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CFS/ME: A New Hope

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Abstract and Figures

Here we describe the root cause of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis, the growing list of related diseases in the proposed spectrum, related cancers, senescent cells, their previously described mitochondrial / metabolic disturbances and their related pattern of metabolite depletions and compensations as being virally-induced by upregulated expression of protein levels for “GLS1 - KGA, GAC” and “GLUD1”, “GLUD2”. We further describe some practical solutions to this problem, in plain language. [PLEASE NOTE: This is a "special edition", intended for a wider audience and hyperbole contained here may not be present in the final version.] {Errata, second paragraph on Page 9 of 39 should read: First, if α-KG levels are low - converting glutamate into α-KG (while importantly making ammonia and NADH) - this was incorrectly written as NAD+}
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CFS/ME: A New Hope
Authors: Joshua Leisk, Aline Noçon ©2021
Here we describe the root cause of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis, the
growing list of related diseases in the proposed spectrum, related cancers, senescent cells, their
previously described mitochondrial / metabolic disturbances and their related pattern of
metabolite depletions and compensations as being virally-induced by upregulated expression of
protein levels for “GLS1 - KGA, GAC” and “GLUD1”, “GLUD2”.
We further describe some practical solutions to this problem, in plain language.
We recently shared our novel understanding of a rather complicated disease model by
submitting a few articles for peer-review and journal publication purposes[1][2].
This model appears to accurately describe the pathophysiology of a very large number of
diseases and disorders in a way that allows them to be treated and potentially cured[1][2]. Large-
scale testing has not yet been performed.
There have been some early challenges in communicating our understanding of this model, as
the language used was unfortunately as complicated as the disease model itself[1][2].
Consequently, hardly anyone understood what the heck we were actually talking about. We’ll
treat that as a personal failure.
As an apology for making everyone read some of the previously inhuman levels of technical
jargon, this article is an attempt to remedy these earlier communications challenges, by way of
narrative - we are going to tell a story about how the underlying disease works in this model and
show you what we can already do about it with the knowledge gained. There are significant
additional insights to describe.
Sadly, this story needs certain technical words (..sorry..), but since they are relevant to
understanding and enjoying the story, we are going to try explaining them along the way and
relate them to “normal people stuff”.
We’re also going to need a number of diagrams to visualise this, as the arrays of items being
discussed are... still uncomfortably large... Apologies, really, however this is a rather
complicated disease model. We’ll do our best.
Page 1 of 39
Later, we are going to expand this story into another tale about how senescent cells (AKA
“zombie-recruiting, polluting troublemakers” which also deplete essential nutrients) and many
cancer cells work - as the current literature describes them as having the same profile of gene
expression. This results in upregulated protein levels for “Glutaminase (GLS) - kidney-type
glutaminase (KGA) & glutaminase C (GAC)” expressed by the GLS1 gene and Glutamate
Dehydrogenase (GDH) expressed by “GLUD1” & “GLUD2” genes, which means they have the
same metabolic features and weaknesses[1][2]5][6][7][8].
This probably means that how we solve this disorder will also solve many ageing issues..
and various cancers.. and likely the 40+ other misunderstood “diseases” that already
appear in various parts of the spectrum being described[32][33][34][35].(“Hey, Rocky - watch me
pull a rabbit out of my hat..!”)
Inside the cells that make up our bodies, there are tiny little “engine clusters” called
“mitochondria”. These engines are incredible feats of biological engineering with typically 3 or
more layers of redundancy for every single task they perform[1][2].
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In our described model, which we labelled the “Herpesviridae Autoimmune Spectrum Disorder
(HASD)”, our familiar foe, “Chronic Fatigue Syndrome / Myalgic Encephalomyelitis” (CFS/ME) is
described as a mitochondrial and metabolic disorder. It is also placed in the upper end of this
“Metabolism” is the process in which products are converted into other products[1].
This disorder features a number of vicious metabolic loops / cycles / compensations / depletions
that center around the induced faulty behaviour of our mitochondrial engines. These are
primarily found inside infected liver cells and other cells[1][2].
These loops “trap” people in a state of “impaired living”, where putting a foot in any normal
direction leads to pain and misery[1][2].Ironically, the acuteness of the disorder is also likely
responsible for people being significantly more intelligent than normal, but we’ll come back to
that a little later[30][31][32][33].
Like the engine in your car, these biological “engines” have many similar concepts. Various
things, like fuels and oils, go into the engine, where some reactions occur and then various
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products come out. In the process of creating these products, energy is also created in the form
of “adenosine triphosphate” (ATP), which is then used to power the cell[1].
Some of these output products could also be defined as “highly useful, yet toxic waste
products”. This is because excessive amounts of certain products can also represent a danger
to the cell[1].
Two of these highly useful, yet toxic waste products are loosely grouped and defined as[1]:
1.“Nitrogen”.(A term that refers to the sum of all nitrogen-related metabolites,
including alpha-ketoglutarate, glutamate, glutamine, ammonia, pyrroline-5-carboxylate and
the urea cycle metabolites - citrulline, arginine, argininosuccinate, urea and ornithine)
2. “Reactive Oxidative Species” (ROS).(ROS are a group of extremely reactive
chemical molecules, which are formed due to the electron receptivity of oxygen.)
Examples of ROS include: peroxides, superoxide, hydroxyl radical, singlet oxygen and
alpha-oxygen. The reduction of “oxygen” produces “superoxide”. Superoxide is the precursor of
most other reactive oxygen species. (Think about how violently hydrogen peroxide reacts when
combined with various substances...)
The cells normally do an amazing task of efficiently recycling all of these “highly useful, yet toxic
waste products” wherever possible - mostly storing them as a future source of energy for eg.
protein synthesis tasks, creation of new cells and/or for various processes / pathways like
excitatory / inhibitory functions in the brain[1].
Now, high levels of ROS cause the mitochondria to "slow down" or induce "rate-limiting" effects
to stop them from overheating, blowing up and simply causing the cell to “pop” - spilling its
internals into the blood and creating a cascade of inflammation and messes to clean up. This
form of cell death is also known as “necrosis”[22].The spilled intracellular calcium from this event
also leads to atherosclerosis in our disease model, especially when combined with the already
high levels of low-density lipoproteins created by the infected cells[9][10][11][12].
One of the ways mitochondria “sense” the need to slow down is when elevated levels of ROS
decrease a critical enzyme called “alpha-ketoglutarate dehydrogenase” (α-KGDH)[1].
An enzyme is like a tool that converts or modifies a product into a different product.
The mitochondria need α-KGDH to produce another enzyme called “ATP Synthase” or
“Complex V”[1].
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α-KGDH is located directly after what we’re going to label as our main “multipurpose exhaust
pipe and recycled energy input” for the whole engine at “alpha-ketoglutarate” (α-KG) (where the
highly useful, yet toxic waste comes from) and directly before the “main energy output” of the
mitochondrial engine comes from, as ATP[1].
In a nutshell, if the mitochondrial engine gets “too hot”, it self-limits energy production to prevent
self-destruction and/or diverts excess into storage for later. Mitochondrial energy is further
regulated by the ratio of activity between two enzymes - the previously mentioned α-KGDH and
neighbouring “glutamate dehydrogenase” (GDH)[1].
In herpesviridae (HHV)-infected cells, GDH IS HIGHLY ACTIVE ALL THE TIME. This is
thanks to virally-induced upregulation of protein expression for “GLUD1” and
This means that when there are high levels of the “reduced form” of “nicotinamide adenine
dinucleotide” (NADH) and low levels of its “unreduced form”, NAD+,GDH will preferentially
divert mitochondrial energy, currently as α-KG, into glutamate, making more NAD+. It makes
this from any leftover α-KG which hasn’t already been converted by α-KGDH into Complex V,
making ATP to power the cell[1].
Page 5 of 39
When the ratio of NAD+ is higher than NADH, the opposite is true - the cell will take glutamate,
convert it into α-KG, feeding energy back into the engine, making NADH. In this way, GDH is
largely responsible for regulating “energy recycling” functions and also ammonia levels[1][14].
From the “multipurpose exhaust pipe and recycled energy input”,our cells normally first
converts the α-KG created in the previous mitochondrial reaction to a “highly useful, yet toxic
waste product” called glutamate (where the vast cascade of virally-induced metabolic
problems are first observed, while simultaneously consuming ammonia) and then finally
converting glutamate to a safe energy storage metabolite - glutamine (...while consuming ATP
and more ammonia)[1][2].
As glutamine, it can be safely stored and used again later as a highly efficient mitochondrial
energy source, in a process called “glutaminolysis” and/or for synthesis of many metabolites that
start with glutamate. It can also be disposed of through a pathway we’ll describe later[1][2].
Glutaminolysis is where these last 2 steps happen in reverse and feeds the mitochondrial
engines at α-KG. This normally happens in “low glucose” states (fasting / sleeping), “high
lactate” states and “high glutamine” states (triggering anabolism / proliferation)[1][2][30][31][32][33].
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In HHV-infected cells, GLUTAMINOLYSIS HAPPENS ALL THE TIME, regardless of the
amount of fuel needed by the mitochondria. This is thanks to virally-induced
upregulation of protein expression for “GLS1” - both as “KGA” and “GAC”[1][2][5][6][7][8][71].
ROS is “engine heat” and α-KGDH acts as the sensor and limiter. It’s supposed to “cool down”
the mitochondria and limit cell activities[1].
In the HASD CFS/ME disorder model, relative to dietary inputs, the virally-induced metabolic
dysfunction creates an unwanted run-away elevation of “nitrogen” metabolites (and later, under
most circumstances, lactate)[1][30][31][32][35][36].
These acute elevations of nitrogen levels are directly related to any energy use - movement,
brain activity, metabolism[1].
The virally-induced excess nitrogen accumulation quickly leads to a crisis state, which triggers
each affected cell to reach critical levels of some “nitrogen” metabolites - glutamate, glutamine
and ammonia->urea, prioritising an equally urgent purging process to run, at a metabolically
expensive cost of also proportionally sacrificing / depleting some “absolutely essential
Page 7 of 39
This happens extremely quickly when ROS is high, causing α-KGDH to be low / impaired.
The mitochondria are being virally “programmed” to ignore this “rate-limiting state”, by
blindly continuing to fuel the mitochondria from the recycled energy or “highly useful,
yet toxic waste products''. This is a run-away process that is largely self-sustaining, yet
consumes “aspartate” as fuel. This process is called “transamination”[1][2].
Page 8 of 39
Transamination could be thought of as a “back door” process that can bypass the
mitochondrial rate-limiter, α-KGDH. This is a tricky “dual-metabolism” process, whereby;
[First, if α-KG levels are low - converting glutamate into α-KG (while importantly making
ammonia and NAD+),
Converting α-KG into glutamate while simultaneously consuming and converting an
“absolutely essential metabolite” called aspartate into a mitochondrial fuel on the “other side
of the engine cluster” called oxaloacetate[1][2][54].
To allow ongoing production of mitochondrial energy, this transamination process repeats until
aspartate is depleted and/or the “rate limiter” is disabled, ie. if ROS is reduced, proportionally
restoring α-KGDH to normal levels[1]. This “back door” process will create a LARGE ammonia
burden, by design.
Some of that ammonia can be metabolised into the urea cycle and fed back into the
mitochondria as fumarate… until aspartate is depleted.
Some GABA can be metabolised as succinate… until P5P is depleted or NAD+ runs low.
Hypoxia and acute fatigue will occur at this point.
Meanwhile, the virally-modified “code” inside the cell continues to blindly force
conversion of glutamine, the “energy storage metabolite” into glutamate. This process
decreases glutamine and increases glutamate (while importantly making ammonia). In
addition to previously described mitochondrial energy storage functions, dietary input also
contributes to elevated glutamine and glutamate levels[1][2][5][6][7][8].
In the event that glutamate and ammonia (or more accurately, urea - which is downstream of
ammonia and discussed later) can’t be converted and/or purged quickly enough through urine,
they reach a critical level which causes an array of really unpleasant symptoms[1][2].
Elevated glutamate and/or urea is the catalyst for the primary symptoms
observed in CFS/ME[2].”
The first set of symptoms include: post-exercise malaise (PEM), extreme fatigue - yet with
unrefreshing sleep, anhedonia, irritability, headaches, overstimulation, head pressure, itchy
skin, connective tissue disorders, anxiety, anger, possible psychosis, weakness, confusion,
overstimulation / oversensitivity to normal inputs - lights, sounds, activities, conversations.
These symptoms and metabolic alterations also appear to feature in autism spectrum
Page 9 of 39
When levels of these nitrogen metabolites become too high and the cell can't recycle them for
useful purposes, the cell will normally choose to excrete them - typically by disposal through the
blood and then kidneys, bladder and urine. However, by doing this, the cell also sacrifices
some other VERY useful metabolites in the process, described later. This is an extremely
wasteful / “metabolically expensive” process that the cell prefers to avoid[2].
You could perhaps think of this situation as a highly efficient engine that is intentionally
converting “fuel” and “oil” into “energetic toxic waste”, then using an “alternate fuel” to convert
and recycle most of that “energetic toxic waste” back into “fuel” and “oil” again...
However, once there is too much “energetic toxic waste”, this triggers the engine to change
modes and start using a group of other “useful fluids” to convert the “energetic toxic waste”
into “smoke” and purge it through the exhaust pipe - also polluting the quality of the incoming
air to the engine and “choking” it. This “purging” process uses much more “alternate fuel”,
“useful fluids” and “oil”.
(This same mode is normally used for sustainable periods of protein synthesis via “mTOR”.)
Eventually it runs low on any of these three items and is stuck idling - waiting for more
“alternate fuel”, “useful fluids” or “oil”, so it can continue purging the “energetic toxic waste”.
When the useful metabolites are depleted they further limit mitochondrial efficiency and pause
the nitrogen / “energetic toxic waste” purge process itself. This process urgently resumes as
soon as any depleted metabolites become available[2].
This ongoing state of metabolite depletion acutely impairs every other “less urgent” metabolic
process that relies on them, prioritising the survival of the cell, which is unable to signal for
apoptosis / replacement thanks to virally-induced dysregulation of C-terminal Binding Protein
(CtBP),Sirtuin-4 (SIRT4) and Nuclear Factor-Kappa Beta (NF-κB)[2][23][24[25][26][27][28][29][59].
“The depletion of these useful metabolites is the second most serious
problem in CFS/ME. It is the causal factor in the large number of
secondary symptoms[2].”
(These secondary symptoms could also be considered as the primary symptoms at the
“milder” end of this spectrum of disorders, such as hypothyroidism, hypogonadism,
anhedonia, sleeping disorders, GABA deficiency, urea cycle disorders, alopecia, connective
tissue disorders, rheumatoid arthritis, irritable bowel disease / syndrome, neurodegenerative
diseases, depression, bipolar disorder, schizophrenia, Addison’s disease, endometriosis,
polycystic ovary syndrome, etc., etc.[1][2])
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Circling back, when cells are not efficiently recycling these nitrogen metabolites for making
energy or other products, there are at least TWO pathways available to convert and dispose of
nitrogen metabolites through urine - urea and phenylacetylglutamine (PAGN)[1][2][13][14][15].
Urea largely disposes of ammonia through an ongoing cycle of metabolites, powered by
aspartate. The urea cycle can also be recycled and fed back to the mitochondrial engine as
PAGN largely disposes of ammonia / glutamate /glutamine excess and creates aspartate. In
this way, disposing of excess glutamate /glutamine allows urea to be created and also allows
the “backdoor” energy creation process transamination to continue until PAGN precursors are
Let’s take a look at these two disposal processes in more detail:
The first disposal pathway (urea) commences by taking ammonia (which the body treats as
highly toxic and makes a priority to eliminate, when not using small amounts to balance lactic
acidosis) and then rapidly metabolising that ammonia into the urea cycle, where "urine" gets its
name from. Urea is a “lower cost” disposal route. The cell can also incorporate ammonia into
Page 11 of 39
glutamine, which will also be disposed of as PAGN, assuming glutamine is not already too
highly elevated[1][2][13][14][15].
Urea needs to be kept to a minimal level in our blood and is filtered through our kidneys and
excreted through urine. This requires appropriate water and urination[1][2][13][14][15].
Until further complicated by progression towards symptoms seen in chronic kidney
disease[40][41][42][48][49][50], in early CFS/ME the kidneys are usually functional - they’re just
chronically overloaded with work and often running low on resources to complete this
demanding job. Urea is a toxic metabolite and in excess it can cause the dangerous symptoms
of "uremia"[1][2].
Symptoms of uremia include: hiccups, abnormality of taste, extreme tiredness or fatigue, little or
no appetite / severe unintentional weight loss, headache, head pressure, nausea / vomiting,
trouble concentrating / mental confusion, itchy skin, pain / numbness / cramps in muscles -
caused by nerve damage, swelling and inflammation[1][2].
These should be highly recognisable symptoms to most CFS/ME patients. Left unchecked,
uremia leads to high blood pressure, anemia and some damage to neural tissues[1].
Fortunately, in CFS/ME phasic neural tissue damage is normally balanced out by increased
neural cell creation or “neurogenesis”. Neurogenesis is triggered by another feature of the
disease - high levels of lactate and enhanced protein synthesis, as observed in cancers[77][78][79].
This will be discussed in more detail further on. High intelligence appears to be a long-term
beneficial symptom of the disease. However, frequent memory loss during an untreated acute
infection could easily be expected[1][2][30][31][35][36].
The cruel and ironic duality is that the significantly increased intelligence that appears to be
provided by these virally-induced elevations to “lactate” and “glutaminolysis” is also
paradoxically shackled by the debilitating effects of the “nitrogen” elevation and “metabolite
These give a range of symptoms from “mild” - eg. attention deficit disorder, anxiety, obsessive
compulsive disorder and extend to the far end of autism spectrum disorders, bipolar disorder,
With ageing and reduced lactate production and/or a CNS tissue-specific latent infection with
concomitant immunological response (eg. amyloid beta), neurodegeneration appears. One of
the brightest known minds in our recent history was sadly trapped in his own body by
amyotrophic lateral sclerosis (ALS)[1][2][19][20][21][30][31][35][36][37][38].
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The second disposal pathway is much more costly. It’s initiated by converting glutamine and
another required metabolite, phenylacetate (PA), into PAGN, to be excreted with water, in urine.
The required metabolite PA is created by beta-oxidation (requiring adrenaline and acetyl-CoA)
from a parent metabolite phenylbutyrate (PB), further derived from glycerol phenylbutyrate
(GPB) using pancreatic lipases[13][14][15].
Ironically, while PA and PB are both commercially produced as low-cost raw chemicals, they
are also precursors to making methamphetamines, thus also making them restricted in most
However, when used as highly effective non-curative prescription treatments for urea cycle
disorders or hyperammonemia, they typically cost upwards of USD$3000 per month, making
them a prohibitively expensive treatment option[13][14][15].
Without these “minor” inconveniences, a phenylacetate or phenylbutyrate compound would
have replaced many items in the v2.x treatment protocol design. We have subsequently found
some related compounds which have further demonstrated the impact that resolving the
described metabolite depletion has on key immune functions[68][69][70].
Excessive activity of these two nitrogen disposal pathways comes at the cost of losing a LOT
more than just the stored energy, in the form of “highly useful, yet toxic nitrogen
There is a third “artificial” nitrogen disposal pathway available, created by consumption of
benzoate, usually in the form of sodium benzoate. This allows the safe conversion of
ammonia,Coenzyme A (CoA), glycine and benzoate into hippurate, to be then excreted with
water, in urine. This is still a “moderately expensive” process and requires co-administration of
proportional doses for cofactors glycine,cysteine and pantothenic acid[14].
JL found regular dosing of sodium benzoate, up to a total of 3g per day and spread over 4-8x
doses, with adequate hydration and co-administration of cofactors reliably ameliorated uremic
symptoms as part of v1.x protocol design testing. (Case reports to follow.)
The growing list of other highly useful (and non-toxic) metabolites and/or cofactors also being
excreted during nitrogen disposal processes include: acetate, aspartate, butyrate, cysteine,
oxaloacetate, pantothenic acid, phenyl(alanine) and pyridoxal 5-phosphate (P5P). This also
consumes ATP and water[2][14].
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However, despite the metabolic cost, when faced with looming cell death, these mission-critical
nitrogen disposal processes are now dominating almost all other metabolic requirements for
these metabolites and ATP[2][14].
This means that all other less-essential metabolic pathways are deprioritised or
rate-limited. At any time that depleted metabolites become available, they will be urgently
prioritised for mission-critical nitrogen disposal over any other less-essential activities[2].
These “less-essential”, by comparison, rate-limited activities include producing key metabolites
that requires -
1. Coenzyme A (CoA)
CoA is made from 2 precursors - cysteine and pantothenic acid (Vitamin B5). It is an
absolutely essential cofactor in carbohydrate, lipid, and amino acid metabolism. If CoA,
cysteine or pantothenic is depleted, the downstream cascade of effects is devastatingly
long, including synthesis of glutathione, listed as a key depletion in many diseases in the
proposed spectrum of disorders[2][45][54][56].
2. Acetate
Acetate is secreted by gut bacteria and also derived through dietary input. Notably, it is a
metabolite for combining with CoA to create the highly essential acetyl-CoA[2].
3. Acetyl-CoA
Acetyl-CoA is synthesised from acetate +CoA. It is a critical cofactor for the synthesis of
every single acetylated metabolite[2][45].
Acetylcholine (involved in cognition and muscle activation)[1][2].
Acetyl-L-Carnitine (involved in burning fat for energy, or “beta-oxidation pathways”)[1][2].
Acetylation of histones, performed by Histone Acetyltransferase (HAT) (the opposite
process of "histone deacetylase" (HDAC) - both are intricately involved in DNA
N-Acetylserotonin (involved in neurological pathways)[2].
.. and a vast number of others.
4. Aspartate
L-aspartate is converted into D-aspartate in tissues heavily involved in protein synthesis
Liver, heart, lung, stomach, intestines, salivary glands, semen, central nervous system,
knee cartilage, thyroid, testis, pre-ovulatory ovarian follicle and retinae[2].
A depletion of aspartate will impair the protein synthesis functions of these organs /
Page 14 of 39
When there is low dopamine (from depleted phenylalanine pathways), aspartate binds to
N-methyl-D-aspartate receptors (NMDAR) to enable the release of GABA. This has been
observed in “amacrine” cells, which are inhibitory cells that are found in eyes or
5. Butyrate
Butyrate is secreted by gut bacteria and also derived through dietary input. Buyrate has
many important roles in maintaining gut health, causing apoptosis in cancers and HHV
infected cells via NF-κB, plus key roles as a HDAC inhibitor in DNA transcription events,
including B-cell differentiation[2][51][52][53].
A depletion of butyrate will induce negative consequences for gut health, cancer risk,
and immune response.
6. Oxaloacetate
Oxaloacetate is traditionally considered to be a key mitochondrial metabolite and the
normal “first step” of the cycle of enzymatic reactions, when first fueled by pyruvate,
through acetyl-CoA.Oxaloacetate is also frequently involved in transamination with
aspartate, during a simultaneous and reversible reaction between a-KG and
If acetate or acetyl-CoA is depleted, oxaloacetate can be consumed and hydrolyzed into
oxalate and acetate (and combined with CoA to make acetyl-CoA). This is a process
which may lead to kidney stone formation and chronic kidney disease, when
7. Phenyl(alanine)
Phenylalanine is derived from dietary amino acid intake and is a precursor to tyrosine,
dopamine,thyroxine,melanin and other critical pathways such as converting ATP to
adenosine monophosphate (AMP), needed for muscle activation, in process called
When phenylacetylglutamine is excessively excreted in urine, the depletion of
phenylalanine to expedite this nitrogen purging process causes impairment to thyroid
function, skin pigmentation, muscle activation, emotional wellbeing - including
depression and anhedonia, along with a very large number of other systems[2][14].
8. Pyridoxal 5-phosphate
P5P is the active form of vitamin B6. It’s used as a cofactor for synthesis of amino acids,
aminolevulinic acid,neurotransmitters (including GABA,serotonin,norepinephrine),
sphingolipids and many other metabolites[47].
A depletion of P5P causes catastrophic system-wide impairments.
Page 15 of 39
The Key Questions
1. Why does a disorder that is based around a chronic energy shortage also create
absurdly large amounts of ROS - to the point of impairing a-KGDH, while creating a
never ending supply of nitrogen waste products and lactate? This is combined with a
system-wide cascade of never-ending metabolite depletions - to the point that the cell
simply can’t keep up.
2. Aren’t these actually very strong signals that cells are using a lot of energy and causing
the mitochondria to struggle keeping up with the demand?
3. What can cause the mitochondria to run beyond their normal operating parameters?
4. What does all of that energy get used for?
5. Is the symbiotic evolution of the herpesviridae family and their metabolic alterations
directly responsible for the increased intelligence of homo sapiens as a species, while
simultaneously shortening our lifespan via creating cancers and senescent cells?
(Interestingly, HHV appears to function as a ubiquitous / highly transmissible viral
equivalent of the “Apple from the Tree of Knowledge” described in Biblical texts. If
someone wanted to deploy a resilient “software patch”, this is a really logical way to
facilitate that.)
Page 16 of 39
6. Has the “fitness-for-purpose” or efficiency of the virus evolved and increased in recent
centuries, to the point where the viruses are less helpful and more harmful.. OR have
modern lifestyles, including industrialised agriculture and food supply chains, the
concomitant prevention of being able to maintain normal microbial diversity through daily
exposure via outdoor activities and raw / uncooked, unwashed foods, caused a complete
disconnection from the microbial symbiosis seen in nature? (Hygiene
7. Have “high carb / sugar” diets (to overload cellular energy storage) unbalanced cellular
metabolism and enhanced viral activity by changing the environment the viral code runs
8. Are senescent cells infected with HHV, or do they simply display the same protein
expression profile by coincidence?
9. Can we disable the viral features by negating the protein expression alterations?
10. Can we selectively induce apoptosis or necrosis in infected cells / cancer cells /
senescent cells? Will this extend our lifespan? How long for?
11. If we eradicate the viruses, can we replicate the beneficial parts of the viral infection?
12. Is SARS-CoV-2 itself less of a “big scary problem” and perhaps it co-infects, reactivates
and potentially alters HHV protein expression[67]? Is this the reason that people who are
the most susceptible to COVID-19 are also the ones with existing HHV (or senescent
cell)- induced metabolic disorders?
13. Will ameliorating HHV metabolic alterations resolve COVID-19 “long haul” symptoms?
It’s ironic that this disorder was often labelled “Chronic Fatigue Syndrome”, because we suspect
this name may have adversely shaped thought processes and problem-solving efforts.
We don’t have all of the answers yet - the nature of some questions make that quite difficult. eg.
It may take hundreds of years to answer the question about longevity and perhaps a
time-machine to answer the questions about the origins and timeline of our species.
However, some questions are more direct and easier to answer...
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We propose the following solution:
CFS/ME is a virally-induced EXCESS of dysregulated mitochondrial activity, to the point
of frequently “tripping virtually every available cellular overload / circuit-breaker”[1][2].
This ultimately benefits unregulated viral protein synthesis - lipoproteins,antigens and
proliferation tasks, while causing an unsustainable amount of waste products, thus
causing metabolite depletion.
The basis for this solution comes directly from examining the virally-induced elevated protein
expression profile for GLS1 - KGA, GAC and GLUD1,GLUD2[1][2]5][6][7][8][59].
These elevated protein expressions explicitly mean that:
1. GDH enzyme activity is increased (GLUD1, GLUD2).
Elevated GDH enzyme activity increases the rate of metabolism between α-KG and
glutamate in both directions.It also increases the rate of any transamination that involves
α-KG and glutamate, eg. oxaloacetate and aspartate.
2. Glutaminase enzyme activity is increased (KGA, GAC).
Elevated glutaminase activity increases the rate of metabolism between glutamine and
glutamate in one direction only. This prioritises increasing glutamate levels and depleting
glutamine levels.
The ability to overload mitochondrial activity is initially caused by the simultaneous
“dual-fuelling” of the mitochondria from both pyruvate / acetyl-CoA and “anaplerosis” at α-KG.
This is followed by high-speed transamination, as described. (Anaplerosis is a term that means
“fuelling the mitochondria from a source other than pyruvate->acetyl-CoA”.)
Earlier, we described that in normal mitochondrial behaviour, “glutaminolysis” and “anaplerosis”
at α-KG are usually triggered at specific times, to keep the mitochondrial energy balanced - eg.
1. Where energy entering the mitochondria via pyruvate / acetyl-CoA is low[59].
2. Where lactate is high.
3. Where glutamine is high (protein synthesis tasks).
At other times, mitochondrial energy (as α-KG) is regulated by a competition between α-KG
levels versus GDH and α-KGDH activity. When α-KG levels exceed the activity of α-KGDH
and/or when GDH is more active than α-KGDH (while NADH levels exceed NAD+ levels), a
proportional amount of energy from mitochondrial reactions (now as α-KG) is diverted out of the
reaction cycle to glutamate and then stored as glutamine.
Page 18 of 39
In HHV-infected cells, the key difference is that “glutaminolysis” is programmatically running all
the time[1][2]5][6][7][8], even to the point of potentially depleting glutamine, which further triggers
mitochondrial fusion” and also high ROS. This will provide excessive energy to mitochondrial
reactions (while NAD+ levels exceed NADH levels), impairing α-KGDH, causing transamination
and exponentially creating more ammonia to metabolise, at a cost of metabolite depletion[55].
When elevated glutaminolysis (via GLS1 - KGA, GAC) is combined with the
virally-induced high level of the enzyme GDH (via GLUD1, GLUD2), this combination
creates the entire cascade of metabolic alterations seen in CFS/ME and every other
disease on the proposed spectrum. Elevated GDH enzymatic reactions alone can also
cause this, eg. C.diff infection[1].
1. When NADH is high, as created by ongoing high levels of mitochondrial activity, the
virally-elevated GDH enzyme “pushes” an unusually large amount of cycle energy from
α-KG towards glutamate, at a high rate. This creates some NAD+ and reduces
2. As the virally-elevated glutaminase enzyme is also “pushing” glutamine towards
glutamate (and creates ammonia), glutamate thus becomes an elevated “hot-spot”
and creates an imbalance against GABA.
This glutamate elevation is exacerbated by the accompanying depletion of key
metabolites - acetate,aspartate,cysteine, etc. These depletions remove options to
convert this growing level of glutamate into eg. GABA (to offset the high glutamate and
then potentially be converted into succinate)[1] or glutathione (to reduce ROS)[56].
3. With low glutamine OR excessive mitochondrial activity (where ROS has sufficiently
increased inside the mitochondria), the reaction cycle “breaks” or limits at α-KGDH.This
causes rapid, unregulated transamination at α-KG and simultaneously causes ongoing
creation of ammonia and lactate to metabolise in the process, depleting key
metabolites and cofactors to excrete the ongoing excess of ammonia metabolites[1][2][55].
4. The array of metabolites being frequently depleted further creates a catastrophic
cascade of metabolic alterations, as described earlier, depending on which metabolites
are depleted at a particular time. eg. The acetyl-CoA deficiency selectively impairs
beta-oxidation and creates dysautonomia. This is also phasic and relates to activity,
meal timing and composition[2].
5. The elevated lactate may exit the cell and signal neighbouring cells to also trigger
glutaminolysis. Other cell-cell signalling via eg. cytokines and MiRNA may also occur[57].
It’s expected for cells in each tissue to act in unison, as also seen in senescent cells[1].
6. Feeding additional energy to the α-KG step of the mitochondria, via high-carbohydrate
and high-glutamate dietary input and/or activity, perpetuates and aggravates the primary
Page 19 of 39
symptoms by additional glutamate and ammonia creation, while providing minor /
temporary relief to secondary symptoms.
“This is a horrible and debilitating trap.”
7. The maximum capabilities of the mitochondria and cell are always going to be
utilised for viral activity and resulting urgent waste excretion until any
process-limiting metabolites are depleted. This behaviour mimics cancer and
senescent cells, also presumed to be eg. HHV-infected[1][2]5][6][7][8].
8. This behaviour also means that feeding / replacing the vast array of depleting nutrients /
metabolites in the cells and then managing the rising levels of ammonia /nitrogen by
increasing urea cycle and PAGN activity is not the right long-term answer[77][78][79].
We have already been able to demonstrate, as described in soon-to-be-published case
reports - that when the induced metabolic defects are adequately treated and balanced,
this rather difficult juggling act is able to give both energy and some kind of normal life
back to an infected person, by ameliorating the described symptoms. However, by doing
this without also disabling viral replication tasks we will also give the virus exactly what it
needs to continue taking ownership of the host, further progressing the growing array of
symptoms / individual diseases already described[1].
TESTING THIS HYPOTHESIS: Clinical data to support this solution, on an untreated patient,
can be obtained by performing a Genova Diagnostics NutrEval report[100], where succinic acid is
low or non-existent and lacate typically higher than pyruvate.
Additional confirmation can be obtained by urine testing for PAGN[99].
(Taking both morning & afternoon samples, following activity, would be suggested as
A“glutamine challenge” could also be considered[101].
Page 20 of 39
For HHV-induced CFS/ME, the answer is in the viral code. The HHV family viral strengths are
also simultaneously their weaknesses and their differences to normal cells can thus be
Let’s look at some of these key HHV cell features / differences:
1. GLS1 - (KGA, GAC) protein expression is upregulated[1][2]5][6][7][8][59].
- If the glutaminase enzyme is always elevated, unlike normal cells, this may
represent an exploitable feature.
- We could also simply normalise glutaminase to prevent the cascade of
2. GLUD1,GLUD2 protein expression is upregulated[1][2]5][6][7][8][59].
- If the GDH enzyme is always elevated, unlike normal cells, this may represent an
exploitable feature.
- We could also simply normalise GDH to prevent the cascade of symptoms.
3. The infected cell is also programmed to “blindly” carry out a vast array of protein
synthesis tasks / mTOR, with no regard for maintaining metabolites (just like a weed, or
common “mint” plant). It will keep carrying out these tasks until resource depletion
prevents it from doing so, or until the high rate of protein synthesis activity causes
- This feature alone is easy to exploit by disabling “late-stage replication” with eg.
tenofovir or spironolactone and then overfeeding cells every nutrient they
normally deplete, while specifically increasing ROS to simply let the mitochondria
burn out and pop the infected cells. This is a less-preferred exploit - particularly
as necrosis, let alone wide-spread necrosis, is almost never a good thing[22][58].
- The unregulated nutrient / metabolite depletion could be potentially used as a
selector to target apoptosis or necrosis.
4. CtBP=>SIRT4=>NF-κB pathway is dysregulated[2][23][24[25][26][27][28][29][59][60][66].
CtBP dysregulation appears to be responsible for a cascade of alterations which
includes the increased expression of GLS1,GLUD1,GLUD2 and also the prevention of
normal apoptosis, by increasing NF-κB.
-CtBP is modulated by butyrate and NAD+, so increasing butyrate and/or NAD+
(preferably by also preventing their ongoing rampant depletion) may allow for
normal programmed cell death, while simultaneously modulating viral alterations
to GDH and glutaminase enzymes, preventing a continuance of CFS/ME
Page 21 of 39
By considering just these features, 2 clear strategies are presented.
NB. Before introducing these 2 strategies, a key point needs to be understood - there is
currently no road back to health that does not include an immune response.
Getting the immune system to start working normally and replacing the infected cells
is an integral part of both these strategies.
Given the virulence, people can expect this experience to feel just like having a really bad
case of flu. It won’t be enjoyable at first, but that’s how the immune system works. We’ll
indicate parts of the process that can be slowed down or paused if tolerance is low.
*Prerequisite note on ammonia management:
When commencing either strategy detailed below, previous viral alterations to eg.
the purine nucleotide cycle will be ceased.
This would normally cause a “flood” of ammonia needing to be urgently
metabolised and downstream symptoms of uremia - “head pressure /
headaches”, etc. This is also largely avoidable.
(1) FASTING: Administer 750-1000mg of the food preservative sodium benzoate,
4x a day for 3-4 days.
(2) NON-FASTING: Administering 750-1000mg of the food preservative sodium
benzoate, 1000-2000mg of glycine, plus sufficient P5P and cysteine, 4x a day for
the first 3-4 days may be highly advantageous over other “metabolically
expensive” nitrogen disposal routes, thus preventing or ameliorating those
Page 22 of 39
(Inducing apoptosis in infected cells by selective mitochondrial starvation.)
Most of the CFS/ME or HHV-related problems are being created by alterations to/from
the pathway that enters/exits the mitochondrial reaction cycle at α-KG.This is
controlled by the enzyme GDH and is highly elevated by the viruses (and C.diff.)
Likewise, the “main” entrypoint into the mitochondrial reactions originates from:
a) Fatty acid oxidation, which then needs acetyl-CoA, one of the key metabolites
depleted by unregulated viral protein synthesis, to enter the cycle of
mitochondrial reactions.
b) Glucose,glycolysis, which all become pyruvate, which then needs acetyl-CoA,
one of the key metabolites depleted by unregulated viral protein synthesis, OR
separately, ATP, to enter the cycle of mitochondrial reactions.
This means that we can exploit the HHV cell differences by simultaneously:
a) Performing a 3-5 day staged “water fast”. This will deprive all cells of additional
nutrients and carbohydrate-based fuel - some of which are being rapidly depleted
by the viral activity. “Water fasting” means simply not eating ANY food or
Page 23 of 39
supplements which can provide energy to the mitochondria, or metabolites to the
cells, while consuming 3 or more litres of water over each day and electrolytes.
The water needs to contain sufficient daily amounts of some electrolytes
(minimally sodium chloride, however adding potassium chloride and magnesium
oxide will benefit - not using citrate/gluconate/other forms is important) to
maintain daily requirements and also induce diarrhea, thus preventing secretion
of organic acids and/or short-chain fatty acids from the gut microbiome that would
also “rescue” the depleted metabolites and/or supply mitochondrial any alternate
fuels such as fumaric acid, malic acid, citric acid, etc[2].
(This would also confer an additional bonus for the many CFS/ME patients with
Small Intestine Bowel Overgrowth (SIBO) or gut microbiome dysbiosis /
b) Completely knocking down the enzyme GDH during this water fast by using an
ongoing very high dose (eg. daily total 1500-3000mg) of the green tea extract,
epigallocatechin gallate (EGCG), by simply adding it to the water being
consumed. EGCG has a 3.4 hour metabolic half-life[64][65].
This will prevent energy from going into the mitochondria via anaplerosis at
α-KG, or out, with an approximate 4-6 hour effect from each dose / drink of water.
This means that no mitochondrial fuel can be derived from the glutamate
pathway, including from glutamine storage.
This also means that any energy from the mitochondria that would have been
diverted to storage eventually as glutamine will be kept inside the cycle. (JL:This
author’s personal experience has been that this may provide a surprising amount
of energy availability / efficiency for uninfected cells and ameliorate hunger
c) Impairing glycolysis, by adding resveratrol to the water or, if performed in a
clinical setting, using dichloroacetate at least every 12 hours[1].
d) Performing basic movements to assist with energy depletion and autophagy.
NO food within 6-8 hours of any EGCG dose. Food will cause SUFFERING by
shutting off the mitochondrial energy supply at α-KGDH by causing a ROS
NO other supplements.
Page 24 of 39
Any dangerous medications which must be maintained due to tolerance or
withdrawal symptoms should be continued eg. “FrankenGABAAKA
Cannabis is allowed, where legal and may assist the process.
-THC may increase appetite, which could be problematic if not
-CBD may decrease appetite, increase selective apoptosis and improve
Drinking additional plain water is fine.
Succinate / succinic acid should be kept on hand for managing any emergency
event caused by mitochondrial overload and/or to exit to the fast.
Day 1:
Take 3 empty 1L bottles.
Add to each bottle -
a) 3 cups of previously steeped strong green tea or 50mg of clean
b) 2g of sodium chloride (NB. Make sure it’s high quality ground “rock salt”,
NO fillers!)
c) 3g of potassium chloride (DO NOT USE: Nu-Salt, Morton’s Salt
Substitute. DO USE: pharmaceutical grade / NOW Foods. If in doubt,
leave it out. Definitely DO NOT USE citrate, malate, fumarate or other
mitochondrial energy sources - check labels carefully.)
d) 250-500mg of a clean magnesium oxide supplement. (NB. Definitely NOT
citrate, malate, fumarate or other mitochondrial energy sources - check
labels carefully. If in doubt, leave it out.)
e) 50mg “clean” resveratrol per bottle.
f) Fill the rest of each bottle with water.
Drink all three bottles over the day.
NB. Diarrhoea will likely commence towards the end of day 1. This will get a little
tedious over the duration of the fast and application of some “barrier cream”
and/or use of “wet wipes” would be suggested.
Day 2:
Take 3 empty 1L bottles.
Add to each bottle -
a) >500mg of “clean” EGCG.
b) 2g of sodium chloride (NB. Make sure it’s high quality ground “rock salt”,
NO fillers!)
c) 3g of potassium chloride (DO NOT USE: Nu-Salt, Morton’s Salt
Substitute. DO USE: pharmaceutical grade / NOW Foods. If in doubt,
leave it out. Definitely DO NOT USE citrate, malate, fumarate or other
mitochondrial energy sources - check labels carefully.)
Page 25 of 39
d) 250-500mg of a clean magnesium oxide supplement. (NB. Definitely NOT
citrate, malate, fumarate or other mitochondrial energy sources - check
labels carefully. If in doubt, leave it out.)
e) 50mg “clean” resveratrol per bottle.
f) Fill the rest of each bottle with water.
Drink all three bottles over the day.
NB. Diarrhoea will continue.
Day 3+:
Take 3 empty 1L bottles.
Add to each bottle -
a) >500mg of “clean” EGCG.
b) 2g of sodium chloride (NB. Make sure it’s high quality ground “rock salt”,
NO fillers!)
c) 3g of potassium chloride (DO NOT USE: Nu-Salt, Morton’s Salt
Substitute. DO USE: pharmaceutical grade / NOW Foods. If in doubt,
leave it out. Definitely DO NOT USE citrate, malate, fumarate or other
mitochondrial energy sources - check labels carefully.)
d) 250-500mg of a clean magnesium oxide supplement. (NB. Definitely NOT
citrate, malate, fumarate or other mitochondrial energy sources - check
labels carefully. If in doubt, leave it out.)
e) 50mg “clean” resveratrol per bottle.
f) Fill the rest of each bottle with water.
Drink all three bottles over the day.
NB. Diarrhoea will continue.
Exiting the Fast:
[Begin implementing the strategy described in
“Ameliorating symptoms and selectively inducing apoptosis.”]
6-8 hours after drinking the last dose of “salty EGCG cocktail”, resume food
consumption. Ideally this should initially contain a reasonable portion of soft and
fibrous plant-based foods with maximum exposure to diverse, beneficial
microbes. Diarrhoea will continue for typically ½ a day or more. Beneficial tissue
adaptations will continue over the next week.
(Unscheduled / emergency)
[See “IMPORTANT SAFETY CONSIDERATIONS”, Section (a) for more details.]
Page 26 of 39
How does this process work, technically?
In all cells:
- Stored energy cannot be derived from glutamate or glutamine storage.
Glycogen will be depleted. Nutrients will either be recycled and/or
depleted, making anaplerosis increasingly more difficult with time, energy
and metabolite depletion.
In uninfected cells:
-Acetyl-CoA will be regenerated by normal operations and fuel supplied by
fatty acid oxidation / catabolism.
- These cells survive.
In infected cells:
- When acetyl-CoA and energy sources are depleted by the forced /
unregulated “high-priority, virally-induced” protein synthesis tasks and
these can’t be replenished, the mitochondria will no longer have fuel from
the “main” entry point into the reaction cycle.
- With no fuel from glutamate /glutamine storage available, the primary
“backup power” is also gone.
- With the microbiome unable to provide organic acids, this “backup
source” of fuels is gone.
- When the other cofactor metabolites are depleted, like P5P, other routes
to anaplerosis are gone.
- These infected cells simply die from starvation, preferably triggering
apoptosis ahead of necrosis.
Page 27 of 39
a) Eating ANY food during this “GDH-knockdown” method of
water-fasting can be expected to cause BLACKOUTS,
NECROSIS or DEATH, relative to the dose efficacy of EGCG.
GDH is knocked down. This means ALL energy entering the
mitochondria cannot be balanced / diverted and stored as glutamine
and must therefore be used for activities.
This means that anything which enhances fat-burning - eg. caffeine,
cAMP promoters, beta-agonists like Salbutamol and/or any forms of
energy that come from dietary inputs or anapletoric microbiome
secretions have the ability to cause hypomania, as seen in bipolar
“High intensity” (relative term) exercise can induce hypomania. Gentle
movements may resolve it.
Page 28 of 39
Hypomanic symptoms should be treated with caution.
In excess, this energy can “overload” the ROS limiter and cause α-KGDH
Under normal circumstances, α-KGDH impairment would result in
transamination at α-KG.
However, with GDH knocked down, transamination at α-KG is
With no other energy sources, this would cause the mitochondria to
STOP, easily causing necrosis, blackouts and derealisation.
Reducing ROS, by coadministering R-Alpha Lipoic Acid (R-ALA) at eg.
200-300mg, every 4-6 hours, may increase the safety margin around any
hypomanic events. This has not yet been tested.
The ONLY antidote to this state is via anaplerosis at succinate -
Administer 50-100mg dose of succinic acid, with repeated dosing every
25 minutes, if fatigue is still present (or none if energetic), until EGCG is
fully metabolised (8-10 hours from last EGCG dose). The fast can be
simply resumed at this point, or simply aborted with food.
b) Avoid driving, travelling or operating heavy machinery. Ideally, people should take
time off “everyday life” to complete this process. A nice, calm environment is
c) The gut microbiome and mucosa will need to be rebuilt at the end of this fast.
Bathroom trips may be more “urgent” for a few days.
Activities that may assist with this process: Gardening, nature walks, getting
“dirty”, playing with animals, eating raw / unwashed / organic plant based foods
(and/or potentially consuming a “good” probiotic/prebiotic mix) and generally
“being exposed to nature” with plenty of hand-mouth interaction.
(JL: There are thousands of years of anecdotal evidence supporting the efficacy
of these approaches[72][73][74][75][76]... We’ve made a real mess of this in recent
Page 29 of 39
This is the “ongoing treatment” plan, which has already been demonstrated to provide
complete remission of CFS/ME symptoms in early testing. So far this has only been
tested / implemented by people who have previously arrested their HHV lytic phase
replication using spironolactone and also “Passed through the Eye of the Needle”.
However, this treatment plan is expected to work in others who have not performed
these previous steps. It is anticipated that any secondary “autoimmune” symptoms
caused by an active HHV-mediated lytic phase may take some additional time to resolve,
owing to the metabolic half life of Immunoglobulin G (IgG) being around 21 days,
however this is entirely untested[80][81]. Current data suggests the main symptoms should
resolve in less than a week.
For persons in an extremely weakened state, or those who fear “Passing through the
Eye of the Needle”, this can be an acceptable and more gentle approach, however it’s
expected that people will see previously missing “normal” immune activity and this may
be understandably unpleasant at times.
The biggest instruments in providing this immune response are the triterpenes and beta
glucans. These can be introduced gently, as tolerance allows. Starting at a full dose may
induce acute immune response, pain and inflammation.
Dietary butyrates eg. butter and a functioning microbiome that provides secretion of
butyrates would be advantageous in viral remediation[2].
a) EGCG - “GDH normalisation”
A correctly dosed schedule of green tea extract EGCG can normalise elevated
GDH[64][65]. This logically prevents most of the issues seen in the HHV disease
spectrum. (JL’s research suggests that between 20-35mg of EGCG, dosed every
4.5 hours was a clinically effective dose to put CFS/ME into remission, when
combined with other compounds.)
This appears to be roughly equivalent to 1-2 cups of strong green tea, however
the variability of EGCG content in tea may be problematic.
An acute reduction in viral protein synthesis activity should be also observable.
NB. Any excess of EGCG should be noticed clinically by a minor elevation of ALT
(providing enough dietary protein is consumed), simply indicating backup-path
replenishment of glutamate via alanine transamination,rather than being
misinterpreted as EGCG hepatotoxicity.
Page 30 of 39
b) Reishi - “Triterpenes + Beta-glucans”
Alcohol extracts of Reishi are known to contain large amounts of unique
triterpenes, such as ganodermic acid, which have a demonstrated ability to
ameliorate viral alterations, induce apoptosis in Epstein-Barr Virus (EBV) and
cancer cells, while providing normalisations to mitochondrial function and
Our early testing has shown that an effective dose appears to be equivalent to
500mg of 1:1 reishi extract, 3-4x per day. It’s possible that smaller doses are still
quite effective.
A suggested starting dose may be ¼ of this.
c) Lion's Mane / Oat Bran / Wheat Bran / Barley - “Beta-glucans”
Lion’s Mane,oat bran,wheat bran and barley are all good dietary sources for
Oat bran contains a very high content of beta-glucans, at approximately 8%, by
weight. Wheat bran is closer to 3%. Barley is around 10%.
Beta-glucans have demonstrated potent immunostimulatory and antineoplastic
effects. These appear to be highly synergistic with the similar effects provided by
triterpenes in Reishi[84][85][86][87][88][89][90][91][92][93][94][95][97][98].
Our early testing has shown that an effective dose of Lion’s Mane appears to be
250-500mg, 3-4x a day. It’s possible that smaller doses are still quite effective.
(JL: We’ve been combining Lion’s Mane with liberal amounts of dietary oats / oat
bran. This has demonstrated a potent immune response - temporary symptoms
have included: rashes, enlarged lymph nodes, cold / flu symptoms, inflammation,
gastrointestinal distress.
It’s highly plausible that this highly-stimulated immune response, while extremely
helpful, is also generally unpleasant to experience and probably responsible for
the “non-coeliac” wheat / oat intolerances often reported.)
A starting dose may be ¼ teaspoon of oat bran, once and then testing tolerance /
appetite for immune response symptoms over the next 2 days. The beginning
can be a little “rough”, proportional to the dose.
d) R-Alpha Lipoic Acid - “ROS reducer”
As a general ROS reducer, R-ALA is recommended at 200-300mg, 3x a day[1].
Page 31 of 39
Treatment Next Steps:
A NutrEval report should confirm normal mitochondrial flow parameters typically within
one week of treatment commencing, if not sooner. A PAGN urine analysis can also be
As CFS/ME symptoms should now be ameliorated, it’s suggested that monitoring
serology markers for efficacy, where not confounded by Intravenous immunoglobulin
(IVIg)[96]. This protocol should be continued until serology for eg. EBV Viral Capsid
Antigen (VCA) IgG or other HHV is barely detectable, allowing 3-4 week lag for
metabolism of IgG, after infected B-cells are killed.
Additional markers for detecting levels of latent infection may become apparent.
How do we retain the benefits of the virus?
JL: It seems highly plausible that these viruses have played an important role in our
evolution and development as a species.
If this is the case, the beneficial features need to be maintained and I also can see (and
have briefly tested) clear ways for them to be conceivably enhanced.
An additional paper will be released shortly, detailing different methods for achieving this
and other ergogenic effects.
Have modern high-carbohydrate diets played a role?
JL: YES. However, although this is highly relevant to the level of infection. When large
amounts of high-glycaemic index carbs are (frequently) consumed, this places an
additional burden on where and how they can be stored. Excess glucose will enter the
mitochondrial cycle and get rapidly converted to glutamate. This effect is significantly
more debilitating once transamination has occurred.
CSIRO in Australia has studied the effects of a “low carbohydrate, high protein” diet
against type-2 diabetes - a metabolic disease within the proposed spectrum - with
positive results[102]. This style of eating would have been similar to pre-industrialised
agriculture and food supply.
Similarly, ketogenic diets are frequently reported to alleviate many CFS/ME symptoms,
however these effects become less apparent after some months, once fatty acid
oxidation and ketogenesis efficiency has improved - excessive cycle energy, caused
dysregulated pressure to/from α-KG, which would not exist without the viral infection,
induces the same cascade of symptoms.
Page 32 of 39
How far does this go?
JL: I’m a former CFS/ME patient, who managed to somehow defeat the infection in my teenage
years, after a brutal 2 year battle that still brings tears to my eyes, if I think of it.
The secondary puzzle of how I managed to achieve that rare victory is now finally clear to me.
I’d like to think the life I’ve had is probably a good example of what someone else who has been
similarly altered by the viral infection and then escaped it is also capable of. I will enjoy seeing
what the world looks like when people are no longer burdened by this landscape of illnesses.
Perhaps, together, we can make it a Paradise.
We hope to see further research in attempting to apply this model to -
Multiple Sclerosis, Parkinson’s Disease, Alzheimer’s Disease, ALS, bipolar disorder,
schizophrenia, autism spectrum disorder, anxiety disorders, depression, narcolepsy, sleeping
disorders, eating disorders, fibromyalgia, fibrosis, rheumatoid arthritis, psoriatic arthritis,
polycystic ovary syndrome, endometriosis, mast cell activation syndrome (MCAS), eczema and
other skin disorders, clubbed fingernails, atherosclerosis, alopecia, hirsutism, colitis, irritable
bowel disorder, coeliac disease, gut microbiome disorders with elevated butyrate, Raynaud’s
Syndrome, Ehlers Danlos Syndrome, Addison’s Disease, Hashimoto’s Disease, Lupus / SLE,
myasthenia gravis, primary biliary cirrhosis, NAFLD, type-1 diabetes, type-2 diabetes, Leigh
Disease, Reye Syndrome, Fumarase Deficiency Syndrome, mitochondrial diseases where
genomic sequencing is negative, lymphomas, multiple myeloma, food allergies, lactic acidosis,
congenital lactic acidosis, urea cycle disorders, Sudden Infant Death Syndrome (SIDS), colic,
cancers featuring the “Warburg” or “Reverse Warburg” effect, “Long COVID” syndrome, as well
as dislipidemia, insulin resistance, hypogonadism, Post Finasteride Syndrome and Post-SSRI
sexual dysfunction[1][2].
Page 33 of 39
We would like to thank every single person - researcher or thinker - whose diligent work in
discovering, experimenting and reporting the “dots”, thereby allowed them to be connected here
and thus made this work possible.
JL: With special thanks to J Carlson, Mateusz Kaczmarek (credit for: Reishi, purine nucleotide
cycle), Denisa, S Asnani, Tiffany, Sharon, Karolin, Janet, Andre, Fran, Frigo, Robbie, Iliya, Alex,
Memo, Stefan, Scott, Ian, Tyler and everyone else for believing in me and challenging me to do
<tinfoil hat firmly on> I also realise that this discovery may lead to a very large reduction in
pharmaceutical revenue. In the (hopefully unlikely) event of my untimely demise, I'd like to state
that I clearly have a sense of humour - I’m not eg. depressed or suicidal, nor do I have
information that will lead to the arrest of Hillary Clinton. My car is new and serviced regularly. I
rarely fly on light aircrafts. I also have zero interest in child pornography - I’d like that not to exist
at all.
We have a patent. There’s room for everyone and we’re always open to talking.
Data Availability Statement
All materials used have been cited. Images were created in Draw.IO and source files to extend
this model are available upon request to the corresponding author. High resolution images of
figures are available in the supplemental files.
Author Contributions
JL conceived the design and authored the manuscript. AN provided material support, reviewed
methodology, provided oversight and guidance, expert lab experience, analysis skills and
audited / validated citations. All authors critically reviewed the final manuscript.
This work was unfunded and conducted out of human interest.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of interest. Authors have
previously joint-filed a patent relating to the formulation of a treatment protocol.
Page 34 of 39
The use of this material is entirely at your own risk.
Please seek advice from your doctor and obtain medical clearance before using information
provided here, especially if you have any other medical conditions or concerns.
The authors, editors, affiliates and representatives assume no responsibility or liability for any
errors or omissions in the contents of this material. All information is provided on a "best effort"
basis with no guarantees of completeness, accuracy, usefulness, performance or timeliness.
“Don’t do this at home”. JL: However, if you do - please sign our guestbook and share your
experience: :)
Page 35 of 39
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Abstract In cells, where mitochondria are utilising glutaminolysis and transamination - whether caused by normal function or when specifically altered by eg. virally induced overexpression of KGA, GLS1, GLUD1 and/or GLUD2 - key enzymatic reactions for energy production are reversed during the transamination of aspartate=>oxaloacetate and α-KG=>glutamate + ammonia, consuming additional pyridoxal 5-phosphate (P5P). Excessive glutaminolysis and transamination increases nitrogen / urea burden, while consuming aspartate, before further consuming acetate and butyrate for increased α-KG=>[..]=>glutamine disposal via the phenylacetylglutamine (PAGN) pathway to urine. Further, this elevates lactate and affects neighbouring cell metabolism via the lactate shuttle. Depletion of acetate could lead to many impaired reactions involving acetyl-CoA, with implications to beta-oxidation pathways, mitochondrial function, pyruvate:lactate balance and any pathways that require an acetyl donor, such as choline=>acetylcholine and carnitine=>acetyl-L-carnitine. Depletion of acetate would cause further dysregulation to the urea cycle (UC), creating an elevation of glutamate, acting as a rate limiting factor for glutaminolysis and further causing impairment of mitochondrial Nicotinamide Adenine Dinucleotide (NAD+):NADH redox, favouring NADH. Aspartate depletion also dysregulates production of reactive oxygen species (ROS), sex hormones, thyroid hormones, alpha-melanocyte-stimulating hormone, GABA and dopamine release. Depletion of butyrate dysregulates immune and mitochondrial apoptotic regulation via Nuclear Factor Kappa B (NF-κB) signalling. It further impacts nitrogen metabolism. The depletion of NAD+ acts as a rate limiting factor for many enzymatic reactions, including glutamate dehydrogenase (GDH), further impairing glutamate<=>α-KG metabolism. We further describe a role for acetate, aspartate, butyrate, P5P and Vitamin B5 in a therapeutic intervention against the HASD model for CFS/ME.
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Abstract Here we propose a hypothetical model seeking to map the pathogenesis of a herpesviridae-positive serology subtype of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) as a simultaneous α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) deficiency, with degraded beta-adrenergic signalling cascade and impaired hepatic gluconeogenesis, phasic hyperlactatemia and hyperammonemia - as caused by herpesviridae-mediated antibodies and latent cell burden. For example, “M37GO37” targets dihydrolipoamide succinyltransferase from the α-ketoglutarate dehydrogenase complex (α-KGDC), creating an acute deficiency of α-KGDH, impairing Citric Acid Cycle (CAC) metabolites from succinyl-CoA / Complex V through malate, accumulating α-ketoglutarate (α-KG), reducing adenosine triphosphate (ATP), NAD+ and respiration. “M18GP8”, “M82GP8”, “M37GPl1” antibodies to pyruvate dehydrogenase complex (PDC), plus hypoxia, low physical activity and/or antibodies creating beta-adrenergic dysregulation can each cause a decrease in PDH, Cori Cycle efficiency and insulin resistance. When combined with succinate and argininosuccinate (ASA) deficiency, plus elevated α-KG, nitrogen disposal shunts to nitrogen retention via metabolism to L-glutamate and L-glutamine, triggering glutaminolysis. Sleeping, fasting and respiration decrease lactate and nitrogen retention via metabolic shunting, partially rescuing succinate availability for CAC, urea cycle metabolism via GABA. Each of these α-KGDH, PDH and beta-adrenergic cascade deficiencies are able to cause both of the others, adding additional complexity to diagnosis and treatment. These phases can be accompanied by debilitating symptoms associated with hyperammonemia, GABA deficiency, glutamate-induced excitotoxicity, uremia, hyperlactatemia, adrenergic and cortisol dysregulation, with accompanying hair, skin, GI, collagen, immune, sphingolipid, endocrine, sleep and neurological disorders. This further suggests investigating the herpesvirus family as causal for numerous disorders.
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Abstract Chronic kidney disease (CKD) is characterized by retention of uremic solutes. Compared to patients with non-dialysis dependent CKD, those requiring haemodialysis (HD) have increased morbidity and mortality. We wished to characterise metabolic patterns in CKD compared to HD patients using metabolomics. Prevalent non-HD CKD KDIGO stage 3b–4 and stage 5 HD outpatients were screened at a single tertiary hospital. Various liquid chromatography approaches hyphenated with mass spectrometry were used to identify 278 metabolites. Unsupervised and supervised data analyses were conducted to characterize metabolic patterns. 69 patients were included in the CKD group and 35 in the HD group. Unsupervised data analysis showed clear clustering of CKD, pre-dialysis (preHD) and post-dialysis (postHD) patients. Supervised data analysis revealed qualitative as well as quantitative differences in individual metabolites profiles between CKD, preHD and postHD states. An original metabolomics framework could discriminate between CKD stages and highlight HD effect based on 278 identified metabolites. Significant differences in metabolic patterns between CKD and HD patients were found overall as well as for specific metabolites. Those findings could explain clinical discrepancies between patients requiring HD and those with earlier stage of CKD.
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Mitochondrial dysfunction is considered one of the pathophysiological mechanisms of autism spectrum disorder (ASD). However, previous studies of biomarkers associated with mitochondrial dysfunction in ASD have revealed inconsistent results. The objective of this study was to evaluate biochemical markers associated with mitochondrial dysfunction in subjects with ASD and their unaffected family members. Lactate and pyruvate levels, as well as the lactate-to-pyruvate ratio, were examined in the peripheral blood of probands with ASD (Affected Group, AG) and their unaffected family members (biological parents and unaffected siblings, Unaffected Group, UG). Lactate ≥22 mg/dl, pyruvate ≥1.4 mg/dl, and lactate-topyruvate ratio >25 were defined as abnormal. The clinical variables were compared between subjects with higher (>25) and lower (≤25) lactate-topyruvate ratios within the AG. The AG (n=59) had a significantly higher lactate and lactate-to-pyruvate ratio than the UG (n=136). The frequency of subjects with abnormally high lactate levels and lactate-to-pyruvate ratio was significantly higher in the AG (lactate 31.0% vs. 9.5%, ratio 25.9% vs. 7.3%, p<0.01). The relationship between lactate level and the repetitive behavior domain of the Autism Diagnostic Interview-Revised was statistically significant. These results suggest that biochemical markers related to mitochondrial dysfunction, especially higher lactate levels and lactateto- pyruvate ratio, might be associated with the pathophysiology of ASD. Further larger studies using unrelated individuals are needed to control for the possible effects of age and sex on chemical biomarker levels.
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Epstein–Barr virus or human herpesvirus 4 (EBV/HHV-4) is a ubiquitous human virus associated with a wide range of malignant neoplasms. The interaction between EBV latent proteins and host cellular molecules often leads to oncogenic transformation, promoting the development of EBV-associated cancers. The present study identifies a functional role of GLS1 isoforms KGA and GAC in regulating mitochondrial energy metabolism to promote EBV-infected cell proliferation. Our data demonstrate increased expression of GLS1 isoforms KGA and GAC with mitochondrial localization in latently EBV-infected cells and de novo EBV-infected PBMCs. c-Myc upregulates KGA and GAC protein levels, which in turn elevate the levels of intracellular glutamate. Further analysis demonstrated upregulated expression of mitochondrial GLUD1 and GLUD2, with a subsequent increase in alpha-ketoglutarate levels that may mark the activation of glutaminolysis. Cell proliferation and viability of latently EBV-infected cells were notably inhibited by KGA/GAC, as well as GLUD1 inhibitors. Taken together, our results suggest that c-Myc-dependent regulation of KGA and GAC enhances mitochondrial functions to support the rapid proliferation of the EBV-infected cells, and these metabolic processes could be therapeutically exploited by targeting KGA/GAC and GLUD1 to prevent EBV-associated cancers.
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An excessive hyperinflammatory response-caused septic shock is a major medical problem that is associated with pathogenic bacterial infections leading to high mortality rates. The intestinal microbiota and the associated elaborated metabolites such as short chain fatty acid butyrate have been shown to relieve pathogenic bacterial-caused acute inflammation. Butyrate can down-regulate inflammation by inhibiting the growth of pathobionts, increasing mucosal barrier integrity, encouraging obligate anaerobic bacterial dominance and decreasing oxygen availability in the gut. Butyrate can also decrease excessive inflammation through modulation of immune cells such as increasing functionalities of M2 macrophages and regulatory T cells and inhibiting infiltration by neutrophils. Therefore, various approaches can be used to increase butyrate to relieve pathogenic bacterial-caused hyperinflammation. In this review we summarize the roles of butyrate in attenuating pathogenic bacterial-caused hyperinflammatory responses and discuss the associated plausible mechanisms.
Selective destruction of senescent cells Senescent cells are associated with a variety of age-related medical conditions and thus have been proposed as potential targets for therapy, but we do not yet have a full understanding of the underlying mechanisms. Johmura et al. used RNA interference to screen for enzymes essential to the survival of senescent cells (see the Perspective by Pan and Locasale). The authors identified a key role for glutamine metabolism, particularly the enzyme glutaminase 1, and demonstrated that inhibition of this pathway induced the death of senescent cells. Glutaminase targeting also ameliorated aging-related organ dysfunction and obesity-related disorders in mouse models, suggesting the potential therapeutic value of this approach. Science , this issue p. 265 ; see also p. 234
The pathogenesis of autoimmune diseases (AIDs) is not only attributed to genetic susceptibilities but also environmental factors, among which, disturbed gut microbiota has attracted increasing attention. Compositional and functional changes of gut microbiota have been reported in various AIDs, and increasing evidence suggests that disturbed gut microbiota contributes to their immunopathogenesis. The accepted mechanisms include abnormal microbial translocation, molecular mimicry, and dysregulation of both local and systemic immunity. Studies have also suggested microbiota-based classification models and therapeutic interventions for patients with AIDs. Further in-depth mechanistic studies on microbiota–autoimmunity interplay in AIDs are urgently needed and underway to explore novel and precise diagnostic biomarkers and develop disease and patient-tailored therapeutic strategies.