Stella Maris, LLC - Overview - Non-Confidential

STELLA MARIS, LLC

OVERVIEW

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The information in this document is provided for informational purposes only. Stella Maris, LLC does not offer any guarantee for the accuracy and comprehensiveness of its contents. Stella Maris, LLC makes no representations or warranties of any kind, whether express, implied or statutory or otherwise, as to the information in this document and specifically disclaims implied warranties of merchantability or fitness for a specific purpose. The information contained in this document is subject to change without notice.

© 2016 Stella Maris, LLC Page 1

STELLA MARIS, LLC

OVERVIEW

Despite decades of research, Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), Autism and Alzheimer’s disease (AD) are destructive diseases affecting millions of people in the United States and millions more worldwide, each without an agreed upon etiology or standardized treatment protocol. While these diseases affect disparate groups of people, each one is characterized by mitochondrial damage and oxidative stress, genetic predispositions and irregularities with metabolic processes, including the methylation pathway.

In fact, patients suffering from ME/CFS, Autism and Alzheimer’s disease share numerous possible symptoms or co-morbidities that include:

Genetic predispositions Methylation pathway problems Mitochondrial damage and dysfunction Oxidative stress Aggressive behavior Autoimmune disorders Brain region hypo perfusion Circadian Rhythm disturbance Cognitive function impairment Cytokine (pro-inflammatory) levels elevated Depression Glutathione level reduction Gluten sensitivity Headaches Insulin resistance Irritable Bowel Syndrome Muscle pain Narcolepsy


Serotonin low or its antibody is elevated Sleep disturbances including sleep apnea Triglyceride levels elevated

Additionally, common to all three diseases are irregularities involving:

Cerebral imaging Dopamine levels GABA / Glutamate Gut biome Hypothalamic-Pituitary-Adrenal Axis Insulin-like growth factor 1 Nicotinic Cholinergic System Nitric Oxide Platelet Derived Growth Factor Thyroid function Transsulfuration metabolism

Based on these common symptoms shared by patients diagnosed with these three diseases, it is possible to group them together as Mitochondrial Damage Diseases (MDDs) occurring at different periods on the spectrum of a human lifetime. The onset of Autism begins in childhood, the onset of ME/CFS takes place from the teen years to middle age and the onset of Alzheimer’s disease occurs from late middle age to old age. Besides sharing common symptoms, MDDs also share common nutritional deficiencies.

Stella Maris, LLC was founded with the purpose of addressing the health and nutritional needs of people affected by Mitochondrial Damage Diseases.


Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

According to the Solve ME/CFS Initiative website (www.solvecfs.org), ME/CFS is a disease characterized by the following symptoms, all lasting more than six months:

Concentration problems Pain Post-exertional malaise Unrefreshing sleep

People with ME/CFS also frequently suffer from the following:

Allergies and sensitivities to odors, chemicals and medications Brain fog and cognitive impairment Chills and night sweats Dizziness, balance problems and fainting Gastrointestinal disturbances Irritability, depression and mood swings Visual disturbances (e.g., blurring, eye pain, light sensitivity) For women, gynecological problems including PMS

Common conditions that occur along with ME/CFS are:

Chronic pelvic pain Fibromyalgia Irritable bowel syndrome Interstitial cystitis (bladder pain syndrome) Multiple chemical sensitivity Orthostatic (standing upright) intolerance Temporomandibular joint disorder (problems with jaw and face

muscles)

In the United States, at least one million people are affected by ME/CFS and millions more worldwide have been diagnosed with the disease. Studies have shown that ME/CFS disproportionately affects more women than men. Diagnosis of ME/CFS can be difficult since the disease shares symptoms with


http://www.solvecfs.org/

other diseases and there is no single test or biomarker that can be used to diagnose the disease conclusively. Since no cause or cure has been identified for ME/CFS, there is no single treatment prescribed that resolves the disease. It is possible that millions of people suffering from ME/CFS have not been properly diagnosed.

The total annual economic cost in the United States associated with ME/CFS has been estimated to range from $9.1 billion to $23.9 billion.i ii

Autism


According to the Autism Speaks website (www.autismspeaks.org), Autism spectrum disorder (ASD) and Autism are terms applied to a group of complex brain development disorders having their genesis in very early brain development. In the 2013 publication of the DSM-5 diagnostic manual, all subcategories of Autism disorders were merged into one broad diagnosis of ASD.

ASD is characterized by:

Nonverbal communication difficulties Verbal communication difficulties Repetitive behaviors Social interaction difficulties

ASD patients may also have:

Attention deficits Difficulties in motor coordination Gastrointestinal disturbances Intellectual disabilities Sleep disturbances

Despite these symptoms, some people diagnosed with ASD may show exceptional talent in math, music and art.

It is estimated by Autism Speaks that in excess of 3 million people in the United States and tens of millions more globally are affected by Autism Spectrum Disorder. In the United States, 1 out of 42 boys and 1 in 189 girls are diagnosed with Autism, resulting in 1 out of 68 American children being placed on the ASD spectrum. This represents a ten-fold increase in 40 years, with prevalence rates increasing by more than 10 percent annually. There are no commonly agreed upon reasons for this continuing escalation in the incidence of Autism.

Most scientists specializing in the disease believe there is no single cause of Autism. Rather, research has shown that genetic predispositions when


http://www.autismspeaks.org/

combined with outside, environmental stress add to the increased risk of a child being affected by ASD.

In the United States, the yearly cost of caring for Autism patients has been estimated at $236 billion, with $61 billion of the total spent on children and $175 billion spent on adults. The lifetime cost of caring for an Autistic individual with an intellectual disability averages $2.4 million; the total lifetime cost of caring for an Autistic individual without an intellectual disability is estimated to be $1.4 million.iii

Alzheimer’s disease


According to the Alzheimer’s Association website (www.alz.org), AD is the most common form of dementia and causes problems with thinking, behavior and memory. While symptoms may vary widely, at least two of the following functions must be significantly impaired to be considered dementia (and therefore AD):

Ability to focus and pay attention Communication and language Memory Reasoning and judgment Visual perception

A primary risk factor for AD is aging and the time of onset is usually between the ages of 60 and 70 years. The symptoms of Alzheimer’s disease develop slowly and become worse over time during a seven stage process. In the early stages, memory loss is mild but in the later stages AD patients can lose the ability to carry on a conversation or respond to their environment. In AD’s later stages, patients typically require high levels of assistance with daily activities and personal care. Current treatments cannot halt the progression of AD but may slow the advance of its symptoms and increase the quality of life for AD patients and those caring for them.

In 2016, an estimated $230 billion will be spent in the United States to care for the 5.3 million people suffering with AD and other forms of dementia. The cost of caring for Americans affected by AD and other forms of dementia could exceed $1.1 trillion annually by 2050. It is estimated that 46 million people worldwide are affected by AD today and that the number is expected to grow to 115 million by 2050.iv

Processes Implicated in Mitochondrial Damage Diseases


http://www.alz.org/

Just as the three diseases - ME/CFS, Autism and AD - share dozens of common symptoms, they also share numerous nutritional deficiencies which either contribute to the cause of each disease or exacerbate its symptoms. Stella Maris believes that mitochondrial damage and oxidative stress are significant contributing causes of each MDD and that deficiencies in the antioxidant defense system are associated with each one. Two important processes implicated in mitochondrial damage and oxidative stress are cellular respiration and epigenetic regulation.

Cellular Respiration

Cellular respiration is the group of metabolic processes and reactions that take place in the cells to convert biochemical energy from nutrients to adenosine triphosphate (ATP). Cellular respiration’s processes and reactions break large molecules into smaller ones, releasing energy. The energy stored in ATP can be used to drive processes requiring energy, including physical locomotion, the movement of molecules across cell membranes and biosynthesis. The three main stages of cellular respiration are glycolysis, the Krebs (citric acid) cycle and electron transport/oxidative phosphorylation.

Mitochondria are one of the components of human cells, with muscle cells containing as many as 5,000 per cell. Mitochondria are known to be the “powerhouse of the cell” because they generate 90% of the body’s energy by making ATP, which is the main source of the body’s energy supply. Mitochondria “contribute to many cellular functions including bioenergetics processes, intracellular calcium regulation, alteration of reduction-oxidation potential of cells, free radical scavenging and activation of caspase mediated cell death”v. American and Korean researchers have stated that “mitochondria are critically important in providing cellular energy as well as” being involved in “anti-oxidant defense, fat oxidation, intermediate metabolism and cell death (apoptosis) processes.”vi

ATP is itself known as the “molecular unit of currency” because of its role in intracellular energy transfer. The adult human body contains approximately


250 grams (8.8 oz) of ATP which is recycled continuously so that it turns over its own body weight of ATP each day.

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen and are formed as a natural byproduct of the normal metabolism of oxygen. “ROS have crucial roles in normal physiological processes, such as through redox regulation of protein phosphorylation, ion channels and transcription factors”vii as well as in cell signaling and homeostasis. “Oxidative stress occurs as a consequence of an imbalance between ROS production and the available antioxidant (defense) against them.”viii

Poorly functioning cellular respiration results in mitochondrial damage and dysfunction the effects of which can be worsened if the methylation pathway (see below) isn’t working efficiently. Dozens of studies have shown that mitochondrial dysfunction and oxidative stress, including elevated levels of ROS, are characteristic of MDDs. ix x xi xii

Healthy mitochondria are required to synthesize ATP efficiently in the Krebs cycle and electron transport/oxidative phosphorylation. If ATP is not made efficiently, energy production is impaired and the body lacks the energy required to carry out the functions needed every moment of every day. Without an efficient supply of ATP, chronic disease ensues.

A paper published in April 2015 by researchers at the University of Pisa illustrates the role of healthy mitochondria in good health and conversely, the role of damaged mitochondria in chronic disease. These scientists discuss the role of mitochondrial dysfunction in Alzheimer’s disease and focus “on the mechanisms that lead to mitochondrial impairment, oxidative stress and neurodegeneration – a vicious circle that ends in dementia.” xiii

In short, ATP is essential to the performance of bodily processes and healthy mitochondria are imperative for good health because of their role in the production of ATP.

Epigenetic Regulation


Epigenetics is the study of cellular and physiological phenotypic trait variations that result from external or environmental factors that affect how cells express genes and switch genes on and off. A significant metabolic process involved in epigenetic regulation and which is implicated in ME/CFS, Autism and AD, is the methylation pathway. Studies have shown that patients with each of these MDDs have both a higher incidence of methylation problems and MTHFR polymorphisms. xiv xv xvi xvii xviii xix xx xxi

The process of methylation involves the addition of methyl groups, composed of one carbon atom bonded to three hydrogen atoms, to various constituents of DNA, proteins and other molecules. Methylation processes occur in hundreds of essential chemical reactions in the human body. The functions of the methylation pathway includexxii:

Coenzyme Q10 production Detoxification in the liver Folate metabolism Genetic protein synthesis Glutathione synthesis Hormonal regulation Inflammation reduction Neurotransmitter synthesis and utilization

One of the primary functions of the methylation pathway is to make and repair DNA and to regulate the switching of genes on and off. Nerve function is dependent on this process working properly since without efficient methylation proper communication between the nerves won’t occur. Methylation also controls the production and subsequent breakdown of neurotransmitters which function as the chemical messengers in the nervous system and brain and act as a means of communicating with the immune system’s cells.

Another role of the methylation pathway is to process and remove fats and cholesterol so that they won’t clog blood vessels. Methylation also regulates the function of the hormones testosterone and estrogen and the levels of histamine within the body. Additionally, the methylation pathway repairs


proteins, including hemoglobin, which are a part of the red blood cells that delivers oxygen throughout the body and then returns with waste products for disposal. The process of methylation can also affect cell membrane permeability.

One of the most detrimental consequences of poor methylation is the buildup of homocysteine, which is produced when a methyl group is taken from SAMe (S-adenosylmethionine). If methylation is efficient, the body recycles homocysteine back to SAMe by adding a methyl group; the cycle is complete and then begins again. However, when the methylation process is hampered, homocysteine can become elevated beyond normal levels.

Higher than normal levels of homocysteine have been implicated in:

Accelerated agingxxiii

Alzheimer’s disease and dementiaxxiv

Depressionxxv

Heart diseasexxvi Liver diseasexxvii

Strokexxviii

Possible Causes of Mitochondrial Damage Diseases


While the incidence of ME/CFS, Autism and Alzheimer’s disease has risen notably in the past 50 years, human genetics haven’t changed. Rather, Stella Maris believes that the increased harm to human health from exogenous environmental stress may be one of the most significant contributors to the accelerating prevalence of MDDs during the past five decades. People with chronic, multi-factorial diseases are the greatest sufferers from heightened environmental stress since they are likely the most genetically susceptible to diseases in which numerous environmental factors play a role.

Dozens of studies have demonstrated that patients diagnosed with ME/CFS, Autism and Alzheimer’s disease often have mitochondrial damage and impaired metabolic processes. xxix xxx xxxi xxxii xxxiii xxxiv xxxv xxxvi xxxvii xxxviii xxxix xl xli

Stella Maris believes that these 10 classes of environmental stress have significantly contributed to the rise of MDDs during the past several decades:

Commonly Prescribed Drugs

Acetaminophen Macrolide and other antibiotics Nonsteroidal anti-inflammatory drugs

Food and Drink Related

Alcohol Chloroacetic acid Fructose High fat diet Propionic Acid

Heavy metals

Ionophores

Manufactured Natural

Pathogens


Bacterial infections Viral infections

Personal Consumer Products

Aluminum Butylparaben Fluoride

Pesticides and Herbicides

Smoking

Advanced Glycation End Products (AGEs)

Drugs of Abuse

Stella Maris believes that a common characteristic of all these sources of environmental stress is that they disrupt efficient ATP production and cause mitochondrial damage and oxidative stress.

One hypothesis is that the dozens of common symptoms of MDDs are the consequence of oxidative stress and mitochondrial damage and dysfunction. Mitochondrial damage may cause oxidative stress, which in turn, may cause further mitochondrial damage, resulting in the dozens of downstream symptoms enumerated above. Furthermore, these environmental stresses may combine to create an allostatic load that causes chronic disease such as MDDs, especially among people who are genetically susceptible, including people who have MTHFR and other genetic polymorphisms.

Commonly Prescribed Drugs


Commonly used household drugs can cause a reduction in ATP synthesis. Acetaminophen is a well know painkiller and fever reducer that is known to increase ROS production, induce oxidative stress and reduce the mitochondrial glutathione pool. xlii xliii xliv In a 2012 study, Czech researchers concluded that rats fed a high fat diet were more susceptible to the acute toxic effect of acetaminophen, compared to those with a non-steatotic liver. xlv

Widely prescribed antibiotics such as Azithromycin and Clarithromycin are used to treat bacterial infections yet both are macrolide antibiotics (and ionophores) which may cause mitochondrial dysfunction. The mitochondrial ATP Synthase F1F0 complex is highly sensitive to macrolide antibiotics, which block proton conductance through the inner mitochondrial membrane, resulting in the inhibition of ATP synthesis and hydrolysis. xlvi While macrolide antibiotics are proven to be effective compounds to treat bacterial infections, they may substantially reduce ATP production by inhibiting ATP Synthase (Complex V) in the electron transport chain and disrupting the proton gradient in the mitochondria.

It has been shown that non-macrolide antibiotics can severely impair mitochondrial function. In March 2015, researchers from the Swiss Federal Institute of Technology in Lausanne, Switzerland published a paper in which tetracycline-based antibiotics are shown to have significant negative effects on mitochondrial ability to produce ATP. xlvii xlviii These researchers stated their belief that the long term consequences of these antibiotics on metabolic processes have not been adequately considered by research scientists. In 2011, 5.6 million kilograms of tetracycline were administered to US livestock.

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, among others, are effective inhibitors of ATP production due to their effect on mitochondrial complex I. xlix Dutch researchers found in 2012 that “mitochondria and oxidative metabolism also contribute to the toxicity of the NSAIDs, ibuprofen and naproxen.” l

Food and Drink Related


Alcohol has been shown to induce mitochondrial damage and oxidative stress. In 2000, researchers at the Indiana University School of Medicine wrote that “important mechanisms responsible for alcohol-induced liver injury include mitochondrial damage and the loss of ATP…. (and) release of the reactive oxygen species from (the) mitochondrial electron transport chain.” li A University of Alabama at Birmingham researcher stated in 2003 that “ethanol has been demonstrated to increase the production of reactive oxygen and nitrogen species and decrease several antioxidant mechanisms in (the) liver.” The article examined the “critical role of these reactive species in ethanol-induced liver injury with specific emphasis on how chronic ethanol-associated alterations to mitochondria influence” the production of ROS. lii

Chloroacetic acid (CA), a toxic chlorinated analog of acetic acid, is widely used in manufacturing a variety of products including herbicides, pharmaceuticals and cleansing agents used in shampoos. liii Taiwanese scientists found in 2013 that “in addition, CA has been found as a by-product of chlorination disinfection of drinking water … (and) the toxic effects and molecular mechanisms of CA-induced neuronal cell injury are mostly unknown.” They went on to summarize their findings that treatment of Neuro-2a cells with CA resulted in mitochondrial dysfunction, increased the generation of ROS, significantly reduced the number of viable cells and reduced the levels of intracellular glutathione. liv

Fructose is a common sweetener used in soft drinks and food products and has been linked to increases in triglyceride levels, body weight and visceral adipose tissue. According to a 2013 paper published by a Louisiana State University researcher, “fructose is metabolized primarily in the liver. When it is taken up by the liver, ATP decreases rapidly as the phosphate is transferred to fructose in a form that makes it easy to convert to lipid precursors. Fructose intake enhances …. the production of uric acid. ” lv Mexican and American researchers stated in 2015 that “long term hyperuricemia (excess levels of uric acid) induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress and mitochondrial dysfunction and decreased ATP levels” and that “renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which


represent an additional pathogenic mechanism induced by chronic hyperuricemia.” lvi Based on these and other studies, the linkage between oxidative stress in people consuming food and beverages containing excessive amounts of fructose has been made.

A high fat diet has been shown to decrease oxidative phosphorylation (the process of ATP production), result in nonalcoholic steatohepatitis and increase gene expression of cytokines in rats. lvii Rats fed a high fat, high sucrose diet for 8 months demonstrated a decreased level of glutathione production and decreased ATP production. lviii Scientists at Seattle’s Virginia Mason Medical Center have also found that leptin-receptor deficient mice fed a “diet high in unsaturated fat develop weight gain and NASH (nonalcoholic steatohepatitis) through adiponectin depletion, which is associated with adipose tissue inflammation and hepatic mitochondrial dysfunction.” lix

Research scientists regularly use propionic acid to simulate the effects of Autism in order to understand the mechanism of neurotoxicity in lab animals.lx lxi Remarkably, propionic acid and propionates are used extensively as preservatives in foods for human consumption (such as baked goods) and in animal feed, due to their ability to inhibit bacterial and mold growth. Propionates occur in small amounts in foods such as cheese and are also produced during the digestion process in human and ruminant guts. However, propionic acid is known to induce autistic behavior in lab animals, which is a reason for its use by research scientists. A Vitamin B-12 dependent enzyme is required to metabolize propionic acid to succinyl-CoA, an intermediate which can then be used in the Krebs cycle. Yet, if an individual’s methylation pathway functions inefficiently due to a genetic inability to synthesize Vitamin B-12 in its active form, a hypothesis is that propionic acid can build up and result in autistic behavior, mitochondrial damage and oxidative stress. lxii

Heavy Metals


Heavy metals such as lead, mercury, cadmium and arsenic have been implicated in Alzheimer’s disease due to their ability to increase beta-amyloid peptide and the phosphorylation of Tau protein, which are biomarkers of brain plaque characteristic of the disease. In a 2015 study conducted by researchers based in Mexico City, these heavy metals were associated with oxidative stress and mitochondrial dysfunction involved in neurodegenerative diseases, including AD. lxiii In a 2014 study of children diagnosed with Autism, an Egyptian researcher found significantly higher blood levels of mercury and lead in the ASD patients than in a control group. Moreover, this researcher found that autistic symptoms declined with a decrease in the blood levels of mercury and lead.lxiv Researchers at Cleveland State University in 2015 argued “that changes in oxidative metabolism, thiamine homeostasis, heavy metal deposition and cellular immunity have a role in the etiopathogenesis of autism and ASD.” They went on to state that “we suspect that children with ASD and forms of autism may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations.”lxv

Ionophores

Manufactured (synthetic) ionophores are an example of an environmental stress that can greatly reduce the amount of ATP people produce. Ionophores are known uncouplers of the actions of the electron transport chain from ATP production, which is known as oxidative phosphorylation. There are many well known ionophores and uncouplers used by scientists to perform a variety of actions, including the separation of the action of the electron transport chain from oxidative phosphorylation. Due to their toxic effects, ionophores are considered poisons. lxvi

Calcium ionophore A23187 is actively used to study cell injury. University of North Carolina researchers in 1999 used this ionophore to induce the opening of the mitochondrial permeability transition, cell death and significant ATP depletion. lxvii Scientists at the University of Lodz in Poland found in 2005 that rat neonatal cardiac myocytes treated with Calcium ionophore A23187 responded with an increase of ROS, decreased


mitochondrial potential and ultimately cell death. lxviii Another ionophore, valinomycin, has been shown to depolarize the proton gradient in mitochondria and induce apoptosis, mitochondrial swelling and minor nuclear changes in cell lines. lxix lxx lxxi Disrupting ATP production can be caused by numerous environmental sources. In 2008, Johns Hopkins researchers published a paper in which they identified more than 250 natural and synthetic inhibitors of ATP Synthase including ionophores. lxxii

People may be exposed to the harmful effects of ionophores by eating poultry and beef, since commercially available synthetic ionophores are used extensively as feed additives for both chickens lxxiii lxxiv and cattle. lxxv lxxvi lxxvii The use of ionophores as feed additives in the beef industry has been promoted on the basis of its economic benefit. lxxviii However, the long term consequences of humans eating chicken and beef produced from animals that have been fed ionophore additives have not been thoroughly researched, particularly for people with the inability to excrete ionophores efficiently due to poorly functioning methylation.

Besides synthetic ionophores, there are ionophores that occur in nature including dinoflagellates (salt water and fresh water plankton) and mycotoxins produced by mold. The work of Dr. Ritchie Shoemaker (see www.survivingmold.com) is especially significant as he has identified various natural ionophores. Dr. Shoemaker has also created a treatment protocol for people suffering from Sick Building Syndrome, which is often the result of mold produced mycotoxins. lxxix lxxx

Toxins produced by mold and other naturally occurring ionophores can have a profound effect on human health. Scientists use a mycotoxin produced by dinoflagellates, okadaic acid, to induce neurotoxicity in lab animals. Okadaic acid has been shown to impair memory function, cause mitochondrial dysfunction, induce cholinergic dysfunction and cause oxidative stress. lxxxi lxxxii Moreover, okadaic acid has been linked as a cause of the hyperphosphorylated tau protein present in the intraneuronal neurofibrillary tangles that are a characteristic feature of AD’s neuropathology. lxxxiii In summary, both synthetic


http://www.survivingmold.com/

and natural ionophores can cause mitochondrial damage and reduce ATP production.

Pathogens

Both viral and bacterial pathogens can cause mitochondrial damage. For example, the Epstein Barr virus which causes mononucleosis has been shown to cause mitochondrial dysfunction and alterations in gene expression months after the initial infection. lxxxiv Lyme disease is transmitted by the bite of a tick infected by the bacterial spirochete Borrelia burgdorferi. Researchers have found an imbalance in ROS and cytosolic calcium in Lyme disease patients, indicating oxidative stress and mitochondrial dysfunction. lxxxv Of special significance is the association research scientists have found between mothers with Lyme disease and their children with Autism spectrum disorders. lxxxvi

Personal Consumer Products

Aluminum is a lightweight metal that is found in abundance in the Earth’s crust. It has numerous uses in manufacturing including in cutlery, baseball bats and airplane and car parts. Aluminum is also used in personal consumer products such as antiperspirants and as vaccine adjuvants. Researchers have linked aluminum to the production of oxidative stress, which in turn, has been linked to various neurodegenerative diseases. lxxxvii In a rat model, aluminum induced oxidative stress caused reduced mitochondrial biogenesis. lxxxviii

Butylparaben is an organic compound that is used as an antimicrobial preservative in cosmetics. In February 2015, Egyptian researchers found “several parallels between paraben intoxication signs and the effects of paraben in an autism like rat model. These parallels included: oxidative stress, decreased glutathione levels, mitochondrial dysfunction, pro-inflammatory cytokine levels in the brain and a significant disturbance in the production of ATP” and other energy carriers. The study’s authors commented that “paraben may, to some extent, either cause or contribute to


the brain physiopathology in ASDs (autism spectrum disorders) or pathogens that produce the brain pathology observed.” lxxxix It has also been found that “butylparaben and methylparaben demonstrate transplacental passage” in humans xc and that “prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA (valproic acid) model of autism” in rat pups. xci

Fluoride is a primary ingredient in toothpaste. It has been shown to induce oxidative stress, generate ROS, deplete glutathione, cause DNA damage and lead to apoptosis in a number of research studies. xcii xciii xciv xcv xcvi xcvii

Pesticides and Herbicides

Portuguese researchers published a paper in 2014 stating that “for the main neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) there are evidences linking their etiology with long-term/low-dose exposure to pesticides such as paraquat, maneb, dieldrin, pyrethroids and organophosphates. Most of these pesticides share common features, namely the ability to induce oxidative stress (and) mitochondrial dysfunction.” xcviii

Iranian scientists wrote in 2013 that “there is a huge body of evidence on the relation between exposure to pesticides and (the) elevated rate of chronic diseases such as …. neurodegenerative disorders like Parkinson’s, Alzheimer’s and ALS.” They went on to state that “the common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides’ primary action like perturbation of ion channels, enzymes, receptors, etc.”; their objective was to “present the highlighted evidence on the association of pesticides’ exposure with the incidence of chronic diseases and introduce …. mitochondrial dysfunction and oxidative stress”, among other things, as “the effective mechanisms of action.” xcix


Chlorpropham is an herbicide and plant growth regulator used as a sprout suppressant for, among other things, grass weeds, beans, blueberries, carrots, cranberries, onions, spinach and tomatoes. Chlorpropham is also used in potato storage to inhibit sprouting. Japanese scientists found in 2004 that chlorpropham when exposed to rat hepatocytes “caused a concentration and time dependent cell death accompanied by a loss of cellular ATP and adenine nucleotides … and (it) led to a strong decrease in cellular ATP content compared to (two) of its metabolites.” These researchers further stated that chlorpropham “toxicity is associated with a rapid depletion of ATP via impairment of mitochondrial function related to oxidative phosphorylation.”c Belgian researchers stated in 2002 that “studies carried out in 1999 by the University of Ghent showed that 36% of potatoes’ samples contained chlorpropham residues and that 7.9% of them exceeded the maximal limit of residues, fixed at 5 ppm.”ci The USDA, in a study published in November 2012, found that chlorpropham was detected in 57.8% of sampled organic potatoes at or exceeding a level of 0.01 ppm. cii

Smoking

Smoking is another cause of mitochondrial damage and oxidative stress. Researchers in Spain found that tobacco consumption by pregnant women correlated with a reduction in birth weight and mitochondrial impairment and oxidative stress. ciii In 2014, Mayo Clinic scientists found cigarette smoke “induced mitochondrial fragmentation and damaged their network morphology in a concentration-dependent fashion.” civ Australian researchers, after analyzing multiple studies, stated that “a large heterogeneous literature was reviewed that detailed the association between cigarette smoking and …. disorders with structural brain changes, inflammation, and cell-mediated immune markers, markers of oxidative and nitrosative stress (and) mitochondrial dysfunction.” cv


Advanced Glycation End Products (AGEs)

University of Illinois scientists stated in 2010 that “advanced glycation end products (AGEs) are a heterogeneous, complex group of compounds that are formed when reducing sugar reacts in a non-enzymatic way with amino acids in proteins and other macromolecules. This occurs both exogenously (in food) and endogenously (in humans) with greater concentrations found in older adults…In the last twenty years, there has been increased evidence that AGEs could be implicated in the development of chronic degenerative diseases of aging, such as cardiovascular disease, Alzheimer’s disease and with complications of diabetes mellitus.”cvi Korean researchers in a study that same year concluded that “our data showed that APP (amyloid precursor protein) was up-regulated by AGES in vitro and in vivo, and pretreatment with an ROS inhibitor (N-acetyl-L-cysteine) blocked the effects of AGEs. In conditioned medium, the level of Abeta (1-42) increased after AGEs treatment. Furthermore, the combination of AGEs and aggregated Abeta (1-42) increased ROS production and decreased cell viability.” cvii AGEs have been implicated in both the formation of amyloid beta and neurofibrillary tangles associated with AD. cviii cix

German researchers wrote in 2006 that “the morphological hallmarks of SAD (sporadic Alzheimer’s disease) neuritic plaques and neurofibrillary tangles have been demonstrated to crosslink AGEs causing an increased rate of free radical production.” cx Significantly, in 2015 a researcher at the Medical School in Poitiers, France looked at the effect of dietary AGEs and the prevalence of AD and found that “reduced dietary AGEs significantly correlates with reduced AD incidence. For ecological studies, estimates of dietary AGEs in the national diets corresponded well with AD prevalence data even though cooking methods were not well known”, concluding that “dietary AGEs appear to be important risk factors for AD.”cxi

Finally, a Salk Institute researcher in 2012 suggested that AGEs and methylglyoxal (MG), its precursor, are linked to Autism. She wrote that “both MG and AGEs can induce oxidative stress, inflammation and mitochondrial dysfunction and are implicated in diabetic complications and multiple, age-


related neurological diseases. Dietary consumption of AGEs and MG correlates with food intake which has increased 20% - 30% over the past 20 years … It is hypothesized that diet derived MG and AGEs in combination with inborn genetic vulnerabilities that affect cellular redox status are major contributors to the development of autism and provide a causal link between oxidative stress, inflammation and mitochondrial dysfunction.”cxii

Drugs of Abuse

Drug addiction is a worldwide public health problem, affecting millions of people and having a negative economic effect in the hundreds of billions of dollars annually. Researchers at Portugal’s University of Coimbra looked at the role of oxidative stress in drugs of abuse in a paper published in 2013. They wrote that “the most abused illicit substance is cannabis, followed by amphetamines, cocaine and opioids, with different prevalence in different countries. Several evidences support a role for oxidative stress in the toxicity induced by many drugs of abuse in different organs, such as the brain, heart, liver or kidneys. This leads to oxidation of important cellular macromolecules, and may culminate in cell dysfunction and death....oxidative stress (is) a relevant mechanism contributing (to) the cytotoxicity of drugs of abuse and (to) behavioral changes associated with drug addiction.”cxiii These same Portuguese researchers have connected amphetamine drug abuse to Parkinson disease-like symptoms, writing that “dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD (Parkinson disease) and amphetamine neurotoxicity.” cxiv

Scientists at San Diego State University in 2005 set forth the idea that the unifying theme for the toxicity and addiction of abused drugs is oxidative stress, ROS and their effects in the electron transport chain cxv cxviand have published a separate paper on the role of oxidative metabolites of cocaine in toxicity and addiction, focusing on oxidative stress and disruptions in the electron transport chain.cxvii Researchers at the Polish Academy of Sciences examined mitoepigenetics and drug addiction in a paper published in 2014. They wrote that mitochondrial DNA (mtDNA) “can be regulated by direct


epigenetic modifications. Up to now, very little data shows the possibility of epigenetic regulation of mtDNA. Mitochondria and mtDNA are particularly important in the nervous system and may participate in the initiation of drug addiction. In fact, some addictive drugs enhance ROS production and generate oxidative stress that in turn alters mitochondrial and nuclear gene expression.” cxviii

Based on the foregoing, it is clear that there are many commonplace sources of exogenous environmental stress that cause the disruption of human ATP production, mitochondrial damage and oxidative stress. The health problems and diseases caused by drug abuse, smoking, a high fat diet and bacterial and viral infections are well known by the public but the mitochondrial damage these environmental stressors cause by producing oxidative stress is largely underappreciated by most people.

What is most striking about many environmental stresses is their involvement in seemingly innocuous actions. Yet, by performing such everyday activities as taking commonly prescribed drugs; eating fruits, vegetables, bread, beef or chicken; drinking chlorinated water or alcoholic or fructose containing beverages; using consumer products such as antiperspirants or cosmetics; or living or working in buildings with Sick Building Syndrome, millions of people may be unwittingly disrupting the normal process of cellular respiration and inducing oxidative stress within their bodies, thereby causing chronic disease.

Stella Maris believes that the mitochondrial damage, oxidative stress and various symptoms of millions of people diagnosed with Mitochondrial Damage Diseases are the evidence of the disruption of normal processes of cellular respiration on a massive scale. Additionally, Stella Maris believes that the manifestation of a specific MDD depends on the type(s) and duration of environmental stress an individual is exposed to and his or her genetic susceptibilities, age, sex, etc.


Furthermore, Stella Maris believes that the association between the disruption of efficient cellular respiration as a cause of MDDs and the associated symptoms and co-morbidities is not well understood. Infrequent reductions in ATP production caused by exposure to environmental stress may be inconsequential for most people. However, for the genetically susceptible, repeated and often daily exposure to environmental stress can disrupt the body’s ability to produce ATP in a quantity sufficient to respond to the demands of modern living and cause the oxidative stress linked to numerous diseases, including AD, Autism and ME/CFS.

This may be especially true for small children who may demonstrate symptoms of Autism after exposure to environmental stress, which can occur in utero. Young adults who are genetically susceptible may find that an event such as being exposed to a virus (such as Epstein Barr) or bacteria (such as Borrelia burgdorferi) may be the tipping point for the onset of ME/CFS. And an elderly person who is genetically susceptible may succumb to Alzheimer’s disease after a lifetime of exposure to environmental stress that causes unrelenting mitochondrial damage.

The incidence of MDDs continues to grow and the scientific proof for possible causes of these diseases is at hand as shown above. By recognizing the causes of the problem, possible solutions can be created to address the health of millions of people diagnosed with the MDDs of ME/CFS, Autism and Alzheimer’s disease.


Nutritional Requirements of Mitochondrial Damage Diseases

In general, Americans do not receive the recommended daily allowance for many vitamins and minerals. The United States Department of Agriculture (USDA) estimates that millions of Americans fall short in receiving an adequate intake of numerous nutrients. For example, the USDA estimates the percentage of Americans receiving an adequate intake of Vitamin E, an important antioxidant that stops ROS formation when fat undergoes oxidation, is 13.6%. Below are the percentages of Americans receiving an adequate daily intake of the nutrient specified: cxix

Folate (Vitamin B-9) 59.7% Vitamin C 51.0% Magnesium 43.0% Calcium 30.9% Vitamin E 13.6% Fiber 8.0% Potassium 7.6%

These are averages for the overall population and do not account for the heightened nutritional needs of people affected by various disease states.

Stella Maris believes that in order to address the nutritional needs of Mitochondrial Damage Disease patients, nutritional supplementation is required well beyond the RDAs of many nutrients. Heightened nutritional supplementation is required since patients diagnosed with MDDs have severe nutritional deficiencies or biomarkers indicating a metabolic disturbance, either of which requires supplementation to address those issues.

One hypothesis is that MDDs may be the result of antioxidant defense system deficiencies caused by dysfunction of intracellular transport or enzymatic abnormalities caused by a combination of genetic polymorphisms and environmental stress.

For example, inefficient cellular respiration and the resulting oxidative stress necessitate the need for supplements critical to the improved operation of the Krebs cycle and the electron transport chain pathways of cellular


respiration. And inefficient methylation cycling necessitates the need for increases of those nutrients important in the methylation pathway. Yet the standard American diet is sorely lacking in the nutrition required to meet the daily needs of otherwise healthy persons, not to mention the needs of patients diagnosed with the Mitochondrial Damage Diseases of ME/CFS, Autism and Alzheimer’s disease.

Stella Maris believes that one of the most effective and cost efficient ways to overcome these deficiencies is for patients to use nutritional supplements or medical foods that target their underlying antioxidant defense impairments and restore normal metabolic function. In order to address the needs of ME/CFS, Autism and AD patients, Stella Maris has created several different formulations that will help them to meet their nutritional requirements.

Summary and Discussion


Stella Maris has made three significant contributions to the understanding and treatment of Mitochondrial Damage Diseases. First, by recognizing the dozens of symptoms common to Autism, ME/CFS and AD based on extensive research, Stella Maris has grouped these three diseases together as MDDs so that their similarities can be compared. By changing the way these diseases are perceived, Stella Maris hopes to focus research efforts that will definitively determine the etiology and pathogenesis of each MDD.

Second, Stella Maris has identified these 10 classes of environmental stress that cause mitochondrial damage and oxidative stress characteristic of MDDs:

Commonly Prescribed Drugs Food and Drink related Heavy Metals Ionophores Pathogens Personal Consumer Products Pesticides Smoking Advanced Glycation End Products Drugs of Abuse

This is an important insight since it directly connects many familiar compounds, activities or risks to mitochondrial damage and oxidative stress and the dozens of symptoms that typify MDDs. To prevent MDDs, these forms of environmental stress should be avoided, particularly for people with genetic susceptibilities.

Third, Stella Maris has created several different nutritional supplement and medical food inventions that address the mitochondrial health and symptoms of people with MDDs. This could hold great promise since, if Stella Maris is correct, these formulations may help manage the nutritional needs of those people diagnosed with MDDs.

END NOTES:


i See www.ncbi.nlm.nih.gov/pmc/articles/PMC449736/

ii See www.dynamic-med.com/content/7/1/6

iii See www.autismspeaks.org/science/science-news/lifetime-costs-autism-average-millions

iv See www.ncbi.nlm.nih.gov/pubmed/26608097

v See www.ncbi.nlm.nih.gov/pubmed/25221640

vi See www.ncbi.nlm.nih.gov/pubmed/25465468

vii See www.ncbi.nlm.nih.gov/pubmed/22903797

viii See www.ncbi.nlm.nih.gov/pubmed/25354680

ix See www.ncbi.nlm.nih.gov/pubmed/21119085

x See www.ncbi.nlm.nih.gov/pubmed/17462670

xi See www.ncbi.nlm.nih.gov/pubmed/24753527

xii See www.ncbi.nlm.nih.gov/pubmed/23543009

xiii See www.ncbi.nlm.nih.gov/pubmed/25973139

xiv See www.ncbi.nlm.nih.gov/pubmed/21069446

xv See www.ncbi.nlm.nih.gov/pubmed/25111603

xvi See www.ncbi.nlm.nih.gov/pubmed/25043477

xvii See www.ncbi.nlm.nih.gov/pubmed/24223459

xviii See www.ncbi.nlm.nih.gov/pubmed/23659764

xix See https://www.ncbi.nlm.nih.gov/pubmed/26820674

xx See https://www.ncbi.nlm.nih.gov/pubmed/25486592

xxi See https://www.ncbi.nlm.nih.gov/pubmed/23659764

xxii See www.advances.nutrition.org/content/3/1/21.full

xxiii See www.ncbi.nlm.nih.gov/pubmed/16600290

xxiv See www.ncbi.nlm.nih.gov/pubmed/23109556

xxv See www.ncbi.nlm.nih.gov/pubmed/15585771

xxvi See www.ncbi.nlm.nih.gov/pubmed/25559959

xxvii See www.ncbi.nlm.nih.gov/pubmed/25881985

xxviii See www.ncbi.nlm.nih.gov/pubmed/25206613

http://www.ncbi.nlm.nih.gov/pubmed/25206613






http://www.advances.nutrition.org/content/3/1/21.full

https://www.ncbi.nlm.nih.gov/pubmed/23659764


















http://www.autismspeaks.org/science/science-news/lifetime-costs-autism-average-millions

http://www.dynamic-med.com/content/7/1/6

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC449736/

xxix See www.ncbi.nlm.nih.gov/pubmed/24557875

xxx See www.ncbi.nlm.nih.gov/pubmed/20937116

xxxi See www.ncbi.nlm.nih.gov/pubmed/23236553

xxxii See www.ncbi.nlm.nih.gov/pubmed/23600892

xxxiii See www.ncbi.nlm.nih.gov/pubmed/24795646

xxxiv See www.ncbi.nlm.nih.gov/pubmed/21250997

xxxv See www.ncbi.nlm.nih.gov/pubmed/24795645

xxxvi See www.ncbi.nlm.nih.gov/pubmed/23333625

xxxvii See www.ncbi.nlm.nih.gov/pubmed/23088660

xxxviii See www.ncbi.nlm.nih.gov/pubmed/25206509

xxxix See www.ncbi.nlm.nih.gov/pubmed/19716395

xl See www.ncbi.nlm.nih.gov/pubmed/24372221

xli See www.ncbi.nlm.nih.gov/pubmed/23871825

xlii See www.ncbi.nlm.nih.gov/pubmed/25704631

xliii See www.ncbi.nlm.nih.gov/pubmed/23367660

xliv See www.ncbi.nlm.nih.gov/pubmed/23343353

xlv See www.ncbi.nlm.nih.gov/pubmed/21649732

xlvi See www.ncbi.nlm.nih.gov/pubmed/23597783

xlvii See www.ncbi.nlm.nih.gov/pubmed/25772356

xlviii See www.dddmag.com/news/2015/03/antibiotics-found-have-unexpected-effects-mitochondria

xlix See www.ncbi.nlm.nih.gov/pubmed/22652335

l See www.ncbi.nlm.nih.gov/pubmed/22138569

li See www.ncbi.nlm.nih.gov/pubmed/17023878

lii See www.ncbi.nlm.nih.gov/pubmed/12868485

liii See www.msdssearch.dow.com for Monochloroacetic acid

liv See www.ncbi.nlm.nih.gov/pubmed/23103613

lv See www.ncbi.nlm.nih.gov/pubmed/23493538



http://www.msdssearch.dow.com/





http://www.dddmag.com/news/2015/03/antibiotics-found-have-unexpected-effects-mitochondria




















lvi See www.ncbi.nlm.nih.gov/pubmed/25918583

lvii See www.ncbi.nlm.nih.gov/pubmed/25261569

lviii See www.ncbi.nlm.nih.gov/pubmed/25109264

lix See www.ncbi.nlm.nih.gov/pubmed/24464605

lx See www.ncbi.nlm.nih.gov/pubmed/25852770

lxi See www.ncbi.nlm.nih.gov/pubmed/25173530

lxii See www.ncbi.nlm.nih.gov/pubmed/22531301

lxiii See www.ncbi.nlm.nih.gov/pubmed/25914621

lxiv See www.ncbi.nlm.nih.gov/pubmed/25461563

lxv See www.ncbi.nlm.nih.gov/pubmed/25553376

lxvi See www.bmb.leeds.ac.uk/illingworth/oxphos/poisons.thm

lxvii See www.ncbi.nlm.nih.gov/pubmed/9925795

lxviii See www.ncbi.nlm.nih.gov/pubmed/15949718

lxix See www.ncbi.nlm.nih.gov/pubmed/21739274

lxx See www.ncbi.nlm.nih.gov/pubmed/21877215

lxxi See www.ncbi.nlm.nih.gov/pubmed/24129979

lxxii See www.ncbi.nlm.nih.gov/pubmed/19052322

lxxiii See www.ncbi.nlm.nih.gov/pubmed/24856255

lxxiv See www.ncbi.nlm.nih.gov/pubmed/22963507

lxxv See www.edis.ifas.ufl.edu/an285

lxxvi See www.ncbi.nlm.nih.gov/pubmed/24085413

lxxvii See www.workingranchtv.com/article/60

lxxviii See www.ncbi.nlm.nih.gov/pubmed/22665660

lxxix See www.ncbi.nlm.nih.gov/pubmed/15681119

lxxx See www.ncbi.nlm.nih.gov/pubmed/9716058

lxxxi See www.ncbi.nlm.nih.gov/pubmed/22749976

lxxxii See www.ncbi.nlm.nih.gov/pubmed/23415798

lxxxiii See www.ncbi.nlm.nih.gov/pubmed/23415798







http://www.workingranchtv.com/article/60


http://www.edis.ifas.ufl.edu/an285









http://www.bmb.leeds.ac.uk/illingworth/oxphos/poisons.thm











lxxxiv See www.ncbi.nlm.nih.gov/pubmed/16448567

lxxxv See www.ncbi.nlm.nih.gov/pubmed/25838067

lxxxvi See www.ncbi.nlm.nih.gov/pubmed/17980971

lxxxvii See www.ncbi.nlm.nih.gov/pubmed/24560992

lxxxviii See www.ncbi.nlm.nih.gov/pubmed/24084166

lxxxix See www.ncbi.nlm.nih.gov/pubmed/25461396

xc See www.ncbi.nlm.nih.gov/pubmed/25944699

xci See www.ncbi.nlm.nih.gov/pubmed/24036472

xcii See www.ncbi.nlm.nih.gov/pubmed/25872712

xciii See www.ncbi.nlm.nih.gov/pubmed/25798649

xciv See www.ncbi.nlm.nih.gov/pubmed/24459919

xcv See www.ncbi.nlm.nih.gov/pubmed/24022343

xcvi See www.ncbi.nlm.nih.gov/pubmed/20650267

xcvii See www.ncbi.nlm.nih.gov/pubmed/16534862

xcviii See www.ncbi.nlm.nih.gov/pubmed/24503016

xcix See www.ncbi.nlm.nih.gov/pubmed/23402800

c See www.ncbi.nlm.nih.gov/pubmed/15212809

ci See www.ncbi.nlm.nih.gov/pubmed/12696410

cii See www.ams.usda.gov/AMSv1.0/getfile?dDocName=STELPRDC5101234 pg. 29

ciii See www.ncbi.nlm.nih.gov/pubmed/25186090

civ See www.ncbi.nlm.nih.gov/pubmed/24610934

cv See www.ncbi.nlm.nih.gov/pubmed/23785661

cvi See www.ncbi.nlm.nih.gov/pubmed/22254007

cvii See www.ncbi.nlm.nih.gov/pubmed/20471471

cviii See www.ncbi.nlm.nih.gov/pubmed/25141979

cix See www.ncbi.nlm.nih.gov/pubmed/9064552

cx See www.ncbi.nlm.nih.gov/pubmed/17053873









http://www.ams.usda.gov/AMSv1.0/getfile?dDocName=STELPRDC5101234



















cxi See www.ncbi.nlm.nih.gov/pubmed/25633677

cxii See www.ncbi.nlm.nih.gov/pubmed/22325990

cxiii See https://estudogeral.sib.uc.pt/bitstream/10316/26695/1/20_Teresa%20Cunha- Oliveira%20MROC%203rd%20Proof.pdf

cxiv See www.ncbi.nlm.nih.gov/pubmed/23743292

cxv See www.ncbi.nlm.nih.gov/pubmed/15893124

cxvi See www.ncbi.nlm.nih.gov/pubmed/15607571

cxvii See www.ncbi.nlm.nih.gov/pubmed/15607570

cxviii See www.ncbi.nlm.nih.gov/pubmed/24956109

cxix See www.ars.usda.gov/Services/docs.htm?docid=15685

http://www.ars.usda.gov/Services/docs.htm?docid=15685






https://estudogeral.sib.uc.pt/bitstream/10316/26695/1/20_Teresa%20Cunha-%20Oliveira%20MROC%203rd%20Proof.pdf

https://estudogeral.sib.uc.pt/bitstream/10316/26695/1/20_Teresa%20Cunha-%20Oliveira%20MROC%203rd%20Proof.pdf



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Stella Maris, LLC - Overview - Non-Confidential