Low Toxin Studies OXPHOS promoting pro-metabolic substances work by suppressing ADH and ALDH

[Nick]

I think that for many of Ray's favorite oxidative phosphorylation (OXPHOS) promoting pro-metabolic substances, the pro-OXPHOS action is a direct byproduct of suppressing the ADH and ALDH detox enzymes, thereby freeing up more cytochrome P450 enzyme capacity to allow OXPHOS to continue without a buildup of cell waste.

I'll use the detoxification of retinol as an example. Alcohol Dehydrogenase (ADH) converts retinol into retinaldehyde. Aldehyde Dehydrogenase (ALDH) converts retinal(dehyde) into retinoid acid and it's isomers with the help of several cytochrome P450 enzymes. Before the retoic acid can be glucuronidated and excreted, it requires the activity of multiple cytochrome P450s.
Retinoic acid metabolism and mechanism of action: a review (pubmed abstract)
Retinoic Acid Metabolism and Mechanism of Action: A Review (full text)

For this reason, retinol detox is a burden on the cytochrome P450 enzymes. As are other toxins but I'm using retinol as an example. The cytochrome P450 enzymes are needed for many things such as cleaning up damaged cell constituents (DCC), which OXPHOS creates more of than glycolysis due to reactive oxygen species generation. Rupert Sheldrake has hypothesized that the buildup of DCC in cells with the inability of the organism to clear them out is a primary reason that stressed, diseased, and cancer cells switch from OXPHOS to glycolysis. OXPHOS generates more DCC than glycolysis and then clears them out via asymmetrical cell division, where one part of the cell takes most of the DCC burden and senesces and is cleaned up and detoxed by the immune system, lymphatic system and the liver, the whole process requiring a lot of cytochrome P450 enzyme activity to detox and excrete the DCC. So if cytochrome P450 enzymes are overburdened, cells switch to glycolisis.
Rupert Sheldrake: Cellular senescence, rejuvenation and potential immortality

Therefore, in the presence of excess free toxins in the system like unbound retinol, if you suppress ADH and ALDH you free up cytochrome P450 capacity to allow cells to continue OXPHOS. For example, this is a (the?) mechanism of aspirin increasing OXPHOS (thanks for finding this @youngsinatra)
Inhibition of human alcohol and aldehyde dehydrogenases by aspirin and salicylate: Assessment of the effects on first-pass metabolism of ethanol
In the end this causes toxins like retinol to build up in the liver and tissues in their storage form, and the toxicity always wins in the end.

Any thoughts? I especially welcome any criticism to help improve (or disprove) this theory!
@charlie @haidut @mosaic01

Edited to add: I'm thinking about this as an example of confusing attributes and byproducts. My interpretation is that Ray Peat's approach often treated high oxidative metabolism as a fundamental attribute to seek to improve health. What I'm suggesting here is that it is actually a byproduct of other more fundamental attributes like low toxicity, good structural coherence and nutrient repletion.

Ray was dead on that energy and structure are interdependent at every level, and in some situations one may benefit from using exogenous substances that temporarily create more energy production in order to repair damage to structure, even when they do so at the cost of building up a toxicity backlog. But in the long run it's better to improve energy metabolism as a byproduct of the more fundamental attributes of health.

 

[youngsinatra]

The enzyme ALDH depends on NAD+ so at least B2/B3 (pro-OXPHOS nutrients) should speed up the activity of it.

With low (Mg-)ATP levels due to impaired OXPHOS or low thyroid, many enzyme also slow down that are crucial for liver function and detoxification phase I & II.

 

[LLight]

Is autophagy recycling inside the cell itself?

 

[Nick]

The enzyme ALDH depends on NAD+ so at least B2/B3 (pro-OXPHOS nutrients) should speed up the activity of it.

With low (Mg-)ATP levels due to impaired OXPHOS or low thyroid, many enzyme also slow down that are crucial for liver function and detoxification phase I & II.

Do you think too much NAD+ promotion can cause a bottleneck in the cytochrome p450 part of detoxification?
I'm pretty sure that is what the niacin flush is--too much ALDH, not enough CYP. Also shingles, rashes, sunburn. Retinoic acid isomers and damaged cell consituents build up to where the cell has to switch to glycolysis in order to excrete the retinoic acid and DCCs in extracellular vesicles (exosomes, viruses etc.). This process also releases serotonin and histamine, which are more byproducts of the toxicity than they are the fundamental problem.

I suspect magnesium can help a flush by promoting CYP activity and speeding up finishing the detox and extretion.

Calcium can help (temporarily) by binding to the retinoic acid and DCCs so they can be stored safely in the lymph nodes or other tissues and detoxed slowly later when there is more CYP capacity. For example, if I have a rash or niacin flush and use a topical calcum water, it goes away and my lymph nodes in the area become harder for a bit. But if you rely on the calcium binding (with high calcium intake, high vitamin D etc.) to suppress the inflammation and there is never a chance for CYP to catch up, you end up with long term calcification. This is also the reason that retinoic acid causes the body to want to leach calcium from the bones and teeth, but ends up causing calcification of the tissues, arthritis, innappropriate bone growth and fusion etc.

Therefore I wonder if the anti-calcification, anti-fibrosis properties of "anti-serotonin" substances like cyproheptadine are not (just?) due to a direct anti-serotonin action. Rather, the sustance is doing something that prevents the buildup of dehydrogenated toxins for which there is not adequate CYP capacity.

 

[Nick]

Is autophagy recycling inside the cell itself?

Autophagy occurs in the cell and differs from the cleanup of senescent cells by NK cells and macrophages.

 

[Jamsey]

I think this idea is wrong.

“OXPHOS generates more DCC than glycolysis”

Ray spends a lot of time in his articles talking about why this is not correct. His view is generally the opposite of the rate of living theory. Here’s some studies from haidut showing this as well.

Low, Not High, Metabolism Creates Oxidative Stress

A hugely popular tenet of the "rate of living" theory is that the higher the metabolic rate the more reactive oxygen species (ROS) an organism produces. ROS elevation has already been implicated in a host of chronic disease including diabetes, CVD, cancer, neurological conditions and even mental...

raypeatforum.com

"Reductive" stress harms cells, mitochondria protect by increasing metabolism

Finally a study that provide me with some "ammo" during my arguments with people I know who work in the medical profession. A common topic in such arguments is the mainstream medical idea that it is almost impossible to have too much antioxidants and too little oxidation. In fact, to many...

raypeatforum.com

 

[Nick]

I think this idea is wrong.

“OXPHOS generates more DCC than glycolysis”

Ray spends a lot of time in his articles talking about why this is not correct. His view is generally the opposite of the rate of living theory. Here’s some studies from haidut showing this as well.

Low, Not High, Metabolism Creates Oxidative Stress

A hugely popular tenet of the "rate of living" theory is that the higher the metabolic rate the more reactive oxygen species (ROS) an organism produces. ROS elevation has already been implicated in a host of chronic disease including diabetes, CVD, cancer, neurological conditions and even mental...

raypeatforum.com

"Reductive" stress harms cells, mitochondria protect by increasing metabolism

Finally a study that provide me with some "ammo" during my arguments with people I know who work in the medical profession. A common topic in such arguments is the mainstream medical idea that it is almost impossible to have too much antioxidants and too little oxidation. In fact, to many...

raypeatforum.com

OXPHOS did not generate more DCC than glycolysis for 99.999% of history. For modern humans it does because of excessive EMF interference in the electron transport chain.

The DCC buildup is due to the generation of superoxide radical becaue of excess free electrons. The unpaired electrons from OXPHOS occur because an incoherent electromagnetic environment interferes with the electron transport chain by subtly altering the movement of electrons, enough so that many electrons still move to the correct place, but an increased number of electrons are lost. Differentiated cells evolved for the electron transport chain to function opimally in an environment of mostly coherent EMF (the organism's bioelectric and biomagnetic field generated by the cells and organized by the focusing reflectors of the skull, ribcage and pelvis) with occasional geomagnetic disturbances. Glycolysis does not have this same vulnerability to EMF interference with the energy flow.

Here are several papers showing that EMF increases electron leakage in the ETC:
Role of Mitochondria in the Oxidative Stress Induced by Electromagnetic Fields: Focus on Reproductive Systems
"Numerous studies revealed the detrimental effects of EMFs from mobile phones, laptops, and other electric devices on sperm quality and provide evidence for extensive electron leakage from the mitochondrial electron transport chain as the main cause of EMF damage."
Manmade Electromagnetic Fields and Oxidative Stress—Biological Effects and Consequences for Health
"The production of reactive oxygen species (ROS), potentially leading to cellular or systemic oxidative stress, was frequently found to be influenced by EMF exposure in animals and cells."

This is why the advent of electrification (ubiquitous radio noise from EMI/dirty electricity) and all of the subsequent new sources of non-native EMF aligns precisely with the appearance of the modern forms of cancer, diabetes, heart diease, as described by Samuel Milham here: Historical evidence that electrification caused the 20th century epidemic of "diseases of civilization"
For further reading on this, I recommend "The Invisible Rainbow" by Arthur Firstenburg.

Studies on cell respiration (really all biology) that do not measure non-native EMF in the lab environment as well as geomagnetic conditions and direct solar magnetic coupling (ie. coronal holes) at the time of the experiment are basically uncontrolled studies. In fact, the work of Giorgio Picardi and Simon Shnoll suggests that the same may be true to some degree even of all chemical and physical studies as well, since their experiments showed that geomagnetic, geo-physical, and cosmo-physical variations affected their measurements of chemical reactions in water, gravitational behaviors, and radioactive decay counts.

I'll use one study as an example of how this is relevant. Consider this experiment that appears to show that OXPHOS would generate less DCC than glycolysis:
Individuals with higher metabolic rates have lower levels of reactive oxygen species in vivo
The "individuals" studied were trout, which of course live in water, the water in their tanks shields the trout from EMF. Electromagnetic absorption by water - Wikipedia

One of the threads you linked to looks primarily at this paper: Mitochondrial electron transport chain, ROS generation and uncoupling (Review)
@haidut sums up the study thusly: "Below is a study that discusses the process of ROS generation and how low OXPHOS (through ETC inhibition) drives this process".
I believe this to be causally reversed: OXPHOS is lowered as an adaptive response to high ROS generation due to electron leak from the ETC caused by EMF. From the aforementioned paper:

Due to the existence of electron leak and proton leak, not all electrons in the ETC can be transferred to the final electron acceptor O2 and the energy released by the transferred electrons cannot be completely coupled with ATP generation. However, both the ROS generated by electron leak and the UCPs implicated in proton leak play an important role in the physiology and pathology of cells.

 

[Jamsey]

OXPHOS did not generate more DCC than glycolysis for 99.999% of history. For modern humans it does because of excessive EMF interference in the electron transport chain.

The DCC buildup is due to the generation of superoxide radical becaue of excess free electrons. The unpaired electrons from OXPHOS occur because an incoherent electromagnetic environment interferes with the electron transport chain by subtly altering the movement of electrons, enough so that many electrons still move to the correct place, but an increased number of electrons are lost. Differentiated cells evolved for the electron transport chain to function opimally in an environment of mostly coherent EMF (the organism's bioelectric and biomagnetic field generated by the cells and organized by the focusing reflectors of the skull, ribcage and pelvis) with occasional geomagnetic disturbances. Glycolysis does not have this same vulnerability to EMF interference with the energy flow.

Here are several papers showing that EMF increases electron leakage in the ETC:
Role of Mitochondria in the Oxidative Stress Induced by Electromagnetic Fields: Focus on Reproductive Systems
"Numerous studies revealed the detrimental effects of EMFs from mobile phones, laptops, and other electric devices on sperm quality and provide evidence for extensive electron leakage from the mitochondrial electron transport chain as the main cause of EMF damage."
Manmade Electromagnetic Fields and Oxidative Stress—Biological Effects and Consequences for Health
"The production of reactive oxygen species (ROS), potentially leading to cellular or systemic oxidative stress, was frequently found to be influenced by EMF exposure in animals and cells."

This is why the advent of electrification (ubiquitous radio noise from EMI/dirty electricity) and all of the subsequent new sources of non-native EMF aligns precisely with the appearance of the modern forms of cancer, diabetes, heart diease, as described by Samuel Milham here: Historical evidence that electrification caused the 20th century epidemic of "diseases of civilization"
For further reading on this, I recommend "The Invisible Rainbow" by Arthur Firstenburg.

Studies on cell respiration (really all biology) that do not measure non-native EMF in the lab environment as well as geomagnetic conditions and direct solar magnetic coupling (ie. coronal holes) at the time of the experiment are basically uncontrolled studies. In fact, the work of Giorgio Picardi and Simon Shnoll suggests that the same may be true to some degree even of all chemical and physical studies as well, since their experiments showed that geomagnetic, geo-physical, and cosmo-physical variations affected their measurements of chemical reactions in water, gravitational behaviors, and radioactive decay counts.

I'll use one study as an example of how this is relevant. Consider this experiment that appears to show that OXPHOS would generate less DCC than glycolysis:
Individuals with higher metabolic rates have lower levels of reactive oxygen species in vivo
The "individuals" studied were trout, which of course live in water, the water in their tanks shields the trout from EMF. Electromagnetic absorption by water - Wikipedia

One of the threads you linked to looks primarily at this paper: Mitochondrial electron transport chain, ROS generation and uncoupling (Review)
@haidut sums up the study thusly: "Below is a study that discusses the process of ROS generation and how low OXPHOS (through ETC inhibition) drives this process".
I believe this to be causally reversed: OXPHOS is lowered as an adaptive response to high ROS generation due to electron leak from the ETC caused by EMF. From the aforementioned paper:

Thanks for all the info. While there was no mention of emfs in the original post, I’ll go with it. I see you posted studies showing higher metabolism leads to lower reactive oxygen species generation, in fish. While emf exposure wasn’t measured in this experiment, from what I’ve read it doesn’t seem like fresh water has much of shielding effect at all. Here’s a study I found on this

https://www.scirp.org/pdf/jemaa20110700001_18390291.pdf

So, I’m not particularly sure if the water was relevant, but open to new info if so.
You also posted showing studies showing emfs causing electron leakage and ROS generation in the electron transport chain. This seems to be well supported in the literature I’ve read. However, it seems like quite a leap to say this single handedly makes oxidative phosphorylation more damaging than glycolytic metabolism. Even if emfs are causing more electron leakage, oxphos is till 15-18 times more efficient in atp production versus glycolysis, while producing much more beneficial byproducts of co2 and water, instead of lactate. I would point you to this page with quote from ray on the differences between the two,

Comparison: Oxidative Metabolism v. Glycolytic Metabolism – Functional Performance Systems (FPS)

For the advantage of being able to extract energy from glucose in the absence of oxygen, the anaerobic organism must waste over 90% of the total energy it might be able to obtain if it could oxidize glucose with molecular oxygen to CO2 and H20.

In the aerobic organism lactate does not leave the cell; instead it, or pyruvate, is oxidized to CO2 and H20, with the recovery of much of the other 93% of the energy of glucose. Respiration, the oxidation of glucose with molecular oxygen, is clearly very efficient in extracting all of the possible energy from the glucose molecule…

Because anaerobic glycolysis can extract only a small fraction of the total energy of the glucose molecule, it is corollary that anaerobic cells must use much more fuel per unit of time per unit of weight to accomplish the same amount of cellular work as an aerobic cell. It has been found that anaerobic cells use up to twenty times as much glucose as aerobic cells to do the same amount of work. And they can consume many times their weight of glucose in only short periods of time.” -Albert Lehninger, PhD

As ray always said, energy and structure are interdependent at every level. I feel like you need to read the work of Otto Warburg before continuing to say that cancerous cell metabolism is the better energy generation system.

Also, do you have a study saying oxphos metabolism creates more damaged cell constituents under emf exposure than glycolysis, or is this just your logic of more ROS-> more damaged cell constituents

 

[Nick]

As ray always said, energy and structure are interdependent at every level. I feel like you need to read the work of Otto Warburg before continuing to say that cancerous cell metabolism is the better energy generation system.

I'm well aware of Warburg, and how inefficient and damaging glycolysis is, it's involved in virtually every disease.

But in the presence of excess toxicity the body, in it's divine wisdom, feels that it needs to switch to glycolysis to free up CYP capacity to deal with detoxing and excreting those toxins. Instead of using things like aspirin to strong arm the body into storing the toxins to maintain OXPHOS at all cost, we have to stop the intake (and leakage) of toxins, get the nutrients needed to support detox, and let the body deal with the toxins in the best way it can, even if this means some temporary excesses of glycolysis. If you do these things, when there is no toxic overload, OXPHOS will dominate without the need for aspirin or thyroid.

 

[Bliss]

Do you think too much NAD+ promotion can cause a bottleneck in the cytochrome p450 part of detoxification?
I'm pretty sure that is what the niacin flush is--too much ALDH, not enough CYP.

Nicotinic acid is first converted to niacinamide before it can contribute to the creation of NAD+, and niacinamide does not produce a flush so the flush is an independent attribute of nicotinic acid itself, unrelated to the effects of increased NAD+ (which could still be creating a bottleneck as you say, just not associated with a flush)

 

[Alpha]

Nicotinic acid is first converted to niacinamide before it can contribute to the creation of NAD+, and niacinamide does not produce a flush so the flush is an independent attribute of nicotinic acid itself, unrelated to the effects of increased NAD+ (which could still be creating a bottleneck as you say, just not associated with a flush)

That's not true, NAM is a byproduct of NAD+ and excreted from the cell. It can be recycled back to NAD+ through the salvage pathway. Having high NAM is toxic to the cell and the organism becuase it alters the balance of Sirtuins. The best form of Niacin to take is NMN if you want to avoid the flush of NA.

 

[Bliss]

That's not true, NAM is a byproduct of NAD+ and excreted from the cell. It can be recycled back to NAD+ through the salvage pathway. Having high NAM is toxic to the cell and the organism becuase it alters the balance of Sirtuins. The best form of Niacin to take is NMN if you want to avoid the flush of NA.

Is this article incorrect then?

 

[Jabuger]

Therefore, in the presence of excess free toxins in the system like unbound retinol, if you suppress ADH and ALDH you free up cytochrome P450 capacity to allow cells to continue OXPHOS. For example, this is a (the?) mechanism of aspirin increasing OXPHOS (thanks for finding this @youngsinatra)
Inhibition of human alcohol and aldehyde dehydrogenases by aspirin and salicylate: Assessment of the effects on first-pass metabolism of ethanol

Bump, any revelations on this?

 

[RealNeat]

.

 

[RealNeat]

I'm well aware of Warburg, and how inefficient and damaging glycolysis is, it's involved in virtually every disease.

But in the presence of excess toxicity the body, in it's divine wisdom, feels that it needs to switch to glycolysis to free up CYP capacity to deal with detoxing and excreting those toxins. Instead of using things like aspirin to strong arm the body into storing the toxins to maintain OXPHOS at all cost, we have to stop the intake (and leakage) of toxins, get the nutrients needed to support detox, and let the body deal with the toxins in the best way it can, even if this means some temporary excesses of glycolysis. If you do these things, when there is no toxic overload, OXPHOS will dominate without the need for aspirin or thyroid.

Conjecture, the Ray Peat approach was always "low toxin" just because it wasn't a label of the dietary intervention doesn't mean it wasn't so. Ray has warned about an immense number of compounds that harm humans from natural to synthetic that should be avoided, including vA. Ray has also outlined, really thoroughly, reductive stress, with a much more convincing method of action than your hypothesis. Some of the best summaries of this are on "a neighbors choice" podcast. By pushing oxphos you get those beneficial byproducts that are ordering to cells, not just temporary bandaids but actual healing takes place and such compounds may not even be needed afterwards. Proper oxphos is also key to detoxification so pushing that further only increases the efficiency of toxin elimination as long as enough nutrients are available to fuel the process.

 

[Nick]

Conjecture, the Ray Peat approach was always "low toxin" just because it wasn't a label of the dietary intervention doesn't mean it wasn't so. Ray has warned about an immense number of compounds that harm humans from natural to synthetic that should be avoided, including vA. Ray has also outlined, really thoroughly, reductive stress, with a much more convincing method of action than your hypothesis. Some of the best summaries of this are on "a neighbors choice" podcast. By pushing oxphos you get those beneficial byproducts that are ordering to cells, not just temporary bandaids but actual healing takes place and such compounds may not even be needed afterwards. Proper oxphos is also key to detoxification so pushing that further only increases the efficiency of toxin elimination as long as enough nutrients are available to fuel the process.

Certainly Peat was always aiming for low toxin, I just think he missed the mark on copper and on the amount of vitamin A that is toxic. However, his approach was never pro-detox since many of his favored therapies work by suppressing detoxification. I also think his theories held more water before environmental EMF was so high everywhere, but even then my personal experience suggests to me that forcing oxphos when CYP can't keep up is not a good idea.