Research Group for ME/CFS, Chronic Disease, Ageing and Cancer

Read 877 times

The problem - a never-ending cycle of nutrient depletions.
« on: June 15, 2021, 11:37:30 PM »
In this post, I'm going to attempt to break down and elaborate on the CFS/ME paradox I was describing in the second paper.

Why is it that consuming specific supplements "hurts" us?

As this is already a large amount of information to digest, a breakdown the specific viral alterations will be described in the next post.

The primary reason that consuming any nutrients which are measurably depleted will predictably lead to headaches, PEM, etc. - is all downstream from "runaway" oxidative stress (ROS) and ammonia generation / metabolism / excretion processes.

The metabolites being depleted are common co-factors for many metabolic pathways and some depletions can cause a bottleneck for energy production in the mitochondrial reactions.

By "refilling any nutritional gap(s)" which were stalling cellular activities, these infected cells with "faulty metabolism" are now able to "get back to work" (they're programmed to build viral proteins, etc., using any/all available resources and lack programming for a "quiescent state", if resources are dwindling)... unfortunately this never-ending workload is constantly creating / increasing oxidative stress and further reducing the primary rate-limiting enzyme for the mitochondria - alpha-ketoglutarate dehydrogenase (a-KGDH).

This naturally increases the oxidative stress and ammonia load - which is quickly metabolised to a group of various other metabolites and collectively referred to as "nitrogen". This becomes an escalating problem.
Mito-Build.png
This growing ammonia load (metabolites of which are also the origin of PEM, headaches, etc) triggers an increase of systemic "nitrogen excretion processes".

One of these disposal processes further drains key metabolites, creating an "energy crisis".. again.. and this becomes a vicious cycle, every time we eat, as we continue escalating this vicious cycle.

However, these induced "nutritional / metabolite gaps" also create a cascade of neurological dysfunctions, brain fog, thyroid issues, oxalate production, etc., along with muscle activation issues.

Now this becomes significantly worse, once the ROS increases to a state where a-KGDH is COMPLETELY impaired.

Normally, this should be a temporary event, allowing the mitochondria to briefly "slow down" and let the ROS scavenging processes (glutathione, antioxidants like vitamin E, C and alpha lipoic acid) catch up, cooling things down.

Now, in the event that the mitochondria is "fragmented" at a-KGDH, how is the mitochondria supposed to keep the cell alive? 

"Don't worry", this is biology - there are always a number of redundant pathways for every pathway / process.

The first thing that happens is a "transamination", where a tricky enzymatic reaction bypasses the impaired enzyme at a-KGDH and performs a "dual-metabolism" reaction, where two things happen at once: as a-Ketoglutarate goes through a reaction to make glutamate, aspartate is simultaneously converted into oxaloacetate, bridging through the middle of the cycle and restarting it at the top of the cycle (see the cyan pathway in Figure 5, above.)

Okay.. but what about all of the other cycle reactions after a-KGDH? How are these supposed to be maintained?

Two of these redundant pathways needed to heal the second half of the citric acid cycle are at "succinate" :
GABA + P5P (P5P is active form of Vitamin B6 - needs magnesium, zinc, riboflavin to be created) can be converted into succinate.
B12 + Folate + P5P (riboflavin, magnesium, zinc), can be readily converted into Succinate, via Succinyl-CoA, also (not shown in the diagram below).
(there are a few more)

However using these key metabolites as "backup fuel" too often leads to new problems, as you'll soon run out of them, too.

eg.
1. Methylation issues are observed and you'll expect to see the MCV in haematology reports significantly increase.
2. Without sufficient P5P, you'll see .. many.. issues, however a prominent one is tyrosine synthesis to dopamine is impaired, causing issues for mental health and motor functions.
3. If GABA is now being consumed for fuel, this creates further issues for maintaining a balance between "excitory" signalling (glutamate) and "inhibitory" signalling (GABA).

Now if dopamine is already low, aspartate is supposed to create more GABA in specific cells, such as retinae, as a backup pathway.. (unless aspartate is already low, because..)

The urea cycle can also allow the citric acid cycle to be fueled at "fumarate" .. which is a useful "low cost" way to recycle some of the ammonia being created - until either aspartate or argininosuccinate is depleted. It can also be used to create 5-HTP->L-DOPA->Dopamine.

This will reduce pathology markers for "urea" and reduce PEM.. briefly..

This also temporarily bypasses the "mitochondrial rate-limiter" (a-KGDH), allowing normal respiration and potentially correcting a number of issues around collagen synthesis, energy levels and hypoxia induced transcription factors (HIF-1a), etc.. alleviating those symptoms.

However, the ongoing (faulty) mitochondrial activity continues, the ROS increases, starts damaging the cell, DNA, and this ongoing ammonia overload forces heavier use of the "expensive" ammonia excretion process - via "phenylacetylglutamine" (PAGN).

This is where it all starts to get very unpleasant.

This is because acetyl-CoA (one of the most critical metabolites in the cell), glutamine and upstream metabolites are being constantly dumped from the cells, converted into urinary metabolites and excreted. 
Mito-ComplexMap.png

With the ongoing metabolite depletions, including cysteine (via acetyl-CoA + CoA) and glycine, glutathione production and regeneration gets impaired.

This means that oxidative stress (ROS) cannot be reduced / scavenged.. leading to DNA transcription errors that can't be corrected if acetyl-CoA is impaired, cancers and... yet more ammonia to metabolise.. fortunately, as the B vitamins get depleted and/or aspartate gets depleted, half the cycle shuts down and the mitochondria cools off...


.. meanwhile creating issues with hypoxia, connective tissue disorders like (h)EDS, neurological disorders, thyroid disorders, fatty acid oxidation issues, insulin resistance, POTS / dysautonomia / orthostatic intolerance, etc..


Without sufficient acetyl-CoA, our cells are unable to make "acetylated" metabolites, such as:

Acetylcholine - required for cognitive function and muscle activation

Acetyl-l-carnitine

n-Acetylserotonin (which also mean low melatonin, required to trigger nightly cellular metabolite cleanup processes and give refreshing sleep),



Without acetyl-CoA, this also :

Reduces energy flow into the mitochondrial reactions from pyruvate (glycogen, glucose metabolism) - leading to insulin resistance

Impairs beta-oxidation of fatty acids, further reducing energy availability and causing us to store fat, but not be able to use it efficiently.

As this is tissue specific, the systemic imbalance may lead to excessive epinephrine production, as a form of compensation - leading to POTS / dysautonomia / orthostatic intolerance. (This can be further exacerbated by a dopamine beta hydroxylase deficiency, caused by many factors, including other pathogens such as clostridia-derived mycotoxins and t.gondii, which will be covered in a separate article.)

(Some organs are now receiving too much adrenergic signalling, to allow the impaired tissues to get 'enough' to maintain energy production.)

This also leads to cortisol and further anxiety issues.

This is highly debilitating.. people are left between a choice of:
A) a body crippled with a personal selection of every disease we have named in the papers..
B) headaches, PEM, being incredibly overstimulated / overpowered by their environment to the point of being shutdown or placed on benzodiazapines.
C) an ongoing mix of both, every time we eat... often leading to a snowball effect where you can't eat... which is a slippery slope to hell*.

*NB. The thing about (C) is.. if someone didn't eat *anything* for say 5 days, as may happen in hunter-gatherer day, while perhaps keeping water and electrolytes up.. after going through a few days of their own personal hell, they'd later see a vast reduction in symptoms (perhaps 1-2 weeks after the fast), by having killed off many of the infected cells, simply by using their altered metabolic behavior.

This also bypasses any immune system deficiencies.



The catch-22 is, 5 days of fasting is likely going to consume 2-2.5kg of body fat. If someone is already in a fragile state, this option may not be available to them, initially.

Adding an ongoing high dose of EGCG (and resveratrol) to the fasting process speeds this up dramatically, by removing the other large source of stored energy available to the cell (from glutamine->glutamate-aKG). It also completely disables the transamination I described in the papers - this is why the first day of fasting has "low dose" of EGCG - giving time for the ROS to drop and transamination to "turn off".

This should mean that 3 days of EGCG fasting could be equivalent to 5-7 days of traditional water fasting. You're diving into the "pointy end of the fast", much earlier.

As an alternative to fasting, we have proposed an experimental treatment protocol.

However, implementing the proposed treatment protocol, the expectation is that the first 3-4 days is going to temporarily generate a LARGE amount of ammonia, as various pathways start working again, including the purine nucleotide cycle.

This will induce a (currently unavoidable) "crashed" state for those 3-4 days.

For this reason, we have selected sodium benzoate + glycine (and B5, NAC) to create an outlet for this initial surge.
Even with that adjunct, someone could expect a stunning headache for 3-4 days and extreme PEM.
"Ammonul", if they have deep pockets and a friendly doctor, would be an ideal adjunct to include at this time.
L-ornithine l-aspartate is another option which may be appropriate.

After that, thanks to the metabolic alterations provided by the reishi triterpenes, EGCG and various ROS scavengers (R-ALA / glutathione / NAC / Vitamin C / Vitamin E), someone would expect to be able to consume normal amounts of B vitamins and not create headaches, PEM, or other symptoms... providing they're NOT creating additional "pressure" inside the mitochondrial reactions by overloading the cell with glucose (hence the dietary modifications).

Excessive doses of B vitamins will still be expected to create mitochondrial pressure and ROS, also, by anaplerosis at succinate, as described above.

At this point, things our model suggests things may start improving.. although they'd still be expected to have artefacts of lytic phase "autoimmunity" to wade through for the next 6-8 weeks, unless they've previously been using eg. spironolactone / tenofovir, etc., for a similar period.

However, while all of these life improvements are happening... people are going to get tested.

Their ongoing immune response is going to cause flare-ups and inflammation of every single tissue they've historically had issues with.
It may be very unpleasant, at times.

Having trust that this is both necessary and one of the last times someone would have to experience these symptoms requires personal satisfaction that they're doing the right thing. Having exhaustive pathology markers to refer to during this process may help their resolve. eg. EBV VCA IgG should be decreasing, with a 6-8 week lag (if titres are within the maximum lab ranges... most people's are not..)

If someone is suffering from co-infections, these may require additional remediation. Research is ongoing into co-infections, with some success. HHV is not the only input to this disease model - there are a number of potential causes.

The protocol is being expanded to allow for any additional 'metabolic traps' or impaired pathways identified by further research.

We've since identified the roles of excess DHT, insufficient Vitamin D3, Vitamin A in this disease model.
Further work into the roles of neurotransmitters and metabolites of them is being investigated.

For this reason, we also subsequently discovered that people using spironolactone, as discussed in the 3rd paper, benefited from it performing the same functions as EGCG.

Therefore, without using spironolactone, this has necessitated significantly increasing the doses of EGCG and/or using other plant extracts, which provide the same benefits.

This will be discussed in more detail in other posts.
« Last Edit: September 16, 2021, 07:05:54 PM by joshua.leisk »
NB. I am NOT a doctor and all information provided is for educational purposes only.

Please consult your physician before attempting anything you read here.