years a growing body of peer reviewed literature has established that long term, or in some cases periodic, oxidative stress rising from the mitochondria are the major etiology (cause or source of a disease) of many diseases. Our goal here is to establish that mitochondria are the source of ROS, that ROS cause long term aging and many diseases, and that we have a solution in highly bioavailable astaxanthin. So here we review some of this literature:

Autism and Oxidative Stress in the Mitochondria:

From the following publications we can conclude there is a strong case made that mitochondrial decline and stress is related to ASD:

In their article Mitochondrial dysfunction in autism Legido A, Jethva R, and Goldenthal MJ (Semin Pediatr Neurol. 2013 Sep;20(3):163-75. doi: 10.1016/j.spen.2013.10.008. Epub 2013 Oct 29.) summarize their findings as follows:

Using data of the current prevalence of autism as 200:10,000 and a 1:2000 incidence of definite mitochondrial (mt) disease, if there was no linkage of autism spectrum disorder (ASD) and mt disease, it would be expected that 1 in 110 subjects with mt disease would have ASD and 1 in 2000 individuals with ASD would have mt disease. The co-occurrence of autism and mt disease is much higher than these figures, suggesting a possible pathogenetic relationship. Such hypothesis was initially suggested by the presence of biochemical markers of abnormal mt metabolic function in patients with ASD, including elevation of lactate, pyruvate, or alanine levels in blood, cerebrospinal fluid, or brain; carnitine level in plasma; and level of organic acids in urine, and by demonstrating impaired mt fatty acid β-oxidation. More recently, mtDNA genetic mutations or deletions or mutations of nuclear genes regulating mt function have been associated with ASD in patients or in neuropathologic studies on the brains of patients with autism. In addition, the presence of dysfunction of the complexes of the mt respiratory chain or electron transport chain, indicating abnormal oxidative phosphorylation, has been reported in patients with ASD and in the autopsy samples of brains. Possible pathogenetic mechanisms linking mt dysfunction and ASD include mt activation of the immune system, abnormal mt Ca(2+) handling, and mt-induced oxidative stress. Genetic and epigenetic regulation of brain development may also be disrupted by mt dysfunction, including mt-induced oxidative stress. The role of the purinergic system linking mt dysfunction and ASD is currently under investigation. In summary, there is genetic and biochemical evidence for a mitochondria (mt) role in the pathogenesis of ASD in a subset of children. To determine the prevalence and type of genetic and biochemical mt defects in ASD, there is a need for further research using the latest genetic technology such as next-generation sequencing, microarrays, bioinformatics, and biochemical assays. Because of the availability of potential therapeutic options for mt disease, successful research results could translate into better treatment and outcome for patients with mt-associated ASD. This requires a high index of suspicion of mt disease in children with autism who are diagnosed early.

In her article Autism and Mitochondrial Function: testing and treatments Suzanne Goh, M.D. Board-certified Pediatric Neurologist Director, Pediatric Neurology Therapeutics of TACA reports:

“One of the most exciting areas of research in autism spectrum disorder (ASD) is in the role of mitochondrial function. Research studies looking at mitochondrial function in those with autism are transforming the way we think about the causes of autism and are pointing to medical therapies that could have a significant impact. This article will address the role of mitochondria in autism and the diagnosis and treatment of mitochondrial dysfunction.

What are mitochondria?

Mitochondria are tiny structures located within nearly all cells of the body. They are the parts of the cell that are primarily responsible for creating energy. They do this by generating adenosine triphosphate (ATP), which is the essential “fuel” that drives all of the body’s functions. For this reason, mitochondria are often described as the “powerhouse” of the cell.

A single cell can have up to several thousands of mitochondria. Cells of the brain and muscle are among those that require a lot of energy, so they have a particularly high density of mitochondria to support their energy needs. When mitochondria aren’t working well, these are often the parts of the body to show signs of poor function.

Symptoms of Mitochondrial Dysfunction

When mitochondria are not functioning well, a wide variety of symptoms can emerge, including:

Developmental delay or regression
Language impairment
Social impairment
Intellectual disability
Neuropsychiatric symptoms (ADHD, anxiety, OCD, depression)
Seizures
Headaches
Hearing impairment
Weakness
Small stature
Fatigue
Gastrointestinal symptoms
Endocrine disturbance
and many others

More and more research now suggest that mitochondrial dysfunction may be important in many different health conditions:

Autism
Bipolar disorder
Schizophrenia
Depression
Diabetes
Parkinson’s disease
Asthma
Chronic fatigue syndrome
Alzheimer’s disease
A variety of gastrointestinal disorders
And others…

Mitochondrial dysfunction and Autism Spectrum Disorder

Research in mitochondrial dysfunction in ASD has grown in recent years, and there are now many research studies linking mitochondrial dysfunction to ASD.

In 2010, a groundbreaking study by researchers at University of California Davis showed that 80% of the children with ASD enrolled in their study had blood tests indicating mitochondrial dysfunction (1).

Other research studies have found

Biochemical evidence of mitochondrial dysfunction in post-mortem brain tissue of children and adults with ASD (2, 3)
Markers of mitochondrial dysfunction on brain MR spectroscopy scans of children and adults with ASD (4)
Mitochondrial and immune abnormalities in children with ASD (5, 6)

The cumulative evidence now suggests that mitochondrial dysfunction is present in a substantial portion of those with ASD and that it may be an important factor that contributes to the symptoms of ASD.

Triggers of mitochondrial dysfunction in ASD

Many different types of triggers can lead to mitochondrial dysfunction, and these may be either genetic or environmental, or a combination of both. Some of the triggers include

gene mutations,
shortages of key vitamins and minerals in the diet,
certain chemicals, heavy metals, and drugs,
certain bacteria and viruses,
stress

Mitochondrial dysfunction, therefore, is a potential explanation for how different types of environmental insults might lead to the symptoms of ASD. One theory is that certain environmental insults may affect those with ASD because they already have an underlying genetic vulnerability that, when combined with an environmental insult, can lead to the symptoms of ASD.”

In their article Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders Drs. Richard E. Frye and Daniel A. Rossignol Department of Pediatrics [R.E.F.], The Children’s Learning Institute, University of Texas Health Science Center at Houston, Houston, TX 77030; International Child Development Resource Center [D.A.R.] (Pediatric Research 2011 May ; 69(5 Pt 2): 41R–47R. doi:10.1203/PDR.0b013e318212f16b.)

“Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder. Over the last decade, evidence has emerged that some children with ASD suffer from undiagnosed co-morbid medical conditions. One of the medical disorders that has been consistently associated with ASD is mitochondrial dysfunction. Individuals with mitochondrial disorders without concomitant ASD manifest dysfunction in multiple high energy organ systems, such as the central nervous, muscular and gastrointestinal systems. Interestingly, these are the identical organ systems affected in a significant number of children with ASD. This finding raises the possibility that mitochondrial dysfunction may be one of the keys that explains the many diverse symptoms observed in some children with ASD. This manuscript will review the importance of mitochondria in human health and disease, the evidence for mitochondrial dysfunction in ASD, the potential role of mitochondrial dysfunction in the co-morbid medical conditions associated with ASD, and how mitochondrial dysfunction can bridge the gap for understanding how these seemingly disparate medical conditions are related. We also review the limitation of this evidence and other possible explanations for these findings. This new understanding of ASD should provide researchers a pathway for understanding the etiopathogenesis of ASD and clinicians the potential to develop medical therapies.”

Mitochondrial Decline and Aging:

In their review Oxidative Stress, Mitochondrial Dysfunction, and Aging HangCui, Yahui Kong,and Hong Zhang conclude:

Aging is a complex process involving a multitude of factors. Many studies have demonstrated that oxidative stress and mitochondrial dysfunction are two important factors contributing to the aging process. The importance of mitochondrial dynamics in aging is illustrated by its association with a growing number of age-associated pathogenesis. (They addressed Aging, Parkinson’s, Alzheimer’s, Huntington’s, Cancer among others)

In his instructional article Mitochondrial Dysfunction, Nutrition and Aging Dr. Ward Dean, In Nutrition Review, presents some startling alarming data:

The first is a graphical portrait of how mitochondrial dysfunction arises.

That it happens is not the subject of much debate, but only recently have we come to understand the degree to which it happens over time in our modern society with our modern diet.

Finally, how it happens in various parts of our brains: Note well that the putamen also plays a role in many degenerative neurological disorders:

Mitochondrial Decline and Alzheimer’s:

In their review article, Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology Paula I. Moreira, Cristina Carvalho, Xiongwei Zhu, Mark A. Smith and George Perry (Biochimica et Biophysica Acta 1802 (2010) 2) conclude:

“Mitochondria have a wide variety of functions, including ATP production and control of energy efficiency, calcium homeostasis, ROS generation, and apoptotic signaling. Being a major intracellular source of ROS, mitochondria are particularly vulnerable to oxidative stress. Extensive literature exists supporting a causative role of mitochondrial dysfunction and oxidative stress in the pathogenesis of AD. Furthermore, a link between mitochondrial dysfunction/oxidative stress and autophagy has been reported to occur in AD.”

They also observe these key points:

“Although the brain represents only 2% of the body weight, it receives 15% of cardiac output and accounts for 20% of total body oxygen consumption. This energy requirement is largely driven by neuronal demand for energy to maintain ion gradients across the plasma membrane that is critical for the generation of action potentials. This intense energy requirement is continuous; even brief periods of oxygen or glucose deprivation result in neuronal death.

Mitochondria are increasingly recognized as subcellular organelles that are essential for generating the energy that fuels normal cellular function while, at the same time, they monitor cellular health in order to make a rapid decision (if necessary) to initiate programmed cell death (Fig. 1). As such, the mitochondria sit at a strategic position in the hierarchy of cellular organelles to continue the healthy life of the cell or to terminate it. Mitochondria are essential for neuronal function because the limited glycolytic capacity of these cells makes them highly dependent on aerobic oxidative phosphorylation (OXPHOS) for their energetic needs. However, OXPHOS is a major source of endogenous toxic free radicals, including hydrogen peroxide (H₂O₂), hydroxyl (HO^U) and superoxide (O⁻₂^U) radicals that are products of normal cellular respiration (Fig. 1).

Fig. 1. Dual role of mitochondria. Besides the fundamental role of mitochondria in the generation of energy (ATP), these organelles are also the main producers of oxygen free radicals. If the defense mechanisms are debilitated these reactive species initiate a cascade of deleterious events within the cell. See text for more detail. ETC, electron transport chain; H₂O₂, hydrogen peroxide; mtDNA, mitochondrial DNA; O⁻₂^U, superoxide anion radical; e^-, electrons; O₂, molecular oxygen.

In their review, Mitochondria, Cognitive Impairment, and Alzheimer’s Disease

M.Mancuso, V.Calsolaro, D.Orsucci, C.Carlesi, A.Choub ,S.Piazza,and G.Siciliano begin and end on this theme: (International Journal of Alzheimer’s Disease Volume 2009, Article ID 951548, 8 pages doi:10.4061/2009/951548)

“To date, the beta amyloid (Aβ) cascade hypothesis remains the main pathogenetic model of Alzheimer’s disease (AD), but its role in the majority of sporadic AD cases is unclear. The “mitochondrial cascade hypothesis” could explain many of the biochemical, genetic, and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress, and accumulation of Aβ, which in a vicious cycle reinforce the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mt DNA haplo groups in AD are controversial. In this review we discuss the role of the mitochondria, and especially of the mtDNA, in the cascade of events leading to neurodegeneration, dementia, and AD.

The etiology of AD is complex, and only a minority of cases appears to be primarily genetic. Changes of the expression of mitochondrial and nuclear genes, encoding parts of cytcoxidase and NADH dehydrogenase enzyme complexes, may contribute to alterations of oxidative metabolism in AD[78].The majority of cybrid studies demonstrated similar morphological and biochemical phenotype between cybrid cells and cerebral tissue in sporadic AD, supporting the hypothesis that mt DNA changes might be involved in the mitochondrial impairment of sporadic AD.”

We would note that the main fundamental cause of this oxidation problem is not genetic. While the population surely has variable genetics with variable sensitivity, this problem is population wide and is primarily a dietary problem. If we have the necessary antioxidants, then we will mitigate this oxidative stress over our lifetimes.

Mitochondrial Decline and Parkinson’s:

In their review of this topic in their article Mitochondrial Biology and Parkinson’s Disease Celine Perier and Miquel Vila (Cold Spring Harb Perspect Med 2012;4:a009332) write:

“Mitochondria are highly dynamic organelles with complex structural features which play several important cellular functions, such as the production of energy by oxidative phosphorylation, the regulation of calcium homeostasis, or the control of programmed cell death (PCD). Given its essential role in neuronal viability, alterations in mitochondrial biology can lead to neuron dysfunction and cell death. Defects in mitochondrial respiration have long been implicated in the etiology and pathogenesis of Parkinson’s disease (PD). However, the role of mitochondria in PD extends well beyond defective respiration and also involves perturbations in mitochondrial dynamics, leading to alterations in mitochondrial morphology, intracellular trafﬁcking, or quality control. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of dopaminergic neurodegeneration in PD.”

In their review, Mitochondrial dysfunction in Parkinson's disease Konstanze F. Winklhofer, and Christian Haass (Biochimica et Biophysica Acta 1802 (2010) 29) conclude:

Recent research on the function and dysfunction of PD-associated genes has provided fundamental new insights into biochemical pathways which are associated with the disease process. Moreover, these findings established that mitochondrial dysfunction is a common denominator of sporadic and familial PD, moving mitochondria to the forefront of PD research. Manifold facets of mitochondrial biology seem to be affected in PD (Fig. 2)

Fig. 2. Mitochondrial alterations associated with PD

Mitochondrial Dysfunction and Cancer:

In their review article Mitochondrial dysfunction in cancer Michelle L. Boland, Aparajita, H. Chourasia and Kay F. Macleod (Boland ML, Chourasia AH and Macleod KF (2013) Mitochondrial

dysfunction in cancer. Front. Oncol. 3:292. doi: 10.3389/fonc.2013.00292 This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology.) open with this abstract:

A mechanistic understanding of how mitochondrial dysfunction contributes to cell growth and tumorigenesis is emerging beyond Warburg as an area of research that is underexplored in terms of its signiﬁcance for clinical management of cancer. Work discussed in this review focuses less on the Warburg effect and more on mitochondria and how dysfunctional mitochondria modulate cell cycle ,gene expression, metabolism, cell viability, and other established aspects of cell growth and stress responses. There is increasing evidence that key oncogenes and tumor suppressors modulate mitochondrial dynamics through important signaling pathways and that mitochondrial mass and function vary between tumors and individuals but the signiﬁcance of these events for cancer are not fully appreciated. We explore the interplay between key molecules involved in mitochondrial ﬁssion and fusion and in apoptosis, as well as in mitophagy, biogenesis, and spatial dynamics of mitochondria and consider how these distinct mechanisms are coordinated in response to physiological stresses such as hypoxia and nutrient deprivation. Importantly, we examine how deregulation of these processes in cancer has knock on effects for cell proliferation and growth. We deﬁne major forms of mitochondrial dysfunction and address the extent to which the functional consequences of such dysfunction can be determined and exploited for cancer diagnosis and treatment.

This review article is very comprehensive, citing 408 references.

Some notes on Oxidative Stress

Our Health and exposure to disease and challenges to our health are in so many ways relating to the unmitigated flow of reactive oxidative species, (ROS) Our evolutionary biology and diet kept us healthy by including in our diet a lot of antioxidants, which mitigate ROS at or near the source. These antioxidants are key and a prerequisite for good health because they prevent the causes of disease and aging that arise from oxidative stress. Free radicals are unavoidable, they rise from the mitochondrial processes fundamental to our making energy. Free radicals are very active, unstable and highly prone to enter destructive reactions all over our biology.

We saw earlier the correlation between the rise of sugar consumption and Type II Diabetes. But this rise in sugar consumption also correlates to oxidative stress. How?

How exactly does sugar accelerate oxidative stress? Oxidation occurs during a number of specific processes. Most all sugar we consume gets oxidized so the more sugar we consume the more oxidation occurs.

As we have studied, the mitochondria is the energy source within our cells. Mitochondria reacts oxygen and glucose (blood sugar) with help from COQ10 to make Adeno Tri Phosphate (ATP) which gives you three active electrons and your energy. The production of a portion of this process as reactive oxidative species (ROS) is a natural and unavoidable byproduct of this process in the mitochondria. So the more glucose, especially excess glucose, the more ROS we make.

In our evolutionary diet we had a diet rich in antioxidants which took up residence in the membranes of our cells and mitochondria and “shunted” this production of dangerous and undesirable ROS. Without this defense in place ROS can and does do a lot of damage.

The liver is our body’s detoxification organ. When it is overwhelmed with a high intake of sugar this leads to inflammation production of more free radicals. The key point here is that oxidative stress rises to toxic and even lethal levels both from what we are not eating and what we are eating. The curve on the increase in annual consumption of sugar to more than 8 ounces per day must certainly be seen as correlating in the past 70 years with much of the rise of our diseases. When you add other modern nutritional starches, which are all sugars, and the elimination of antioxidants from our diet, it is clear we built a disease time bomb which is now exploding.

A quick review showing through the various perspectives of social capital, helpful and some not, temps us to look at the rise of the industrial diet and other factors through some lenses that lead to suspect we have a lead on the causes and a lead on solutions.

Very recent peer reviewed literature has begun to show investigations and reports that articulate the relationship between long term oxidative stress and a number of diseases.

For instance:

Autism. Autism has risen dramatically in the past several decades, just as we ratcheted up the level and intensity and long-term oxidative stress we put on our bodies.

Daniel A. Rossignol and Richard E. Frye published a review in 2014 entitled Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism Frontiers in Physiology 22 April 2014

Given the dramatic rise in the loss of antioxidants and the rise of a high content of oxidizing nutrients, the rise in the incidence, following the understanding of this paper, shows a remarkable closely following correlation:

Alzheimer’s:

We should start by first looking at the trends in the incidence of Alzheimer’s in our society:

These curves looks like all the curves we have been reviewing, a very recent event. And the rise of unmitigated oxidative stress due to the lack of antioxidants in our diet and the presence of very strong oxidizing ingredients in our diet mirrors this curve very closely.

Once again in the peer reviewed literature we find new peer reviewed reports linking the long term oxidative stress caused by our diet. For instance we find some exciting links:

WEN-JUAN HUANG, XIA ZHANG and WEI-WEI CHEN report on the link with oxidative stress and Alzheimer’s in their Review: Role of oxidative stress in Alzheimer's disease (Review) in BIOMEDICAL REPORTS 4: 519-522, 2016

Anchalee Prasansuklab and TewinTencomnao get close to this in their paper Amyloidosis in Alzheimer’s Disease: The Toxicity of Amyloid Beta (A𝛽), Mechanisms of Its Accumulation and Implications of Medicinal Plants for Therapy Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2013, Article ID413808,10pages http://dx.doi.org/10.1155/2013/413808

George Perry, Adam D. Cash, and Mark A. Smith report on similar findings to many others in their early paper Alzheimer Disease and Oxidative Stress Journal of Biomedicine and Biotechnology 2:3 (2002) 120–123 PII. S1110724302203010 http://jbb.hindawi.com

There are countless others in this study, many, many are recent. What they tell you is that we constructed a system of nutrition through and in social capital and it causes these problems and they are self inflected unforced errors and can be corrected. However, the industry of medicine and pharmaceuticals will call it life style medicine. But perhaps the only way to avoid and cure these diseases is by education and modification through social capital. Building trust, building network utility value, enhancing communication and integrating helpful human capital, knowledge.

Parkinson’s Disease:

This disease too has been rising on the same kind of curves:

The cure Parkinson’s Trust (https://www.cureparkinsons.org.uk/oxidative-stress-and-parkinsons) uses valuable space at the front of their website to offer these insights:

“Why is CPT interested in the impact of oxidative stress and inflammation in Parkinson's?

In recent years, there has been some considerable interest in the role of free-radical damage or oxidative stress and how the body responds to inflammation, in the Parkinsonian brain. These 'stressor' factors create an environment in the brain which is not conducive to normal function and signs of oxidative damage have been shown to appear long before brain cells - neurons - actually degenerate in Parkinson's (PD):

Oxidative stress is essentially an imbalance between the production of highly chemically reactive substances in cells and the ability of the body to counteract or detoxify their harmful effects, resulting in cell damage or death.
Inflammation is the body's attempt at self-healing; the aim being to remove harmful substances, including damaged or degenerated cells and begin the healing process. When something harmful affects a part of the body, the biological response to try to remove it results in the signs and symptoms of inflammation.

Strong evidence now exists to support a role for abnormal mitochondrial activity and increased oxidative stress, in the cause, development and effects of PD. A complex interplay occurs between mitochondria and other cellular complexes that affects cell survival, as mitochondria not only have a key role in cell energy production, but they are also the main cellular source of free radicals.

Mitochondrial dysfunction leads to increased oxidative stress. Oxidative damage to lipids, proteins and DNA as well as a decrease in the levels of the important intra-cellular antioxidant glutathione, has been detected in post mortem PD brain tissue. These findings provide a plausible link between oxidative damage and the formation of abnormal aggregates of protein that are characteristic of PD, as oxidative damage, it is thought, induces alpha-synuclein clumping and impairs the proper degradation of the proteins.”

They conclude:

As the major energy and metabolite source in the cell, it stands to reason that mitochondrial function is deregulated in cancer and there is growing interest in understanding how altered mitochondrial function may be targeted to inhibit tumor growth. Emerging data identifies key oncogenes and tumor suppressors as modulators of different aspects of mitochondrial metabolism and dynamics. Interestingly, different tumor types may be more or less sensitive to modulation of mitochondrial function depending on which oncogenic lesions drive that tumor type. This is a new and exciting avenue in the continued “war on cancer.”

Our conclusion at this stage of our studies:

As we age while suffering from excess, uncontrolled and unmitigated production of reactive oxidative stress and species, and as these damage the mtDNA in a growing cumulative effect, we can easily understand the probability that all these diseases will rise as a result.

Our evolutionary biology had astaxanthin in our diet. If we want to be healthy we need to have astaxanthin in our cell membranes and mitochondrial membranes. This is becoming crystal clear. So lets study the theme of astaxanthin and mitochondrial and all the interrelated biological processes.

The Nutrition/Health System crisis is exemplified by the doubling of direct health care costs in the past 20 years from 2 to 4 Trillion USD a year, from 8% to 18% of GDP here in the US. The crisis is caused by several causes and so it constructive to address each of these several topics. In each of the areas where we the addressing the nature and problems of these systems, Nutrition/Health System, Economic System and Utility/Trust System, the goal is to develop a clear understanding of how the system evolved, what we did to it, and what the solution looks like.

So at the end of this part of our book, you should have a clear understanding of what all our health issues are, how they nutritionally became issues, and what you can do to optimize your health and well being.

In the case of Nutrition and health System, it can be addressed successfully by individuals, but it will have to be addressed culturally across entire civilizations if we are to mitigate the unbelievable economic costs failure to address this issue will incur upon our economy. Just as is true for the environment and social trust and utility.

The major theme here is that we have millions of years of biological evolution as our foundation, and we have culturally evolved so very rapidly so very recently, that our cultural evolution is so far ahead of our biological evolution that the gap may be lethal. Virtually all our health problems are self-inflicted by our quick cultural evolution and are correctable. Correcting these things is good for an individual, but for our civilization it may be vital for our survival.

Stephen Jay Gould’s theory of Punctuated Equilibrium is a good place to start.

Evolution: Darwin’s theory of evolution tended to suggest that evolution happened through a continuous and very gradual rate of change.

In 1972, paleontologists Niles Eldredge and Stephen Jay Gould published a paper (Eldredge, Niles and S. J. Gould (1972). "Punctuated equilibria: an alternative to phyletic gradualism" In T.J.M. Schopf, ed., Models in Paleobiology. San Francisco: Freeman Cooper. pp. 82-115. Reprinted in N. Eldredge Time frames. Princeton: Princeton Univ. Press, 1985, pp. 193-223).

Eldredge and Gould in their review and studies found that the degree of gradualism commonly attributed to Charles Darwin was nonexistent in the fossil record. They concluded that stasis dominates the history of most fossil species.

And they developed their theory and called it punctuated equilibria. Their paper built upon Ernst Mayr's model of geographic speciation, I. Michael Lerner's theories of developmental and genetic homeostasis, and their own empirical research.

Nature has evolved to fill niches. Evolution adapts in the division of species over time to fill all the “blank spaces” in our ecology. Eldredge and Gould saw evolution happening very quickly when the blank spaces were increased dramatically by an extinction event.

When an extinction event occurs, the power of the incumbent is lost. For instance, a mutation can happen in the population of a species. And that mutation can offer some marginal advantage. But if the mutation is exceptionally small in members of that population, it can be close to impossible for it to find a separate niche in which to flourish.

When we look at social capital and its rise and dominance in our development, it can also be seen to operate within our evolutionary processes while also coming into severe conflict with our evolutionary beings.

We earlier reviewed the concept of “Evo Devo”. And example of this is the evolution of Northern European peoples. They evolved to be able to digest lactose because they continued after childhood to make the enzyme lactase during the past few thousand years. Most mature adults in the world are lactose intolerant: They cannot digest lactose because they cease to make lactase when mature. But most all the peoples of northern Europe can do so. The theory of Evo Devo is that the folk in Northern Europe had available to them a lot of diary products, and there was an advantage to being able to digest this powerful food. So over time, thousands of years, the evolution of the humans in Northern Europe developed a genetic profile that favored digesting of lactose by the mature production of the enzyme lactase.

This is a very quick and specific evolutionary development and since the gene for making lactase was already present, it was probably not the smallest evolutionary gate to be found.

However, for the most part, once social capital developed the power to evolve culture and what we eat and how we live orders of magnitude faster than our biological evolutionary capacity for development, we find massive dislocations.

For the rest, if the food supply and environment are stable and consistent over time, the animals will be healthy. A good example of this is the ecosystems of the seas and oceans.

An Example of a healthy system when Nutrition is Aligned with Evolution:

The seas and oceans are the largest and oldest ecosystems on earth. Probably more than 3 billion years old. And they cover 71% of the earths surface. Here is the key theme: The literature on the diseases and sicknesses and aliments of animals from the sea kept in captivity are not found for the most part in animals living in the wild. And the difference is mostly nutritional. We virtually never sea a sick animal in the wild. We see evidence of dying of very old age, and we see predation, but not illness or disease.

We really don’t know who long fish in the wild can live if they don’t succumb to predation. At the Sustainable Aquatics Hatcheries, where we have worked to optimize feeds to match the wild, we have many 20 to 35-year-old breeding clown fish, a Bat fish that is 25 years old and very healthy, and 28 year old tang, all looking very healthy. And all far beyond the predicted life expectancy, never mind they still breed regularly. Think of the age that animals can reach in the Seas and Oceans eating their natural evolutional diet:

Icelandic Shark: More than 500 years

Many Rock fish, more than 200 years

Bow Head wale, more than 200 years

Qualog shellfish, more than 400 years

Recent progress in the census of the Euphotic zone of the seas has highlighted some very earlier anticipated insights:

In the sea, more than 95% of the food chain begins with the Euphotic zone. It is 8 times more productive in sequestering carbon and making oxygen than all the life on land: 16 x 10^10th tons of carbon are taken up by the sea’s life each year.

While it was earlier thought that most of the plankton were in the range of 5 to 100 microns, we now know that it is mostly in the range of.5 to 10 microns. This is dominated by phytoplankton in the range of .2 to 20 microns. So it is just recently we came to understand the content and dynamics of the Euphotic zone.

What is the Euphotic zone? It is the zone where light penetrates the surface and it ends by conventional definition where only 1% of that light is still penetrating. It is where 95% of the foodchain productivity in this regard is happening.

But the bulk of the plankton in the euphotic zone ends up being “marine snow”. This settles, much of it to the bottom, where ever that is and however deep it is, where it is probably all processed by bacteria and other organisms and eventually comes up in the upwelling to reenter the food chain.

Zooplankton in the range of 20 to 200 microns feed on these.

The food chain is a bit inverted. The biomass is dominated by higher order animals that live a long time. Plankton have very short life spans and reproduce quickly and prolifically. One of their functions is to create “marine snow” which fertilizes the entire seas and spaces.

The euphotic zones around the world are highly dependent on ocean currents and upwellings, such upwellings bringing up the processed marine snow, largely processed by bacteria and the like.

Given that there are very productive euphotic zones in many places in the seas and oceans, the nutritional profiles are remarkably similar, lots of fatty acids in good ratios, selenium, taurine, astaxanthin, lots of trace mineral and metals. Sea water is about 97.5% water, and about 2.5% salts, with the remainder being metals and chemicals such as magnesium. However, over time a wide range of substances, metals, trace minerals, even amino acids have built up in the dissolved organics in the sea, some of which is in the marine snow, some in the plankton and some in the animals in the food chain. This is where taurine and selenium, among others, are maintained in the food chain in the sea

So, this system has been very stable for a long time, billions of years. And the animals in this ecosystem have been evolving within the food chain of this system that entire time. Most evolution results in failure. Those evolutionary developments which are successful give that organism an advantage in some niche. Other than the plankton, most animals in the seas and oceans are very inefficient at producing reproductive offspring.

Actually, that are very bad at doing this. When the reproductive replacement level for a bowhead whale or an Icelandic Shark is stable, they would replace themselves reproductively every 200 and 500 years respectively.

So, the ability to sustain the species requires the ability to live a long time and reproduce consistently over that long time to get some offspring through the predatory gauntlet to reproduction. Having an internal ecosystem that is well aligned with the environmental ecosystem to enable a healthy and long and reproductively productive life is key to survival and success of the species. And in fact, that is what we find in the sea. But not today in humanity.

So, we should take it from this model that if we follow the evolutionary model for nutrition we should be healthy, and from this that most all our health problems are nutritional.

Connecting Nutrition and Health and disease to our environmental Cultural and Biological Development

History

We have seen how a stable and well tuned diet can result in many species living healthy, long disease free reproductively productive lives. What can we learn from this?

After the long-term evolution of hominids, over many millions of years, the short-term cultural evolution of Homo sapiens, which saw the rise of social capital and the agricultural and industrial revolutions in the production of food, has diverted humans from the diet necessary to optimize health and avoid disease. Our short-term cultural evolution has been driven by exceptionally rapid change in our food technology and diet through our social capital which has powerfully conflicted with the very deeply entrenched biology of our long-term evolution. We have far exceeded the possible pace of our biological evolutionary development.

It is through the rise of social capital, starting mostly about 50,000 years ago and culminating in a great rise in technology concerning agricultural food production of domesticated plants and animals about 8,000 years ago, that we dramatically changed our diet and impacted our health. It is this change and the impact of this change that this section will examine. In separate sections we will examine the nature of this evolution and development of social capital and how it did this.

Our purpose is to introduce and describe fundamental nutritional requirements specific to Homo sapiens, requirements for humans to be healthy and avoid many of the diseases and maladies that plague us today but did not in our evolutionary history before the agricultural production of food.

Understanding this story is enabled by the tremendous growth of knowledge and insights that have developed during the past few decades about our biology, our evolution, our history. Understanding these many interacting variables in these regards and how they impact our health is a pathway to eliminating many problems and achieving a much healthier life. What we have learned in these regards in the last 50 years could easily be 99% of what we know today.

The solution to most all our long-term health problems can be found in a relatively simple understanding of the evolution of our diet over millions of years. We dramatically changed our diet about 10,000 years ago when we began to produce food through agriculture. As a result of agricultural food production, we removed thousands of complex foods we had evolved to eat over millions of years and replaced most of them with foods we had never eaten before. We completely changed the nature of human nutrition from what we had been eating for millions of years.

These rapid changes in our nutritional profile have had dramatic impacts on our health. We now believe that some simple dietary supplements taken over a life time can eradicate most all of such diseases as cancer, autism, Alzheimer’s, Parkinson’s, many forms of arthritis, dementia, even many forms of diabetes, stress, sleep disorders and others.

We also have learned that modern hunter-gatherer groups who never suffer from these diseases on their hunter gatherer diet, acquire all these diseases in a single generation when they convert to a modern diet produced by agriculture.

It will be demonstrated that the elimination of a short list of foods, and the supplementation with some highly bioavailability antioxidants and precursors for basic biological regulatory molecules can deliver these benefits.

The approach to understanding the molecular chemistry and biology and molecular processes underlying this understanding has been advancing very quickly in recent years. But the story can be told first in an easy to understand historical narrative. The solutions we need to discover, and implement may not be so obvious without understanding the detailed, profound and complex context of these biological processes, their evolution and the nature of the evolutionary history of our diet and our modern agricultural diet.

A nano emulsion of one of nature’s most powerful antioxidants becomes very powerfully bio-available despite its tendency to encyst and follow a hydrophobic behavior and not enter the blood stream and find residence in the cell plasma membrane and the mitochondria. Nature provides in the natural diet a steady stream of hydrophobic nano, mico and macro nutrients. But the industrial preparation often needs a lot of help.

From an evolutionary point of view, we removed from our food chain a very large set of foods which have a powerful antioxidant power in our biology, we replaced them with foods which have a powerful oxidizing effect on our biology. The result is much of our disease and aliments and sickness.

For the most part it is all avoidable.

The biology of our evolution:

Every good invention starts with a problem and the definition of the problem which is often the largest contributor towards a solution. In this case the context of the problem definition requires a deep and profound understanding of evolutionary biology and molecular biology and chemistry and biological processes. Understanding and believing are necessary for efficacy so this story is part of the justification for the invention.

We can start with a simpler and easier to understand approach to introduce the context of the science: Evolutionary history. In this way this part of the paper will be written in the style of a newspaper article, getting as much introduced early so that maximum benefit and knowledge is derived in the first paragraphs and pages. This understanding is made possible by understanding the long and short evolutionary pathways we humans have traveled. In Part two we will look at the values, foods and context of these factors in health and science.

I will do Part 1 in bullets:

Life has evolved on Earth for about 4 billion years. The timeline map can be thus described:
This diagram gives a different nonlinear picture
So Archaeans are an ancient form of life, probably the most ancient. Fossils of archaean cells in stromatolites have been dated to almost 3.5 billion years ago, and the remains of lipids that may be either archaean or eukaryotic have been detected in shales dating from 2.7 billion years ago.
Hominids evolved over a period of about 6 million years on a diet rich in antioxidants, with a fair amount of fat and protein, and virtually no sugars or refined carbohydrates.
You might ask how we know this! Well, phylogenetics is a tool where we can do regressive analysis of change and rate of change to find the point of divergence in the evolutionary story. So humans have 23 chromosomes and the chimpanzees have 24 chromosomes. If we have a common ancestor, we should be able to find diversity like this and track it back to a point of divergence. The human chromosome number 2 has been understood in the last 15 years to be the result of the head-to-head fusion of two ancestral chromosomes that remain separate in other hominids, which is why we have 23 and other hominids have 24 chromosomes. There are three observations of this chromosome that show evidence of this. The ends of a chromosome are called telomeres and there are normally one at each end. Chromosome 2 has four telomere sequences one at both ends but also two joined in the middle. Then there is the fact that a chromosome normally has one centromere, but the number two chromosome has a second inactive centromere on one side between one of the pairs of telomeres. Finally, the human chromosome 2’s two halves closely matches that of two separate chromosomes found in primates. This particular regression analysis indicates a common ancestor about 6 million years ago.
However, Chatterjee et all in their article Estimating the phylogeny and divergence times of primates using a super matrix approach conclude as to primate divergence that: “Key splits including: Strepsirrhini-Haplorrhini 64 million years ago (MYA), Lemuriformes-Lorisiformes 52 MYA, Platyrrhini-Catarrhini 43 MYA and Cercopithecoidea-Homino idea 29 MYA.”
So we can observe we were hunter gatherers for at least 6 million years and probably much longer.
Life has evolved on earth for about 3.9 billion years.
The first form of life was the Archaea, cells that resemble bacteria, have no nucleus, and evolved on earth during a time when there was very little oxygen, and lots of carbon dioxide and methane. They grow poorly in the presence of oxygen.
The atmosphere of earth was rich in methane and carbon dioxide, and very warm and acidic between 3 and 4 billion years ago. About three billion years ago the atmosphere grew rich in oxygen and nitrogen and waters began collecting in the seas. This was not a great environment for the Archaea.
We believe that Archaea over time evolved in three ways as waters formed up on earth and the atmosphere became oxygen rich:
Some of the took refuge in exotic places, where the temperatures were high, where salinity was very high, places with high acidity, and places where all these conditions were present such as the vents at the bottom of the oceans.
Some evolved into bacteria, which are prokaryotes, cells without a nucleus or organelles.
Some evolved through what is called endosymbiosis and became organelles such as mitochondria. Mitochondria supply most of our energy and use about 90% of the oxygen we process in our bodies. And they make what are called reactive oxidative species, ROS.
About three billion years ago bacteria emerged and started to evolve parallel to the archaea, but also in some regards they joined together in co-evolution, or evolution by endosymbiosis.
About a billion years ago Eukarya emerged. These are life forms with cells including nuclei and organelles. This is where it gets interesting. We believe that mitochondria evolved through endosymbiosis and were Archaea. And that they evolved on earth sometimes independently but also co-evolved with Eukarya.
Eukaryotes are life forms whose cells have a nucleus enclosed within membranes. For instance, the cell plasma membranes composed mostly of phospholipids but containing many other important constituents. Eukaryotes are unlike bacteria and archaea which have no organelles within their membrane cell structure. Eukaryotic cells contain other membrane contained organelles. Some organelle examples are mitochondria and chloroplasts. Animals and plants are all eukaryotes.
Mitochondria make our energy, consume 90% of the oxygen we take in and can make enormous quantities of ROS, and the stream of oxidative species they make are one of two oxidative pathways in our biology. The oxidative pathway of the mitochondria if not mitigated is very destructive.
The Archaea comprise a group of single-celled microorganisms that, like bacteria, are prokaryotes that have no cell nucleus or any other organelles within their cells. So for a long time they were considered to be an unusual group of bacteria and named archaebacteria. The key point here is that until recently we did not understand much at all about this important topic in understanding our own biology.
After years in obscurity and suffering some professional disrespect and dismissal, Carl Woese became famous starting in 1977 for identifying the Archaea as a separate and perhaps originating domain of life. He used phylogenetic taxonomy of 16S ribosomal RNA, a technique he pioneered and which revolutionized the discipline of microbiology. By looking at the change in the evolutionary map, the rate of change indicated to him points of evolutionary divergence. He introduced the three main branches of evolutionary descent as the Archaea, Eukaryota and Bacteria. So now they are classified as a distinctly separate domain in the three-domain system. We understand now that Archaeans have an independent evolutionary history and have numerous differences in their biochemistry.
So Archaeans are an ancient form of life, probably the most ancient. Fossils of archaean cells in stromatolites have been dated to almost 3.5 billion years ago, and the remains of lipids that may be either archaean or eukaryotic have been detected in shales dating from 2.7 billion years ago.

http://www.fossilmuseum.net/Paleobiology/Paleobiologysegues/chemotrophs/Grand_prismatic_spring.jpg
Ancient records and fossils of prokaryotes do not have distinct morphologies, so the shapes of fossils cannot be used to identify them as Archaea. Here is where phylogenetic profiles and models are used on chemical fossils, in the form of the unique lipids found in archaeans dating back to the Archaean. The oldest known traces of these isoprene lipids have been found in Greenland, which include sediments formed 3.8 billion years old and are the oldest on Earth.
The Theory of Endosymbiosis proposes that parts of Eukaryotic life evolved from the Archaea. That is, the theory explains that organelles such as mitochondria and chloroplasts in eukaryotic cells evolved from certain types of bacteria that prokaryotic cells engulfed through endophagocytosis. These cells and the bacteria trapped inside subsequently evolved a symbiotic relationship. In this endosymbiotic relationship, the bacteria lived within the other prokaryotic cells
Our evolutionary diet, from six million and much longer ago, till about 8000 years ago when we industrialized the foods we consume, was very rich in foods with very high Oxygen Radical Absorbance Capacity (ORAC). The addendum to this paper has a list of many of these foods and their ORAC values.
Many of these antioxidants take up residence in the cell plasma membrane and the mitochondria themselves where they strongly mitigate the destructive pathway of ROS originating from the mitochondria.
The other oxidative pathways include the eicosanoid system, which is a basic regulatory system in most organisms. Half of the regulation is by oxidation, the other half by antioxidation. Inflammation and anti-inflammation. Eicosanoids are made and used instantly where and when and as needed. There can be an eicosanoid storm simultaneously impacting every cell in an organism, or signals directed at one cell at a time.
All of the eicosanoids are formed with a fatty acid and arachidonic acid. Eicosanoids have 20 carbons, and arachidonic has 20 carbons just as the eicosanoids do. Arachidonic acid is C₂₀H₃₂O₂
Half of the eicosanoids are made from omega III and half from omega VI fatty acids. One of the most important Omega III fatty acids is Docosahexaenoic acid, (DHA) which is C₂₂H₃₂O₂.
An overview of astaxanthin, CBD and the eicosanoids follows this narrative:

Pathways in biosynthesis of eicosanoids from arachidonic acid: there are parallel paths from EPA & DGLA: https://en.wikipedia.org/wiki/Eicosanoid

This is the other oxidative pathway, and it is very vulnerable to excess oxidative stress. A strong flow of ROS from the mitochondria unmitigated by resident antioxidants such as astaxanthin will result in such a compromise of the eicosanoid regulatory functions that all those diseases will rise up over time and result in death and destruction, literally.

During the past decade, the peer reviewed literature has concluded that long term oxidative stress is a key event in the etiology of most the diseases such as cancer, autism, Alzheimer’s, Parkinson’s, many forms of arthritis, dementia, even many forms of diabetes, stress, sleep disorders and others.

Studies on hunter gatherers, such as the aboriginal populations and many others have shown the rise on these diseases only after they adopted our modern agriculturally produced foods.

During only the past twenty years or so, much of the fundamental research in seeking to understand the etiology (etiology is a fancy way of saying the cause of) of many specific diseases has come to understand that it is almost always oxidation. For instance:

We study here how the process in the mitochondria of making energy through the production of adeno tri phosphate creates a stead flow of reactive oxidative species, and that these do particular harm in three ways:

They consume COQ10 which should not be shunted as an antioxidant, but used to make ATP.
They damage the RNA and DNA by damaging the histone layer
They migrate to the cell plasma membrane where they interfere with essential cellular processes such as making arachidonic acids and the things made with arachidonic acids including many peptides, eicosanoids and others.

We now are beginning to understand that most all progression of disease and aging correlates to diminution of mitochondrial expression due to this oxidative stress and damage;

While COQ10 can be an antioxidant, with an ORAC value of about 3500, it is essential in the mitochondrial process of making Adeno Tri Phosphate (ATP). CoQ10, or CoenzymeQ10, already exists within your body, largely and most essentially in the mitochondrial membranes of your cells. It is part of the process of producing ATP. Which is the source of most all biological energy.

The most powerful anti oxidant, which was clearly in our evolutionary diet, is astaxanthin, which has an ORAC value of 2.8 million and very much takes up residence in both membranes of the mitochondria and the cell plasma membrane.

So, the key to long term health is avoiding a small list of foods, creating a strong eicosanoid system by having the precursors in the right abundance and ratios and protecting the system from the ROS stream from the mitochondria by resident antioxidants such as bioavailable astaxanthin.

What this story tells us can be summarized as follows:

We evolved with an energy generation system based on the assimilation by endosymbiosis of ancient life form called Archaea, which became our energy generating mitochondria. Mitochondria do generate very large, powerful and destructive oxidative stream which do damage on their own, but also interfere with the oxidation stream involving other processes which are regulating and healing and involved in all our metabolic processes.

Our evolutionary diet included foods which exposed us to an abundance of molecules which mitigated the destructive oxidative pathway rising from the mitochondria. And which also formed precursors for the other regulatory pathways and processes.

About 8000 years ago we domesticated our food production, removed most all the original foods which helped control the oxidative pathway from the mitochondria and replaced them with foods which actually caused oxidative stress.

Our new diet triggered the appearance of many modern diseases like cancer, autism, Alzheimer’s, Parkinson’s, many forms of arthritis, dementia, even many forms of diabetes, stress, sleep disorders and others due to imbalance in oxidative pathways.

It will be helpful to understand the nature of health and nutrition before looking at our evolution over a very long period of time to come to an understanding of how our health and nutrition are stunningly interdependent and so very subtly sensitive to the precision and accuracy with which we comply with the dietary requirements which developed for us in a few billion years of evolution.

For instance, we can assemble a list of constituents in our biology that the general community has come to look to their positive contributions to our biology, to their effects and actions because of their antioxidant nature. For instance, COQ 10, Selenium, Arachidonic Acid, Taurine among many others. In terms of ORAC values these materials are not very strong antioxidants.

But the real problem we are identifying is that these are all essential for other functions.

COQ 10 is needed to convert ADP to ATP as well as antioxidation
Selenium especially is needed for thyroid function as well as antioxidation
Arachidonic acid is a precursor for all types of eicosanoids and other actors as well as antioxidation
Taurine is about .1% of the human body mass. It is involved in conjugation of bile acids, osmoregulation, membrane stabilization, modulation of calcium signaling, cardiovascular function, and development and function of skeletal muscle, the retina, and the central nervous system as well as antioxidation.

So in any of these cases do you really want to sacrifice these actors in favor of antioxidation? I think the answer is clearly and absolutely no.

In looking at the food chain in the Rift Valley and in the seashore we find a rich flow of astaxanthin. And in these forms the concentration is not so great, but it is bio available. The ORAC value of astaxanthin is perhaps 1000 times greater than these constituents.

But I think the story is much more complex and exciting.

To begin with, we tend to source commercial astaxanthin from Haematoccocus pluvialis where we find it encysted. To break this cyst requires a lot of energy and some good chemistry with respect to in situ surfactant chemistry. I don't think humans really every got much astaxanthin directly from this alga. It is not biologically available. I think we got most all of it from stuff we ate, sea food, flesh, organs etc. And organs tend to be rich in astaxanthin as is sea food. Our opposing thumbs make eating sea food easily possible. And sea food from the marine environment are very safe to eat with respect to getting sick, getting food poisoning.

This molecule is really powerfully hydrophobic on its backbone of 28 conjugated carbons. But the two six carbon rings are also conjugated but each carry an ester and hydroxy group. So the distance from each ring to the other just happens to be similar to the distance in the cell plasma membranes from the head on one side, the outside, to the head on the mating phospholipid on the other side. The inside of the membrane is full of tails, so very hydrophobic. The two outsides are heads, so hydrophilic. The hydroxyl and ester groups on the rings like to poke towards the outside of the membranes and the backbone is really happy in the inner part full of tails. So the astaxanthin takes up residence in the membranes of the cell plasma membranes and both of the membranes of the mitochondrion.

So in our studies, we have compared astaxanthin extracted by Super Critical Carbon Dioxide extraction with our process. The earlier is not bio available and does not work so well at all. Ours works very, very well.

We are using tremendous energy in our milling, and a solvent and energy in which these oils are highly soluble. But we are not extracting. We are making a true nano emulsion, but doing so with stuff that is really good for us.

So cells are 70% water, and when we look at dry weight it is 80-90% lipids, proteins and carbohydrates. The lipids are a large portion of these. They have three key functions: they store energy, they form the structure of several membranes, and they are precursors for a whole host of signaling molecules. So we are breaking these down and not destroying them, not extracting them, and using them as the surfactant to keep the astaxanthin in a state of nano emulsion. This makes it very completely bio available.

Eicosadose is a new supplement I am developing to solve some of these problems. It has very bioavailable astaxanthin to act as an antioxidant instead of most of these other constituents that can be antioxidants but are best protected for their special roles. We tested some Eicosadose yesterday with very high bioavailability of the astaxanthin.

So a key function in our Eicosadose is that the astaxanthin protects these things like selenium, taurine, COQ 10, arachidonic acid from destruction and loss from oxidation by acting as antioxidants, but their processes are also protected in their process as they are involved often in a process which is mildly, locally, cell by cell, temporarily pro oxidant.

And the dimensions of the process is stunning. There are 30 to the 12th cells in a human and about 1000 mitochondria per cell, and they cycle an ADP to ATP about once every minute. So budgets are a critical tool in understanding biological processes. I think the thing looks like this:

So for a normal human body of about 70 kg this calculation shows we cycle about that amount of mass between ADP and ATP every day.

That creates enormous amounts of ROS that needs to be mitigated. And that requires an antioxidant that is more a catalyst than a critical function part of our biology. Astaxanthin is more or less the only candidate. As we will see, only astaxanthin from the list of such things from our evolutionary diet fills the bill.

Our foods and health and Effects: ORAC Values

We need a diet rich in foods with high ORAC values. We need a certain ORAC value in our diet on a constant basis.

The antioxidant values of foods listed are expressed in ORAC (Oxygen Radical Absorbance Capacity) units, a unit of measurement for antioxidant content which was originally developed by the National Institute on Aging (NIA) at the National Institutes of Health (NIH).

The ORAC (Oxygen Radical Absorbance Capacity) unit, ORAC value, or “ORAC score” is a method of measuring the in vitro antioxidant capacity of different foods and supplements. More than two decades in the making, it was originally developed by scientists working at the National Institutes of Health (NIH) and USDA. Measuring in vivo (meaning inside the human body) is not possible and for that reason, the exact relationship between the ORAC value of a food/supplement and any suspected health benefit it may have as a result is unproven. However, many scientists theorize that foods higher on the ORAC scale may be more effective at neutralizing free radicals.

From: https://modernsurvivalblog.com/health/high-orac-value-antioxidant-foods-top-100/

The USDA recommends an ORAC unit ingestion of about 3,000 to 5,000 units daily.

Note: ORAC values listed here are in units of µmol TE/100g (micromole Trolox Equivalent per 100 grams). Trolox equivalency is used as a benchmark for the antioxidant capacity.

(Trolox is a water-soluble analog of vitamin E sold by Hoffman-LaRoche. It is used to reduce oxidative stress. Trolox equivalent antioxidant capacity (TEAC) is a measurement of antioxidant strength based on Trolox, measured in units called Trolox Equivalents (TE), e.g. micromole TE/100 g.)

Refined carbohydrates;
Sugar – Sugars increases oxidative stress in multiples ways. Sugar is a carbohydrate. When mitochondria process sugar vs fats, it creates more oxidative stress and is less efficient.
Fried foods have fats that get oxidized when we fry them. Our bodies then absorb those oxidized fats, and that oxidation becomes part of our bodies.
Things with lots of sulfur.

We have been told for decades that a good balance between incoming Omega 3 and Omega 6 fatty acids, and an emphasis on DHA were important, but it seems we were never told exactly why. We think that we now understand. Half of the most fundamental regulatory agents, eicosanoids, are made from Omega 3, these are anti-inflammatory. The other half, the inflammatory are made from Omega 6. We changed our diet to disrupt the dietary and residential balance between these two fatty acids: it should be one to two Omega 3 to Omega 6, but in most of the modern diet it is 1 to 20.

Some of the building blocks of understanding include terms and concepts which are critical to telling our story and have only been discovered in the past few decades. Here are the points to study today:

What are the main regulatory systems below the endocrinal systems? The Eicosanoid system is especially important.
Why is the correct balance of Omega 3 and Omega 6 important?
Why is CBD good for us? How does it affect the Eicosanoid system?
An introduction to antioxidants and astaxanthin.

Our foods and health and Effects: ORAC Values

We need a diet rich in foods with high ORAC values. We need a certain ORAC value in our diet on a constant basis.

Refined carbohydrates;
Sugar – Sugars increases oxidative stress in multiples ways. Sugar is a carbohydrate. When mitochondria process sugar vs fats, it creates more oxidative stress and is less efficient.
Fried foods have fats that get oxidized when we fry them. Our bodies then absorb those oxidized fats, and that oxidation becomes part of our bodies.
Things with lots of sulfur.

What are the main regulatory systems below the endocrinal systems? The Eicosanoid system is especially important.
Why is the correct balance of Omega 3 and Omega 6 important?
Why is CBD good for us? How does it affect the Eicosanoid system?
An introduction to antioxidants and astaxanthin.

Eicosanoids:

Eicosanoids: These active elements are very ancient regulatory agents in virtually all our biological systems. They have 20 carbons, hence the Greek route Eico, and there are pairs of them, opposing each other, half made from Omega 3 and half from Omega 6 fatty acids. So balance is good, need both, so now I understood why a good balance between the two fatty acids is a good thing.

Eicosanoids are made and used instantly at the place they are needed. We now understand they play a role in virtually all biological systems and processes. The eicosanoid system cannot function in a healthful way unless it is protected from ROS. Astaxanthin in its antioxidant power and the place where it takes residence, the same place that arachidonic acid is made, make it the clear number one candidate for protecting the important eicosanoids system.

The science we are addressing is evolving and being revised at an amazingly rapid rate, but only recently. For instance, there is virtually no literature available as to the effect of CBD on eicosanoid signaling and immunology, reproductive performance, growth, health and biology of humans and animals. And that what we know today is very different from what we knew even a few decades ago.

For instance, the CB1 receptor was identified in 1990, the CB2 in 1993.

Why is this so? Because CBD was illegal in the US, and not just illegal but a Schedule 1 Narcotic, right alongside heroin and cocaine.

In the Princeton Legacy Library review publication “Eicosanoids and Related Compounds in Plants and Animals” there is not one reference to CBD. But there are some very interesting articles:

The role of Eicosanoids in the haemostatic Mechanisms of Fish”
Eicosanoids in Animal Reproduction: What can we learn from Invertebrates?
Cardiovascular Effects of Eicosanoids in Amphibians.
Enzymes and Factors Involved in the biosynthesis of Eicosanoids
Mammalian Lipoxygenases: Structure, Function and Evolutionary Aspects
Structures, Nomenclature and Biosynthetic Pathways

Particularly in this last paper the Arachidonic Acid Cascade is described. While CBD is perhaps the most powerful agent in promoting the power of this cascade, it is not mentioned in any literature till very recently:

As indicated above, the major source of eicosanoids and related compounds in animals is the Arachidonic Acid (AA) cascade. Upon cell stimulation, AA, or under certain circumstances other precursor fatty acids, are liberated from the membrane phospholipids via activation of lipid cleaving enzymes such as phospholipase A₂. The free fatty acids are subsequently metabolized via three different pathways

The cyclooxygenase (COX) pathway, forming prostaglandins, thromboxanes or prostacyclins
The lipoxygenase (LOX) pathway, forming leukotrienes, lipoxins, hepoxilins and hydro(pero)xy fatty acids

The cytochrome P-450 (cyt P-450) pathway forming hyrooxylated fatty acids and epoxy derivatives.

Endocannabinoids are all part of the eicosanoid system, but with 21 carbons they are different. CBD is powerfully involved in what is commonly called the arachidonic acid storm, which is the precursor to the eicosanoid storms. The arachidonic acid is oxidized along with the fatty acid to make eicosanoids. It is now being learned rapidly that cytokines and eicosanoids are highly interacting and possibly involved in the same processes. CBD being a powerful precursor for making arachidonic acid is ideally situation with regard to most of the CB2 receptors, being in the cell plasma membrane:

https://www.cell.com/cms/attachment/586225/4448094/gr1.jpg

CBD, along with astaxanthin and a healthy ratio of Omega 3 and Omega 6 fatty acids, is among the most important things one can do for one’s health, but also in making feeds for livestock. However, the systems we are addressing are very complex. For instance, one can have all the CBD making AA and all the right balances of Omega 3 and Omega 6, but if the stream of oxidative species from the mitochondria is not mitigated, then things will not go very well.

The accelerated synthesis of arachidonic acid by CBD at the cell plasma membrane from the phospholipids resident there are a key factor in the effect of CBD makes to our health through the eicosanoid system. Humans feeding on the modern agriculturally produced diet, the diet that developed about 8000 years ago, and animals fed on manufactured industrialized feeds, are suffering from deficiencies in the actual molecules, or precursors for those molecules that are made de novo, or both, and also lacking the anti-oxidants that protect us from the toxic flow of ROS from the mitochondria.

By understanding the ancient nature of these systems, and seeing their effects, we can gain a helpful understanding of our evolution, and thereby understand and the deeply embedded nature of these systems. Thus, can we identify their appropriate or even necessary inputs so to best to manage and optimize them. The chances our agriculturally produced diet precisely and optimally satisfies these requirements is very small! Understanding our evolutionary diet and matching up to its profile can help us achieve a more healthful diet before we understand the exact mechanistic science behind it.

Our evolutionary diet gives us clues as to what feeds and biological processes are most healthful for us. About 8000 years ago, we removed many nano, micro and macro nutrients from our diet. We also have done this for the animals we feed for our own consumption. We surely removed most of the antioxidants from our foods.

It is best we come at this from these two approaches: one based on understanding the cause and effect from the evolutionary diets and the mechanisms we are coming to understand, the other from understanding the exact nature and requirements of those mechanisms. One can treat us to benefits now on a kind of macro scale. The other will be more precise and discrete.

So, to start, I would like to establish that organisms evolved the endocannabinoid and eicosanoid systems and components before most evolutionary divergence, billions of years ago. This would mean they are deeply embedded in our biology, and sourced de novo and from basic build blocks .

Over time, biological diversity evolved through Archaea, bacteria, Prokaryotes, and finally when water and oxygen were abundant, to Eukaryotes. For us to evolve as complex Eukaryotes, oxygen and water were necessary. But it is informative that all these forms employ eicosanoids and endocannabinoid-like molecules in their cellular regulatory systems.

Linus Pauling and Francis Crick can be said to have been among those who saw in molecular phylogenetic studies the possibility of a molecular clock being exposed.

Carl Woese in the late sixties and seventies started doing ribosomal RNA studies of hemoglobin reasoning that from an evolutionary point of view this would be an ancient molecule in Eukaryotes. In the mid-seventies he was studying the ribosomal RNA of cell walls, reasoning these were even more ancient from an evolutionary point of view. It was then, studying the cell walls of bacterial that lived without oxygen, in carbon dioxide, methane, high temps, acid, very salty environments that he came to understand a third family, the Archaea.

In 1977 he made the first suggestion that ended up adding Archaea to the other two families, the Eukaryotes and Prokaryotes. But his work was not well received, and it would be 15 years before it was taken more seriously. By that time PCR had risen as a technology to replace electrophoresis in gels.

But by understanding how ancient these regulatory systems function and how deeply embedded they are in our biology; we can better appreciate how their optimal function is fundamental to our health and biology and thus better understand and manage the dietary requirements for optimal function.

And they are ancient. So, it is assumed here that one can successfully suggest that finding these systems in life forms from which there is very wide biological evolutionary divergence hundreds of millions to billions of years ago one can conclude they are so very deeply and broadly integrated into our biological regulatory response and control systems. We find them in most all life forms.

But we are coming to understand the deeper insights into how these systems and precursors work. The many effects of CBD are much plainer to see if one looks at them through the eicosanoid system.

Eicosanoids act like local hormones. They are not stored, and they do not travel. They are made and used locally and instantly, which is why CBD sublingually can have such immediate effects.

Eicosanoid biosynthesis begins when a cell is activated by stress. This can be such as a mechanical trauma, ischemia, other physical perturbations, attack by pathogens, or stimuli made by nearby cells, tissues, or pathogens.

The endocannabinoids are part of the eicosanoid systems. One can hardly explain all the good things CBD does through the lens of the CB2 receptor, which resides in the cell plasma membrane, holding CBD molecules in the exact place where they can do the greatest and instant good.

So, this means that Endocannabinoids are all part of the eicosanoid system: reference: Pertwee RG (April 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview". Int J Obes (Lond). 30 (Suppl 1): S13–8. doi:10.1038/sj.ijo.0803272. PMID 16570099.

Eicosanoids are a very ancient regulatory system in biology. Recent work in terms of molecular phylogenetic modeling has really only begun in the last few decades. In terms of discovery, it is a recent set of insights, that were very vague in description till developments begun about 30 years ago that we now rely on. One can suggest that our work in molecular phylogenetic modeling has only just begin.

But having some understanding of the history of evolution of life on Earth, can teach us how fundamental a system really is. One can assume that the older it is, the more fundamental and important it is.

So eicosanoids regulate most every form of life on earth, for billions of years. In their review and study Production of Eicosanoids and Other Oxylipins by Pathogenic Eukaryotic Microbes Mairi et al say: Descriptions of eicosanoid and oxylipin production by eukaryotic microbes have been scattered through the literature for decades, but they have begun to receive signiﬁcant attention in the last few years following reports of prostaglandins and prostaglandin-like molecules being produced by pathogenic helminths, protozoa, and fungi. Why do these organisms produce oxylipins? Eicosanoids in eukaryotic microbes appear to play a dual role, metabolism or maturation of the organism and communication with the host on a cellular basis. Accumulating data suggest that control of phase change and differentiation in these organisms is controlled by oxylipins, including prostaglandins and lipoxygenase products.

Another reference teaches:

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system is involved in regulating a variety of physiological and cognitive processes including fertility, pregnancy, during pre- and postnatal development, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS is also involved in mediating some of the physiological and cognitive effects of voluntary physical exercise in humans and other animals, such as contributing to exercise-induced euphoria as well as modulating locomotor activity and motivational salience for rewards. In humans, the plasma concentration of certain endocannabinoids (i.e., anandamide) have been found to rise during physical activity; since endocannabinoids can effectively penetrate the blood–brain barrier, it has been suggested that anandamide, along with other euphoriant neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as a runner's high.

For instance in 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized prostaglandin as a component of semen. Burr in the 30s showed that restricting fat from animal's diets led to a deficiency disease, and first described the essential fatty acids. In 1935, von Euler identified prostaglandin. In 1964, Bergström and Samuelsson linked these observations when they showed that the "classical" eicosanoids were derived from arachidonic acid, which had earlier been considered to be one of the essential fatty acids.

In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis. Von Euler received the Nobel Prize in medicine in 1970, which Samuelsson, Vane, and Bergström also received in 1982. E. J. Corey received it in chemistry in 1990 largely for his synthesis of prostaglandins.

Toh et all suggest in 1994 with what today would be considered very crude laboratory tools that these pathways for eicosanoids predate the divergence of mammals. Turns out it was much earlier than this. I want to emphasize the recent insights we are gaining and the cloud of ignorance over this topic till recent years.

The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants, and detection of arachidonic acid (AA) indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around 500 million years ago (silurian; devonian). The phylogenetic distribution of these lipids may be a consequence of interactions/adaptations to the surrounding conditions such as chemical plant-pollinator interactions, communication and defense mechanisms. The two novel EC-like molecules derived from the eicosatetraenoic acid juniperonic acid, an omega-3 structural isomer of AA, namely juniperoyl ethanolamide and 2-juniperoyl glycerol (1/2-AG) in gymnosperms, lycophytes and few monilophytes, show AA is an evolutionarily conserved signaling molecule that acts in plants in response to stress similar to that in animal systems.

So, it is probable that the eicosanoid system and endocannabinoid systems developed in parallel over time, and came to co-function, perhaps more than once. If we look at evolution, once can see that the Archaea in all likelihood rose during a time, about 3.5-4 billion years ago when the environment on our earth was warm, full of carbon dioxide, methane, acids, salts etc. and they were probably a nearly exclusive ecosystem on earth. As water was captured from asteroids about 3 billion years ago, as oxygen was liberated by life forms, bacteria likely evolved using oxygen and these evolved to consume each other and there were suddenly cells with walls and cells with nuclei. As these evolved, they would need a growing complexity in regulatory systems. So, both plants and animals make and use both systems.

See: Eicosanoids and related compounds in plants and animals: A F Rowley et al:

All these systems utilize oxygen but are vulnerable to reactive oxidative stress (ROS). For this reason, the combination of astaxanthin with CBD is essential to good health. Astaxanthin takes up residence in the cell plasma membrane and the mitochondria, where most ROS are created, and protects the cell and the mechanisms of the cell from those destructive ROS. This makes everything more efficient; the yields go up.

Since eicosanoids are made and used locally and instantly and not stored or transported, each cell making them more efficiently with this protection from ROS will be a very good thing.

Also, for the same reason, having a lot of CBD hanging out locally will enable the eicosanoid system and all systems to function much more efficiently.

Finally, having a good ratio of Omega 3 and Omega 6, perhaps one to two or so, will enable all eicosanoid storms to have a good beginning and resolution, and are also essential to good health.

Eicosanoids are intimately involved in virtually all biological regulatory, response and control systems. They have evolved in virtually all life forms performing a myriad of these functions for billions of years. Treating them so they can perform optimally is perhaps one of the most vital health factors we can control in human health and in livestock health as well. CBD is a powerful factor in the eicosanoid system, particularly in the arachidonic acid storm that comes before and during every eicosanoid storm.

We know very little about the nature of CBD in the eicosanoid system for the simple reason that there has been very little study of it. However, we know enough to understand its roles are defined by input and output factors found in the eicosanoid system, far beyond what can be explained by the CB2 receptor.

Antioxidants and Astaxanthin:

Astaxanthin:

All the biological processes are all very vulnerable to ROS and oxidative stress. In some cases, very discrete, small, quick, local oxidative events need to happen without being overwhelmed by ROS. In others, an antioxidant similar scale event has to happen and cannot be overwhelmed by ROS. Having a strong antioxidant in place will optimize these processes. Making astaxanthin bio available and resident in the plasma membranes is a great way to successfully manage the ROS.

Humans industrialized food production starting about 8000 years ago, and in doing so we removed and replaced a lot of critical nutrients. And when we make fish food for aquaculture, we do the same.

Linus Pauling, was a very nice and generous man, and like a waterfall of information and ideas. He was keen on antioxidants, vitamin C and molecules called eicosanoids. He is also one of the originators of what we today call the molecular clock, using rRNA to see rate of change and find points of divergence in the evolutionary history. Unfortunately, he died before PCR became so inexpensive and powerful.

In 2001 a study of the euphotic zone was begun with an international collaboration. By 2006 it was presenting a massive amount of data which I began to analyze. This census was the first that used micron size sieves, earlier they did not get the very small stuff. In collecting connections from this data some meaningful insights emerged. I could see that fish in the sea have a lot of powerful antioxidants in their diet and food chain and astaxanthin was a predominant one. And it gave color too. But the rate of astaxanthin production in the phytoplankton in the sea is very low compared to H pluvialis, but the nature of this inverted food pyramid means a lot of it entered the food chain.

We know that astaxanthin takes up residence in the cell plasma membrane and in the mitochondria themselves. This is where we find reactive oxidative species which rise up and do bad things. And the cell plasma membrane is also where the eicosanoids are formed. So, protecting from ROS with astaxanthin seemed to be an important thing.

In studying astaxanthin it became clear to us that to make it bioavailable we needed to make a nano emulsion, and this would require a lot of energy and shear forces and a solvent based high energy extraction. So, I invented and won patents for a lot cost way of doing this.

When we put this additive to our fish feeds, we never used antibiotics again, so strong were the immune systems of these fish, egg production rose 300%, and growth rates doubled, which means feed conversion rates increased dramatically.

Next, we looked at CBD, which is the non-psychoactive component of Cannabis sativa. The version of Cannabis sativa that has a lot of CBD and almost no THC (the psychoactive part of Cannabis sativa) is called Industrial hemp. The variant with lots of THC is called marijuana.

Our interest in CBD rose from the observation that there were enormous numbers of what must be called anecdotal reports of the many good things CBD does, but really none of these could be explained by the CB2 receptor. So, something else must be going on. But the CB2 receptor resides and hold onto CBD in the cell plasma membrane where it is then instantly available to enter the eicosanoid system.

Well it turns out CBD is associated with the endocannabinoid system, but it probably rose in evolutionary time lines with the eicosanoid system long before that. It is a powerful enzyme in creating arachidonic acid (AA) which is the substrate for making eicosanoids. We find the AA pathway in eicosanoids in animals, plants and bacteria, indicating a very ancient point of divergence.

Eicosanoids are the most fundamental and ancient biological regulatory agents and systems in all biology, and evolutionary studies now show it is probably traceable back to archaea, 3 billion years ago. The point of divergence is before plants, algae and bacteria. Imagine that.

Inflammatory and Anti-inflammatory actions:

MedlinePlus defines inflammation thus: The immune system protects the body from possibly harmful substances by recognizing and responding to antigens. Antigens are substances (usually proteins) on the surface of cells, viruses, fungi, or bacteria. Nonliving substances such as toxins, chemicals, drugs, and foreign particles (such as a splinter) can also be antigens. The immune system recognizes and destroys, or tries to destroy, substances that contain antigens.

Oxidative stress and inflammation: There is debate as to which one comes first, sometimes one, sometimes the other, but always when you find one you find the other.

Reactive Oxidative Species:

These are the bad actors: Reactive oxygen species (ROS) are chemically reactive chemical species containing oxygen. Examples include peroxides, superoxide, hydroxyl radical, and singlet oxygen.

Anti-oxidants: these are the police who control the ROS. They are often complex molecules with limited bio availability and often don’t like water, called hydrophobia which make them difficult to get to the right places.

Astaxanthin: this molecule is what makes salmon so colorful. It is one of the most powerful, stable and long-lasting antioxidants known to man. And it has to be treated right to make it bio available. It is highly hydrophobic, does not like water, (blood) and love oil.

Each of the cells in our body are contained in what is called the cell plasma membrane, or plasma membrane. In the cell there are things like endosomes and lysosomes that play an important regulatory role in the cell. The plasma membrane is 3-10 nm thick and is made of lipids. They can contain any number of lipophilic compounds important to our health, if we can get them there.

Recent literature indicates that bio available astaxanthin takes up residence in the cell plasma membrane and the mitochondria, 65% to the earlier, 35% to the later.

At Sustainable Aquatics, our marine ornamental hatchery, we have looked at the evolutionary, or you might say environmental, diet of marine teleosts. (teleost is the scientific name for fish.) One of the things we have looked at is the census and characterization of the euphotic zone which has become very powerful in data driven observations during the past 15 years. In hatcheries we tend to do to fish what we did to humans 8000 years ago: we industrialized the food and removed many important nutritional constituents and replaced them with non performing and badly performing ingredients which carried energy and fat and proteins but missed important constituents. When we added a nano emulsion of astaxanthin, meaning highly bio available, we realized enormous improvements: Egg production increased 300% and larval growth and development doubled, pairs starting breeding for decades instead of a few years and we threw out all our antibiotics.
So the theme of bio availability is a very key part of understanding and implementing our approach. Here we diverge to the theme of nano emulsions and bio availability:
One of our biological systems is the eicosanoid system, more than 150 eicosanoids have been identified, and they are made and used instantly. Key inputs to this system which makes and uses these important signalers instantly are omega 3 and omega 6 fatty acids, arachidonic acid (AA) and strangely enough, CBD. CBD does not much interact with the CB1 and CB2 receptors. CB1 receptors are abundant in brain and nervous system while CB2 receptors are mostly expressed immune and endocrinal infrastructure. Recent literature makes it clear that CBD is a very powerful agent to release AA and this may indeed be its main functional value. And of course, CBD is made de novo in our biological operations. All these things and more are very vulnerable to oxidative stress. So in addition to the omega 3 and 6, the AA and the CBD, a strong antioxidant process is necessary for our health. It must be dietary and available in our diet.

Oxidative stress happens in many states and cases. When an inflammatory event is under way it is often caused by detection of unwanted antigens. An insult to the organism, it can be an injury or an infection, local or global, will normally result in a “storm” of eicosanoid activity to attack the invasion and put it down. This is triggered mostly by a rise of those antigens, often on the surface of cells in the organism which it recognizes as nonnative

The endocannabinoid system (ECS)

We cannot address the needs for astaxanthin and control of ROS without addressing the endocannabinoid system.

Then there is the Endocannabinoid System (ECB) Wikipedia give us this helpful essay:

The ECS is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system (including the brain) and peripheral nervous system. The endocannabinoid system is involved in regulating a variety of physiological and cognitive processes including fertility, pregnancy, during pre- and postnatal development ^]appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS is also involved in mediating some of the physiological and cognitive effects of voluntary physical exercise in humans and other animals, such as contributing to exercise-induced euphoria as well as modulating locomotor activity and motivational salience for rewards. In humans, the plasma concentration of certain endocannabinoids (i.e., anandamide) have been found to rise during physical activity since endocannabinoids can effectively penetrate the blood–brain barrier, it has been suggested that anandamide, along with other euphoriant neurochemicals, contributes to the development of exercise-induced euphoria in humans, a state colloquially referred to as a runner's high.

This is very well described in Eicosanoid Storm in Infection and Inflammation by Edward A. Dennis and Paul C. Norris published in Nat Rev Immunol. 2015 August; 15(8): 511–523. doi:10.1038/nri3859.

There are two parts of this “storm”. The inflammatory normally comes first and it should be succeeded by a “resolving” or “resolution” phase. This second phase is normally characterized by strong anti-inflammatory activity. An ongoing supply of AA is required to sustain this “storm” through the first and second phase.

There is also ongoing oxidative stress due to the rise and presence of reactive oxidative species (ROS), where in a nice presence of anti-oxidants is desired. Astaxanthin, which tends to find and take up residence in the cell plasma membrane, fills this function very well. This is described below by Ranga Rao Ambati et. al. in their paper Astaxanthin: Sources, Extraction, Stability, Biological Activities and Its Commercial Applications—A Review published in Mar. Drugs 2014, 12, 128-152; doi:10.3390/md12010128

Figure 4. Superior position of astaxanthin in the cell membrane [12]
The astaxanthin is hydrophobic, does not like water. It likes oils and lipids. Once it gets to a plasma membrane is it likely to stay there. This is why astaxanthin builds up in the cells and tissues, and why it is so powerful to pull ROS out of the cell and move it to a Vitamin C.

Nano Emulsions and Bio availability

In her paper Evolution of dietary antioxidants Iris F.F. Benzie of the Ageing and Health Section, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, published SAR, China Received 26 June 2002; received in revised form 15 November 2002; accepted 2 December 2002 considers the questions relating to our evolutionary dietary intake of antioxidants and their bioavailability before and after the industrialization of food production. The industrialization of food production resulted in significant reductions of dietary antioxidants. To achieve good health, we need to address these needs. Here we learn our diets changed, the number of dietary antioxidants were dramatically reduced, and to be healthy we need to supplement.

Here Dr. Benzie cites a variety of sources to look at dietary antioxidants and their bioavailability and concentrations in human plasma:

One of the puzzles in primate evolution is the loss of primates of the power to make vitamin C de novo as do most all other mammals and reptiles. Vitamin C is an important antioxidant and precursor also for making collagen.

Mammals make vitamin C de novo in the liver, reptiles make it in the kidney. Dr. Benzie explains that for the most part evolution is a matter of economics and that there must be a balance in the economic equation with regard to natural selection. So, we lost the ability to make vitamin C, but not the critical need to have it. It must be that our dietary intake satisfied our need for this critical antioxidant:

The antioxidant operation in healthy biological operations is very complex and involve many players. Vitamin C is water soluble and easily eliminated within several hours. It is believed that it can carry away ROS conveyed from inside the cell to the outside by astaxanthin. In Dr. Ambati’s figure 4 above this is clearly illustrated.

The antioxidant system must protect many processes and systems and constituents from ROS if the organism is to enjoy good health and operations.

One of the things we focus on at Sustainable Aquatics, the founder of Sustainable Nutrition and SNCE Laboratories, is the importance of bioavailability and the impact of antioxidants, nutrients, macro, micro and nano nutrients.

We were excited to read Dr. Meor Mohd’s Enhanced Oral Bioavailability of Astaxanthin with Droplet Size Reduction M.M.R. Meor Mohd et. al. Food Sci. Technol. Res., 18 (4), 549–554, 2012 for the reason that it reinforced work we had done here at SA with regard to nano sizing and bio availability. In particular we have focused on astaxanthin, chlorophyll, CBD and the beneficial use of fatty acids as well. Dr. Meor Mohd reported the following data:

Fig. 1. Rat plasma concentration versus time profile of nanosized emulsion, macro sized emulsion and oil solution of astaxanthin after oral administration of 80 mg/kg astaxanthin formulation (n = 9).

Table 3. Individual numerical value of C_max, T_max and. of three types of formulation tested on nine. Individual numerical value of C_max, T_max and AUC_0‒∞. of three types of formulation tested on nine.

This footed very well with much of our own work, though our own work is measured by more visual and tangible results. For instance, we have learned that when fish make eggs it is a very rapid almost violent process which takes place often in just a few hours. The ovaries signal that they are going to be dividing cysts and will need yolk material, which is called vitellogenin. (VTG). This message is picked up by the thyroid which makes a series of seleno proteins, three in particular, and these are issued by the thyroid and picked up by the liver which then uses them to make VTG and issue it so it is picked up in the ovaries, and in the case of marine teleosts, hydrolyzed, and built into yolk. So it is a rapid and almost violent process which requires the endocrinal and supporting systems to be working at top efficiency.

We believe that in nature marine fish eat a diet rich in antioxidants, including astaxanthin. So, we supplement our fish feeds with astaxanthin. Synthetic astaxanthin and from yeast does not work well for us at all. And from Haematoccocus pluvialis we have to nano size it. Here are pictures of blue tang eggs about 18 hours after fertilization, about a few hours from hatching using astaxanthin reduced in size from 50-micron cysts to 3-5-micron cysts by super critical carbon dioxide extraction and nano sized astaxanthin by SN’s process combined with pharmaceutical grade cod liver oil:

SCCO2 Asta blue tang eggs

SN nano sized Asta blue tang eggs

SN’s astaxanthin is nano sized, we use very high energy in warm ethanol to not just extract the astaxanthin, but to break the encysted astaxanthin molecules down to nano sized molecule couples. At about 70 C in food grade ethanol we rotate stirring bars at 1240 feet per minute tip speed in 3 mm hard balls. Within ten to twenty minutes the dis-encystment is complete. This difference in bio availability can be seen in the dramatic increase in eggs, and egg yolk mass.

We have seen this difference in other studies. For instance, in rotifers fed a food including astaxanthin, the two types of astaxanthin showed a remarkable difference in reaction to Juglone stress. Juglone is a chemical used to present oxidative stress to measure reaction and resistance to oxidative stress:

We also looked at the effect in terms of amplification of populations of rotifers, fecundity:

All this seems to present strong evidence that bioavailability in fatty acids, in bio mass, and nanosized is much enhanced and much enhances many biological operations.

In each of these cases we observe that the endocrinal and other systems when liberated from oxidative stress operate at much higher efficiency, quickly measured in clear metrics. This biology is not just not dissimilar to human biology, the causes and effects are identical.

From the literature we have concluded that CBD is much more a part of the eicosanoid system than the endocannabinoid system (ECS). Or that the ECS system is very much a part of the eicosanoid system. CBD does not couple with the CB1 or CB2 receptors. But it does release arachidonic acid from the phospholipids where they are stored.

We need vitamin C but we Homo sapiens, among the rest of the primates, stopped making vitamin C De Novo in our liver a long time ago, even though we very much still need it. It is probable when we stopped making it we could afford this energy saving change because our diet was rich enough in different valuable antioxidants;

Croton lechleri is dominated by phenol structures and is water soluble as is Vitamin C. So thought it has an ORAC value similar to Astaxanthin, it probably cannot do what astaxanthin does in the membranes of the cell and the mitochondria. Astaxanthin presents a challenge for bio availability because of its hydrophobic nature. One has to formulate it so it can pass unencysted through the gut into the blood to the surface of cells. But that is also its advantage since it loves to take up residence in the cell plasma membrane. The backbone is long and exceptionally hydrophobic. The rings and esters on the ring are slightly hydrophilic and anchor it in the area of the heads of the phosphor lipids on the inner and outer surface of the cell plasma membrane and the membrane of the mitochondria while the backbone anchors in the tails of the phospholipids an area of strong hydrophobia. So through Croton lechleri has an antioxidant power similar to astaxanthin because it is phenol dominated and water soluble it is an actor like Vitamin C rather than like astaxanthin.

Astaxanthin was likely rich enough in our regular diet. We accumulated it in our cell structures, and it offered protection against ROS, including protecting other systems.

The eicosanoid system has more than 150 types of eicosanoid types and half of them can be said to be inflammatory and half anti-inflammatory.

A healthy eicosanoid balance of omega 3 and omega 6 fatty acids is about 1:3;

CBD is made De Novo but we also can supplement it, and it is an important player in the eicosanoid system in its ability to supply the arachidonic acid required to make the eicosanoids that are made and used instantly.

Understanding how CBD plays such an important role in the eicosanoid system across most all the eicosanoids system, in a system with our normal modern diet challenged with excessive oxidative stress, explains how supplementation offers so much benefit across such a wide cross section of complaints;

CBD and Astaxanthin become much more bio available when nanosized and presented in solution with fatty acids such as DHA and EPA.

CBD and Astaxanthin are more powerful and more bioavailable when presented nano sized with constituents such as the Haematoccocus pluvialis bio mass, nano sized chlorophyll, other cannabinoids and the like.

It is likely that astaxanthin takes up residence in the cell plasma membrane, the dimensions favor it leaving an ester group on either side of the membrane, and that the oxidative potential between the inside and outside of the cell would favor astaxanthin moving ROS from the inside of the cell to the outside of the cell;

Where Vitamin C catches it and it is removed by the liver/kidney elimination system.

Given the literature cited makes it clear we have dietary deficiencies in a wide range of antioxidants and given the evidence for bioavailability as a function of using fatty acids, nano sizing, nano sized bio mass, an optimal supplement might be cod liver oil rich in DHA, carrying nano sized astaxanthin, CBD and chlorophyll associated with their nano sized biomasses.

In her 2015 article in Bioorganic & Medicinal Chemistry Sumner Burstein titled Cannabidiol (CBD) and its analogs: a review of their effects on inﬂammation. Dr. Burstein teaches us in section 4.1: 4.1. Eicosanoids

4.1.1. Arachidonic acid release: The initiating event in all eicosanoid biosynthesis is the release of free arachidonic acid from phospholipid storage sites where it exists in an esteriﬁed form. Thus, drugs affecting this process, presumably involving PLA2, can have a profound effect on the physiological status of a variety of systems. Both CBD and THC produce a signiﬁcant stimulation of arachidonic acid release in intact human platelets.22 Interestingly, CBD is roughly 1.5 times more potent than THC suggesting that this action may not be involved in the psychotropic activity of THC. It was also found that a product shift from cyclooxygenase to lipoxygenase products occurs as a result of cannabinoid exposure. This probably involves action(s) on downstream events in the arachidonic acid cascade. Stimulated arachidonic acid release was also observed in neuroblastoma cells (NBA2). The arachidonic acid release effect was extended to a series of six primary phyto cannabinoids to produce the following rank order of hydrolytic activity: CBD to CBCy to THC=CBCR= CBN to CBG.23 The model used to obtain these data was the WI38 human lung ﬁbro blast that had been radio labelled by equilibration with free arachidonic acid. Again, CBD was more active than THC in stimulating phosphor lipid hydrolysis. By way of comparison, the anti inﬂammatory actions of cannabinoid analogs such as NAgly24 and ajulemic acid(Fig.2)25 have been attributed to their ability to promote the release of free arachidonic acid. In these examples, a result of this action was the elevation of pro resolving substances such as lipoxin A4 and 15d-PGJ2.26 A similar mechanism may explain some of the anti inﬂammatory actions of CBD.

The Isles of Langerhans, Sugar, Insulin and Glycogen:

These were identified in 1869 by a German Research named Paul Langerhans. We have learned much about them since, but most can only identify one of the two endocrinal hormones produced here for the regulation of glucose.

These islets in the pancreas constitute only about 1% of the pancreatic volume, but receive 15% of the blood flow. The measure blood glucose levels constantly in real time. There are about 3 million islets in each healthy human pancreas and they are each about 100 microns in diameter.

Hormones produced in the pancreatic islets are secreted directly into the blood flow by (at least) five types of cells. In rat islets, endocrine cell subsets are distributed as follows:^[6]

Beta cells producing insulin and amylin (≈70%)
Alpha cells producing glucagon (20% of total islet cells)
Delta cells producing somatostatin(<10%)
Epsilon cells producing ghrelin (<1%)
PP cells (gamma cells or F cells) producing pancreatic polypeptide (<5%)

Our main interest here is the function of insulin and glucagon. To be healthy our bodies seek to regulate blood glucose levels between 70 and 110 mg/dl. Glucose is of particular interest to the brain which has glucose and oxygen as the only things it needs to be happy.

On the other hand our heart generates energy through processing amino acids and enzymes and does not directly process glucose.

Here is how these two things work:

Glucagon: when the blood glucose levels go much below 70 mg/dl, the brain screams out and the isles of Langerhans make glucagon, and glucagon does everything more or less in opposition to insulin:

It converts sugars stored in the glycogen and liver to glucose and makes it available.
It converts LDL to HDL so to turn it into glucose
When this runs out it starts to convert any adipose fat tissue available to glucose. (Fat burning)

Insulin: When blood sugar levels run over 120 mg/dl the Isles of Langerhans issue insulin, and this hormone does everything in opposition to glucagon:

It converts HDL to LDL to shunt its pathway to glucose
It stores glucose in the liver and glycogen
It converts glucose to adipose fat tissue.

In our evolutionary diet we had very little, actually very close to no, modern nutritional starches. So we did not have these things:

White flower
Sugar
High Fructose Corn Syrup
Artificial Sweeteners
Fruit Juices
Soft drinks
Carbonated beverages (The CO2 hits the blood with an acid shift far away from the desired ph.
White flower bread
White Flower pasta
Potatoes
Candy
Cookies
Cake

The cascade and plague of diabetes is almost entirely self-inflicted. In this case I mean to address only Type II Diabetes. So many of us have flooded our bodies with such high sugar levels during our waking ours that we are constantly overloaded with insulin, we become resistant and then we become fat. The big fat bellies we have are an artifact of so much insulin storing glucose that had to be removed from the blood stream as adipose fat tissue.

Heart Disease is similarly self-inflicted:

I founded a company 15 years ago called Prescient Medical to use hyper spectral infrared interferometry in small fibers in catheters to measure the geometries and chemistry of the artery walls immediately after and during heart attacks and strokes. Well we found the hard plaques were virtually never involved in these events, “hot” or “vulnerable” plaques were the cause. The etiology of these turned out to be a combination of scurvy and too much insulin! Google scurvy and smoking! Each cigarette removes 25 mg of vitamin C and for millions of years humans along with ground hogs and apes etc have not made vitamin C in the liver! So you cannot solve lung cancer for smokers, but heart disease can be dramatically reduced by taking large amounts of vitamin C.

None other than Linus Pauling made this a life’s work after winning two Nobel Prizes solo. And the medical doctors published rebuttals saying he was not qualified to do such work since he lacked a medical degree!

(And he missed stealing Watson and Crick’s prize by just 90 days. The summer before they made their discovery, and Rosalind Frankland absolutely deserved full equal credit, Linus sat down with Rosalind Franklin, who was using using X-ray diffraction to study DNA in which Pauling was an expert in X-Ray Diffraction and was taking this approach to learn about DNA himself, and helped her solve her problems resolving the images.)

Well, Pauling learned among other things that we cannot make collagen without vitamin C and that the Federal minimum daily allowance is two orders of magnitude less than we need for optimal health, the MDA supports survival not health.

You don’t make Vitamin C! And you need it to be healthy. From an evolutionary point of view primates stopped making Vitamin C in the liver about 6 million years ago. Comparing our body mass and metabolism to other large animals that make vitamin C in their liver, we probably need about 3-9 grams per day! And to further challenge us, it is water soluble, so as it moves from your digestive tract into your blood, you will eliminate it within four hours!

Thanks to the works and publications of Linus Pawling we know that Human beings and other higher order primates stopped making vitamin C quite some time ago. Vitamin C is critical to making and maintaining collagen, to metabolizing cholesterol, it is a powerful antioxidant, and you don’t make it, you must consume it, probably in four hour cycles all day long.

Pawling believed it was likely we stopped making vitamin C when our predecessors lived in warm and sunny climes and were consuming large regular quantities of foods rich in Vitamin C that satisfied our requirements. He reasoned that evolution would favor only making what we can’t consume; if we can and are satisfying our vitamin C requirements from our diet, it would be inefficient for the body to waste energy making vitamin C.

As time went on, our ability to consume the necessary requirements was diminished as we moved to colder climes, as the ice ages moved in, as our diet changed. And of course the body had to adapt.

Vitamin C is so important on so many fronts, but a key one is the making of collagen. Collagen is the rebar in your connective tissue; skin, arteries veins etc. The body must constantly make collagen to repair, build, and rebuild your connective tissue. Without adequate constant supplies of vitamin C, you cannot make as much collagen as is required to maintaining good health and well-being with regard to connective tissue.

But vitamin C being water soluble also does not so efficiency enter the cell plasma membranes, but is washing by these membranes. When a molecule like astaxanthin is ready to send away a denatured oxygen singlet, vitamin C is there to carry it away and eliminate it through the liver. Most all the vitamin C we consume is eliminated in 4-6 hours.

We now know that the reason the heart attack and stroke causing lesions occur in the first several mm of the coronary arteries is that this is where mechanical stresses are greatest. When there is a deficiency of vitamin C, the body is not able to repair the cracks which can occur in these areas of great mechanical stress on the arteries. These cracks are probably set up by weakened structural integrity in the artery walls. And this is most likely related to weakness caused vitamin C deficiency causing poor collagen fabrication.

Well life does all it can to preserve itself, and so lacking the power to make collagen, the body makes a patch out of a special low density lipoprotein (a) and keeps us alive. In the absence of adequate vitamin C, this patch grows, and, bingo, one day it fails, and you have a heart attack! This patch in this crack is something the LDL wants to find since it is highly hydrophobic and the crack is a way out of the water based blood plasma.

So if we have low grade scurvy, highly enabled by smoking, and we couple this with pre Type II diabetes, highly enabled by a diet rich in modern nutritional starches, we have the two main factors in the etiology of heart disease and eventually you will have a heart attack or stroke. Self-inflicted.

Many leading researchers now consider cardiac heart disease “low grade scurvy”. The required minimum allowances are interesting in this regard: they describe the amount of a vitamin you need to avoid deathly disease! So in this case the RMA for vitamin C is enough to avoid scurvy, which in this case means your gums are not bleeding and your teeth are not falling out. But now it seems that a lower grade scurvy occurs in your heart and causes the lesions that later become heart attacks.

Of course we all know that smokers suffer much higher rates of cardiovascular disease than nonsmokers. I was stunned to learn that each cigarette smoked burns up about 25 milligrams of vitamin C! If a person, for example my parents, smoke 50 cigarettes a day, they are burning up 1,250 milligrams of vitamin C each day. But it is much worse than this due to the fact that cigarette smoking is done continuously all day in micro doses. Such smokers light up upon waking and space their cigarettes evening all day long.

Consider that we believe that most average Americans consume each day at most a few hundred milligrams of vitamin C from their diet, and most pills could add 50-250 milligrams. However, remember, you need vitamin C all day, and if you take that pill or eat only a single meal per day with vitamin C bearing foods, your body eliminates the water soluble vitamin C in a few hours and the rest of the day you are deficient.

If you are smoking all day, you are eliminating vitamin C all day, most of which time you are already deficient. This explains to me why my father spent years with blood in his stool, why he often coughed up blood in a coughing fit, why his wounds took so long to heal, why he died of a heart attack; he had scurvy. Because of his diet and his smoking, he was severely vitamin C deficient; his body was crippled in manufacturing collagen, and his connective tissue was in poor health for decades. In this sense, he did not die from the heart attack; he died from scurvy!

That this should be true in this day and age really does beg the question, is the emperor naked? Sure, he should not be smoking, everyone agrees smoking is bad for your health. But, if you do smoke, you need to take regular time based doses of vitamin C to assure the health of your connective tissue. The cost of these doses is a few dollars a month, the cost of not taking this vitamin C is scurvy.

Some Conclusions:

Astaxanthin is a necessary component of a healthy diet. It is shown than at lease 6 mg of highly bioavailable astaxanthin is a healthy daily dose.

Astaxanthin protects the mitochondria from itself, it takes away the damaging dangerous ROS before they can inflict injury.

In doing so they protect several critical molecular chemistry/biology processes and pathways. These include the eicosanoid system. They also protect the body’s energy furnace to make all the energy required.

The Eicosanoid system is a regulatory system involved in both anti-inflammatory and inflammatory responses, both are required for good health, but in balance;

Because the Eicosanoids are made and used instantly, a healthy balance of Omega 3 and Omega 6 fatty acids in our diet and body is important;

The Endocannabinoid System (ECB System) plays an important role in optimizing the performance of the Eicosanoid system. It does this by stimulating the release of arachidonic acid, a precursor in all eicosanoid biosynthesis.

It is critical to protect these processes from ROS and oxidative stress will optimize these processes. This requires resident anti-oxidants.

CBD is made in our body, which is why it is called an “Endo” system and is essential to our health, Supplementing CBD enhances the body’s function in these regards.

A healthy intake and residence of powerful antioxidants can be very important.

We are unlikely to return to the hunter gatherer diet. But we have to find a powerful way to limit the modern nutritional starches, and we have to find a powerful way to populate our mitochondria and cell plasma membrane with anti-oxidants. As one can see in the addendum, astaxanthin in a bio available form is by far the best way to achieve the later half of this requirement.

And we have to empower, optimize and enable the eicosanoid system, and combing a bio available nano emulsion of CBD and astaxanthin is the most powerful way of doing this.

Nano emulsions of many of these hydrophobic molecules is critical to efficacy.

And the astaxanthin is critical to protecting other constituents necessary for our biological functions, including COQ10, selenium, taurine, arachidonic acid, CBD and many, many others.

So if one follows these very simple and easy to follow guidelines, one is likely to live a long disease free healthy life and avoid autism, Alzheimer’s, Parkinson’s, Heart Disease, Liver and Kidney Disease, Cognitive Decline, many forms of cancer and arthritis and the like.

A lifetime habit and regular intake of a nano emulsion of very small amounts of CBD and,
A lifetime habit and regular intake of a nano emulsion of very small amounts of astaxanthin,
A healthy balance of Omega III and VI (1 : 2 or so) and
Strict limits on modern nutritional starches, sugars, juices, sulfur, refined starches, high fructose corn syrup, artificial sweeteners, alcohol and the like. From diet maintain blood sugar between 70 and 110 mg/dl consistently.
Lots of vitamin C is the basis of a very healthful diet and prognosis for a disease-free healthy life.
Don’t smoke

Understanding the evolution, history, science, culture and context of all this is very complicated. But once addressed the big picture becomes very simple. Understanding our biological systems and functions in the perspective of our evolutionary diet is the best approach to very good understanding.