An optimal metabolism: a look at the furnace within

[Hans]

What should a true metabolism look like?
What should we even look at?

I dived a bit deep on this one and hopefully it provides answers for some. I'm discussing redox couples, such as NAD/NADH, GSH/GSSG and cysteine/cystine and how they affect energy production, ROS, hormone and neurotransmitter levels.

An optimal metabolism: a look at the furnace within » TESTONATION

Why can some people eat a high carb diet and flourish? Why does some nootropics work for some but not for others? Why does one person get great results from one supplement, whereas another gets the opposite reaction? Let’s take dopaminergics for example. One person might feel great whereas...

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At the end, I lay out strategies on how to optimize your metabolism correctly and what to look out for that might be inhibiting your metabolism.
@yerrag @Kram

 

[gaze]

this was extremely helpful. maybe your best article yet

 

[GenericName86]

Thanks Hans, I was really looking forward to this one after you mentioned you were working on it in your recent Dopamine thread.

In regards to using niacinadmie, niacin, NR and NMN since you're using niacinamide do you think it's the best form to use? I've seen people mention needing methylation support when using niacin/niacinamide such as tmg, do you think that's needed or only if supplementing large amounts of niacinamide?

 

[Kram]

Great article and cleared a lot of things up for me. Thanks for writing.

 

[Wilfrid]

Excellent!!!!! Thanks.

 

[yerrag]

Thanks Hans. A lot of things to learn from this article. It must be a very difficult article to write (if I were you) and takes some kind of mastery of the processes and the substrates and the intermediate metabolites produced that form the parts needed for an optimal metabolism. It also brings home how complicated the mitochondrial machinery is, as it becomes plain to see that both oxidants and antioxidants balance each other in getting optimal metabolism going. Far from the conventional thinking that antioxidants are always good, it shows us that a reduced state, a property of antioxidants, is not always helpful when it interferes with metabolism, as when a high ratio of NAD (oxidising-) over NADH is needed for the citric acid cycle to run uninterrupted.

But this piece is rather deep and some parts of it, particularly the last part, is where I find it hard to find continuity with the first part. it gets very detailed. The illustration of young, middle age, and senile - needs to be filled in with more detail.

But I've stopped reading after this. I think it has more to do with me -a lot of heavy material coming at me, which seemed endless. I needed an artificial break, and that the way the article is laid out could help. The breadth covered is wide as well, so it may help to break it into two parts.

But since I have to make a comment, I opted to stop reading, or risk not making a comment at all if I have to finish reading this before I comment. I usually end up not finishing reading most of the time, thinking I can get back to it in the near future, without ever doing so. But this is the risk of being thorough, and trying to be that is much appreciated.

If you allow me some indulgence, I also some reservations on some points made-

-How does a highly reduced state come about from ROS detox being higher than ROS production? Perhaps I'm mistaken, but doesn't the body react to the stress condition and the reaction stops when the stress is relieved? Wouldn't it be logical to think that at most ROS detox would just equal ROS production? Is a runaway ROS detox process involved here? What are some instances of such a situation?

-How does a highly reduced state lead to excessive oxidative stress? Seems paradoxical as I would think it's a highly oxidized state that does that? It would help to cite some instances.

- I'm also not sure why we have to lower NADPH production. Doesn't the body produce NADPH automatically when it needs it, thru the PPP pathway? What would cause NADPH to build up too much? If NADPH is being used for different enzymatic processes, such as in producing ROS, as well as in producing or refreshing antioxidants, as well as some hormones, wouldn't NADPH be produced in line with the rate it's being used? As for the example with beta-lapachone, isn't the very fact that lapachone is an oxidizing agent (being an electron donor) make it also contribute to lowering ROS production during metabolism, and wouldn't this be the reason less NADPH is produced, because less NOX is needed due to less ROS being produced?

-Although I'm the one saying that the scope of this topic is too huge to be covered in one article, I feel the article is lacking in mention of stressors that get in the way of optimal metabolism. Without mention of these stressors, it seems that the article is too concerned in making the numbers that are consistent with good metabolism with the use of substances, such as in the NAD/NADH ratio, instead of enabling the body to naturally and automatically make the numbers, by giving it the right terrain, which is free from stressors such as toxins, external or internal (such as immune complexes) and pathogens, which subject the body to inflammatory conditions that cause stresses, both oxidative and reductive, that detract from optimal metabolism. A lot of the focus is on taking say niacinamide or methylene blue when these are temporary fixes. So without knowing and addressing the root cause of imbalances, one can be continually in need of taking supplements without fixing the root cause. For example, a low-level infection could persist, as no effort is made to address it.

Thanks!

 

[KenzoM]

very comprehensive article! wondering if there is an error in one of your paragraphs

"Complicated explanation, but basically, when the cell is more reduced, it has a much bigger capacity to accept electrons and prevent oxidative stress. An oxidized state is the opposite. I’ll explain more around this concept in just a bit."

Should it be when a cell is more oxidised?

Maybe i'm not understanding things correctly. Anyhow, thanks for creating & sharing

 

[Hans]

this was extremely helpful. maybe your best article yet

Thanks man, glad it was helpful!

 

[Hans]

Thanks Hans, I was really looking forward to this one after you mentioned you were working on it in your recent Dopamine thread.

In regards to using niacinadmie, niacin, NR and NMN since you're using niacinamide do you think it's the best form to use? I've seen people mention needing methylation support when using niacin/niacinamide such as tmg, do you think that's needed or only if supplementing large amounts of niacinamide?

I think niacinamide is definitely effective, but NR or NMN might be more potent at similar doses. So smaller doses of NR or NMN can be used to get the same effects as larger doses of niacinamide.
Niacinamide does drain methyl donors, but I think 100mg x3 daily or even 500mg once daily is fine, unless someone is undermethylating. Someone with high serotonin and histamine, due to poor methylation, might benefit more from using a methyl donor with niacinamide.
And when it comes to larger doses, such as 1.5-3g daily, I still think someone should rather go on symptoms that supplement methyl donors right away. Perhaps just eat more eggs when using such large doses.

 

[Hans]

Great article and cleared a lot of things up for me. Thanks for writing.

Thanks man and thanks for reading!

 

[Hans]

How does a highly reduced state come about from ROS detox being higher than ROS production? Perhaps I'm mistaken, but doesn't the body react to the stress condition and the reaction stops when the stress is relieved? Wouldn't it be logical to think that at most ROS detox would just equal ROS production? Is a runaway ROS detox process involved here? What are some instances of such a situation?

Take for example cancer cells. Cellular function starts to deteriorate and ROS production goes up. The cells have to protect themselves from the ROS, such they upregulate NADPH and glutathione production and recycling.
I some cases, NOX can get out of hand, and that's because there's an excess of NADPH to fuel it. It's most likely estrogen-driven since estrogen puts the P on NADH. This is also seen in thyroid cancer.

How does a highly reduced state lead to excessive oxidative stress? Seems paradoxical as I would think it's a highly oxidized state that does that? It would help to cite some instances.

This is overlapping with my previous answer. But yes, an excessive oxidized state is also harmful. Both too reduced or too oxidized is an issue.

I'm also not sure why we have to lower NADPH production. Doesn't the body produce NADPH automatically when it needs it, thru the PPP pathway? What would cause NADPH to build up too much? If NADPH is being used for different enzymatic processes, such as in producing ROS, as well as in producing or refreshing antioxidants, as well as some hormones, wouldn't NADPH be produced in line with the rate it's being used? As for the example with beta-lapachone, isn't the very fact that lapachone is an oxidizing agent (being an electron donor) make it also contribute to lowering ROS production during metabolism, and wouldn't this be the reason less NADPH is produced, because less NOX is needed due to less ROS being produced?

A major portion of NADPH is created via NNT in the mitochondrial membrane; about 50% IIRC. If the ETC function reduces, then NADPH production goes down as well. When the ETC function reduces, more ROS is most likely being produced as well. So now the body needs to increase NADPH to quench the ROS, so it upregulates glycolysis and the PPP.
Beta-lapachone accepts electrons in its oxidized form and donates them in its reduced form. It's similar to vitamin K2, methylene blue, vitamin C, etc.
Beta-lapachone (BL) activates the enzyme NQO1, which can convert BL to hydroquinone using NADPH. So it's using up the NADPH instead of inhibiting its production.
BL can actually increase ROS production through one electron reduction to semiquinone.

Although I'm the one saying that the scope of this topic is too huge to be covered in one article, I feel the article is lacking in mention of stressors that get in the way of optimal metabolism. Without mention of these stressors, it seems that the article is too concerned in making the numbers that are consistent with good metabolism with the use of substances, such as in the NAD/NADH ratio, instead of enabling the body to naturally and automatically make the numbers, by giving it the right terrain, which is free from stressors such as toxins, external or internal (such as immune complexes) and pathogens, which subject the body to inflammatory conditions that cause stresses, both oxidative and reductive, that detract from optimal metabolism. A lot of the focus is on taking say niacinamide or methylene blue when these are temporary fixes. So without knowing and addressing the root cause of imbalances, one can be continually in need of taking supplements without fixing the root cause. For example, a low-level infection could persist, as no effort is made to address it.

I agree. Removing those metabolic breaks is the most important and I think gut irritation, low-grade infections and stress (under which falls poor sleep, over-exercise, calorie restriction, worry, frustration, low carb diets, etc.) are three of the biggest interrupters.
If you have more suggestions for metabolic interrupters, please share them.

 

[Hans]

very comprehensive article! wondering if there is an error in one of your paragraphs

"Complicated explanation, but basically, when the cell is more reduced, it has a much bigger capacity to accept electrons and prevent oxidative stress. An oxidized state is the opposite. I’ll explain more around this concept in just a bit."

Should it be when a cell is more oxidised?

Maybe i'm not understanding things correctly. Anyhow, thanks for creating & sharing

You are correct, thanks for pointing that out!

 

[Motorneuron]

@yerrag @Hans

Great article! net of intestinal infections, trauma, poor nutrition and deficiencies, general daily stress and genetic anomalies how can we classify ALS? an excess of reduced or oxidized state? from recent research it appears to be a hypermetabolic state ... so why should we insist on the oxidized state?

 

[Hans]

@yerrag @Hans

Great article! net of intestinal infections, trauma, poor nutrition and deficiencies, general daily stress and genetic anomalies how can we classify ALS? an excess of reduced or oxidized state? from recent research it appears to be a hypermetabolic state ... so why should we insist on the oxidized state?

Excess ROS production can lead to oxidation and damage. You need a certain amount of reductants, such as glutathione.

 

[yerrag]

@yerrag @Hans

Great article! net of intestinal infections, trauma, poor nutrition and deficiencies, general daily stress and genetic anomalies how can we classify ALS? an excess of reduced or oxidized state? from recent research it appears to be a hypermetabolic state ... so why should we insist on the oxidized state?

I think ALS has a lot to do with nerves. The neurons cannot produce energy because they are exhausted and eventually die. One way these neurons die is when they are exposed to excitotoxic substances. The neurons get excited and use a lot of energy but that energy is depleted because of poor metabolism due to lack of oxygen or sugar getting into the neurons. Poor acid base balance causes poor oxygenation from lack of carbon dioxide for the Bohr's effect to effect the release of oxygen from the blood to tissues. Or poor blood sugar control causes low blood sugar that disturbs the supply of sugar to the neurons. And the lack of a continuous supply of T3 from low blood sugar disturbs energy production.

I don't really think that ALS is as as much a hypermetabolic state as much as it is an overexcited state where energy usage by neurons is high but energy production is low.

That imbalance is often caused by the intake of pharma drugs, especially as cocktails.

I notice in my parents regular intake of Ciprofloxacin and its class of antibiotics, prescribed to my parents as the drug of choice for UTI, to eventually lead to the decline in their sensorium, which primarily refers to their ability to control the muscles for chewing and swallowing and in controlling the sphincter that keeps food from going into the lungs.

My parents never tooK prescription drugs, but Cipro alone is enough to do them in.

I don't think oxidative stress is what causes ALS. If anything, it is reductive stress- resulting from either a gradual loss of oxidative metabolism by poor lifestyle choices including following the expert doctor's advice.

I hope to avoid the path taken by most educated people who blindly follow experts. Despite very high blood pressure, I avoid bp drugs like rat poison. I suspect that lowering bp thru drugs is the surefire way to lower your metabolism, and tons lowly fade into the twilight of life which everyone accepts as dying of old age.

 

[yerrag]

Until the 1960s, a paralytic disease occurring
in some western Pacific Ocean islands,
“amyotrophical lateral sclerosis/parkinsonism-
dementia complex,” was believed to be caused
by heredity, and then it was thought to be
caused by a virus transmitted by cannibalism,
later by aluminum poisoning, and then by
poison from a toxin in blue-green algae. Start-
ing in 1976, a series of studies found that all of
the affected areas, from western New Guinea
to southern Japan, with a variety of cultural
practices and diets, had in common a nutri-
tional deficiency of calcium, because of the
water and soil in the region. Their soils also
contained a high level of aluminum.
When calcium is deficient, secretion of
parathyroid hormone increases, removing
calcium from bones to meet the regulatory
needs of the rest of the body. This involves
suppressing oxidative metabolism that
produces CO2, and partially replacing it with
glycolytic metabolism, producing lactic acid.
When lactic acid is formed by a cell, the
interior of the cell becomes more alkaline,
causing the structural proteins to be more
negatively charged. This can lead to an
increase of positively charged metal ions
inside cells. When metals other than calcium,
such as aluminum, iron, or lead, are abundant
in food and water, these will be accumulated
in cells along with calcium, where they
will—in proportion to the unsaturation of the
cell’s lipids—accelerate the processes of lipid
peroxidation. The type of degenerative disease
a person develops will depend partly on the
types of metal and fat that accumulate in the
tissues.

Ray Peat newsletter July 2021