Doris Loh, Vitamin C, And Lactate

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Oct 8, 2016
Messages
464
Location
Colorado, USA
Previously, I have been a proponent of ascorbic acid supplementation.[1] However, due to some personal experiments and what I am about discuss, I have begun to reconsider my level of support.

TL;DR:
Intracellular ascorbic acid was able to stimulate lactate transport in both cell types. Extracellular ascorbic acid did not affect this transport. Our data show that ascorbic acid inhibits glucose transport and stimulates lactate transport in neuronal and non-neuronal cells.[8]

Doris Loh is arguably the pre-eminent expert on vitamin C and ascorbic acid. When most people discuss vitamin C, they are very vague and nebulous. She is not. While she does get deep into the weeds, she's the first source I've seen that brings clarity to many of the positive actions attributed to vitamin C. On her forum, she debunks a couple of the warnings about AA that have become popular with health bloggers (ie, AA "blows up" ceruloplasmin, "whole food C").

Unfortunately for me, she drinks from the same pool of knowledge as Jack Kruse, Rhonda Patrick, Joseph Mercola, etc: everything is about blue light, cold, melatonin, vitamin D, circadian rhythms, insulin, low carb, EMFs (the new term is EMR, please note), and fish oil! Their theories are supported by cutting edge science and they can explain mechanisms at a very deep level, but to paraphrase Peat himself, they have only gone "a few elephants down".[2]

Doris Loh has advanced an hypothesis where lactate is the octane, no -- PRIMORDIAL octane fuel of the cell (emphasis mine). Lactate fuels the "ANCIENT pathways" (emphasis not mine) of glycolysis and the pentose phosphate pathway. She asks "If lactate predates mitochondria, would there be a preference for cells to use lactate as fuel source?"[3]

Krusisms aside, I have just realized that the aim of the theories advanced by this intellectual vanguard seems to be to return to the origin of the universe. Only there will we find refuge from our perverse modernity. The deeper into biological history that one can dig, the more one's theories are imbued with the unassailable gravitas of incomprehensible lengths of time. That is what they do. Out of a labyrinth of byzantine mechanisms, they construct a gothic fortress. A fortress that is highly resistant to the arrows of pedestrian inquiry.

It's ironic what these people are doing. They are so focused on understanding evolutionary biology but only to wind the clock back, to devolve. I wonder if they ever thought of what they're doing in such naked terms. Probably not. Narratives tend to overtake your own personal sense of direction without you being conscious of it.

For those that don't know, DHA = Dehydroascorbic Acid. "When ascorbate loses two electrons, it becomes dehydroascorbic acid (DHA), a highly unstable form with a half-life of only 6 minutes under physiological conditions."

If I understand correctly what Doris Loh has written, then taking AA will increase lactate production.

DHA has been shown conclusively to be taken up by red blood cells via GLUT1 transporters. In red blood cells, glucose and DHA have been observed to be mutually competitive for binding to GLUT1. However, it appears that humans, because they are unable to synthesize ascorbic acid, have evolved special adaptive mechanisms.

Human red blood cells have the highest number of GLUT1 transporters among all cells in the body. During the formation of red blood cells in erythropoiesis, expression of GLUT1 is significantly raised. However, transport of glucose decreased while that of DHA is dramatically elevated.

The special adaptive mechanism of humans is left unexplained. The thread is picked up and then immediately put down, and when/if it resurfaces I don't recognize it. I don't know, maybe later it's tied into uric acid?

During the experiment, if ascorbate oxidation was increased, or the reduction of DHA inhibited (meaning DHA was prevented from being reduced or regenerated back into ascorbate), it would be followed by an increase in the production of glucose. Whereas if the pentose phosphate pathway was inhibited, there was a decrease in glucose production, with a concomitant elevation in the accumulation of xylulose 5-phosphate, the sugar metabolite of DHA. [22]

The results from this study showed how animals that synthesize ascorbic acid can obtain glucose generated by the recycling of ascorbate oxidation products from the pentose phosphate pathway, and how DHA under oxidative stress environments play a distinct role in the generation of antioxidants and energy substrates; as well as the regeneration of ascorbic acid in a cycle that involves the pentose phosphate pathway, gluconeogenesis and the hexuronic acid pathway in those animals.

Maybe humans lost the ability to synthesize AA because the sugar metabolites from DHA produce lactate?

The next year, in 1997, they published a ground-breaking paper that showed that in human liver cells (HepG2), the addition of ascorbate or DHA produced a high amount of glucose. Whereas in erythrocytes, MCF7 cells (model cell lines used in breast cancer research), ascorbate and DHA were also metabolized at a high rate; but unlike the liver cells, erythrocytes and MCF7 did not produce glucose from the added ascorbate or DHA. Instead, they produced lactate. [23]

When the scientists added an oxidizing agent to ascorbate, lactate production was doubled. That means oxidizing ascorbate generated more sugar metabolites from DHA that could enter the pentose phosphate pathway, producing lactate.

...Lactate is then oxidized by LDH (lactate dehydrogenase) to form pyruvate and NADH that is used in the TCA cycle by most tissues. [31] It has been demonstrated that in mammals, mitochondria contain their own lactate dehydrogenase that can easily oxidize lactate into pyruvate for use in the TCA cycle. [32] This uncoupling of TCA and lactate is observed in most tissues except muscles and brain. In muscles, lactate could be oxidized without ever leaving the muscle or even the producing cell.[30] In the brain, the story is quite different.

For a moment, I thought I was making progress when I understood that lactate is used in the Pentose Phosphate Pathway, and the PPP is needed to make NADPH. NADPH is important for good redox status. However, it appears the true significance of lactate role here is lactate.

For quite a long time, science regarded pyruvate as the end product of glycolysis. This misconception has now been corrected to the understanding that LACTATE, not pyruvate, is THE end product of glycolysis and related pathways such as the pentose phosphate pathway, possibly under all metabolic conditions in most cells. Lactate is now recognized as the primary element that links glycolysis to oxidative phosphorylation. This understanding effectively translates to the realization that in the absence of lactate, mitochondria will not be able to generate ATP.

I looked at the paper Loh cited for this paragraph, and I don't feel like it proved any of those statements. [4] I did a ctrl-F operation for "mitochondria" and in virtually every instance only the transport of lactate is mentioned, nothing about ATP. The paper found that lactate was virtually always produced by PPP and so therefore we can kick pyruvate out of the throne and install lactate as regent. This kind of simpleton logic can be seen in another paper [5]

Even higher serum lactate concentrations may be seen after surgery. More than 20 years ago Drake et al. (1980) showed that the uptake of lactate by the heart in vivo is directly proportional to its serum concentration.

This is supposed to be taken as evidence that lactate is really, really important -- fundamental, critical, integral. All it shows is that the heart takes what fuel is available to it, and the available fuel is determined by the circumstances of the body.

I don't profess to fully understand everything I've read. I've really been stretching the limits of my knowledge, and my ability to comprehend biology texts at 2AM. There are actually some interesting paths for me to research, even if Loh's grand theory isn't so grand.

However, if vitamin C is seen as beneficial under the gothic 21st century paradigm [6], then under the bioenergetic paradigm I should treat it as suspect as a precaution. A kind of heuristic.

In fact, I realize now that it was probably completely unnecessary to read all of this and better to instead just poke around Google Scholar for some studies on vitamin C and lactate. Loh's piece was just strings-on-a-wall speculation like Kruse and I didn't even realize it. I kind of regret this now. All I needed to know was this:

Intracellular ascorbic acid was able to stimulate lactate transport in both cell types. Extracellular ascorbic acid did not affect this transport. Our data show that ascorbic acid inhibits glucose transport and stimulates lactate transport in neuronal and non-neuronal cells.[8]

iu



[1] Ascorbate And The Copper Hand-Off
[2] Energy, structure, and carbon dioxide: A realistic view of the organism – Functional Performance Systems (FPS)
The question of biological energy is usually handled in the manner of the cosmologist who explained that the earth rests on the back of an elephant; when asked what the elephant stood on, the cosmologist replied that “it’s elephants all the way down.” Several decades ago, it was discovered that ATP mediates many processes in the energized cell, but there is still fundamental disagreement on the question of how ATP is synthesized, and how its energy is used to produce movement, to control the movement of water in cells and organs and to regulate the ionic balance of cells and fluids, and even why its absence produces rigor mortis.

When people actually try to examine the question of how the “high energy bond” of ATP can be transformed into usable energy, they sometimes find that it is easier to propose fundamental changes in the laws of physics than to find an explanation within ordinary physics and chemistry. (For example, Physiologie 1986 Jan-Mar;23(1):65-8, “The non-conservation of parity in the domain of elementary particles and a possible mechanism for the delivery of energy from the ATP molecule,” Portelli, C.) More often, biologists simply prefer not to go beyond the first or second elephant.
[3] Vitamin C - SPECIAL EDITION - Primordial Octane Fuel - EvolutaMente.it
[4] Lactate is always the end product of glycolysis
[5] Lactate – the forgotten fuel!
[6]
[7] https://www.linkedin.com/pulse/vitamin-c-mitochondria-part-1-redox-5g-world-doris-loh/
[8] Ascorbic acid participates in a general mechanism for concerted glucose transport inhibition and lactate transport stimulation. - PubMed - NCBI
 

LeeLemonoil

Member
Joined
Sep 24, 2016
Messages
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Interesting, thanks for writing and sharing.

It would be fabulous to know the evolutionary reason why humans can’t synthesize AA any more.
 

tankasnowgod

Member
Joined
Jan 25, 2014
Messages
8,131
It would be fabulous to know the evolutionary reason why humans can’t synthesize AA any more.

Well, evolution usually presented as a completely random process with accidental mutations. From that point of view, I have no idea why anyone would expect an apex of anything.
 

Tarmander

Member
Joined
Apr 30, 2015
Messages
3,763
I love her stuff

Her piece on Ascorbic acid verse uric acid and its role in evolution was eye opening

Basically, Uric acid is a poor man's ascorbic. When there is plentiful fruit in the diet, ascorbic does the work

When you are a meat eater, or fruit is low in the diet, you tend more towards insulin resistance and uric acid use.

Made me understand Ray's writing on uric acid with more nuance
 

Dave Clark

Member
Joined
Jun 2, 2017
Messages
1,978
Previously, I have been a proponent of ascorbic acid supplementation.[1] However, due to some personal experiments and what I am about discuss, I have begun to reconsider my level of support.

TL;DR:
Intracellular ascorbic acid was able to stimulate lactate transport in both cell types. Extracellular ascorbic acid did not affect this transport. Our data show that ascorbic acid inhibits glucose transport and stimulates lactate transport in neuronal and non-neuronal cells.[8]

Doris Loh is arguably the pre-eminent expert on vitamin C and ascorbic acid. When most people discuss vitamin C, they are very vague and nebulous. She is not. While she does get deep into the weeds, she's the first source I've seen that brings clarity to many of the positive actions attributed to vitamin C. On her forum, she debunks a couple of the warnings about AA that have become popular with health bloggers (ie, AA "blows up" ceruloplasmin, "whole food C").

Unfortunately for me, she drinks from the same pool of knowledge as Jack Kruse, Rhonda Patrick, Joseph Mercola, etc: everything is about blue light, cold, melatonin, vitamin D, circadian rhythms, insulin, low carb, EMFs (the new term is EMR, please note), and fish oil! Their theories are supported by cutting edge science and they can explain mechanisms at a very deep level, but to paraphrase Peat himself, they have only gone "a few elephants down".[2]

Doris Loh has advanced an hypothesis where lactate is the octane, no -- PRIMORDIAL octane fuel of the cell (emphasis mine). Lactate fuels the "ANCIENT pathways" (emphasis not mine) of glycolysis and the pentose phosphate pathway. She asks "If lactate predates mitochondria, would there be a preference for cells to use lactate as fuel source?"[3]

Krusisms aside, I have just realized that the aim of the theories advanced by this intellectual vanguard seems to be to return to the origin of the universe. Only there will we find refuge from our perverse modernity. The deeper into biological history that one can dig, the more one's theories are imbued with the unassailable gravitas of incomprehensible lengths of time. That is what they do. Out of a labyrinth of byzantine mechanisms, they construct a gothic fortress. A fortress that is highly resistant to the arrows of pedestrian inquiry.

It's ironic what these people are doing. They are so focused on understanding evolutionary biology but only to wind the clock back, to devolve. I wonder if they ever thought of what they're doing in such naked terms. Probably not. Narratives tend to overtake your own personal sense of direction without you being conscious of it.

For those that don't know, DHA = Dehydroascorbic Acid. "When ascorbate loses two electrons, it becomes dehydroascorbic acid (DHA), a highly unstable form with a half-life of only 6 minutes under physiological conditions."

If I understand correctly what Doris Loh has written, then taking AA will increase lactate production.

DHA has been shown conclusively to be taken up by red blood cells via GLUT1 transporters. In red blood cells, glucose and DHA have been observed to be mutually competitive for binding to GLUT1. However, it appears that humans, because they are unable to synthesize ascorbic acid, have evolved special adaptive mechanisms.

Human red blood cells have the highest number of GLUT1 transporters among all cells in the body. During the formation of red blood cells in erythropoiesis, expression of GLUT1 is significantly raised. However, transport of glucose decreased while that of DHA is dramatically elevated.

The special adaptive mechanism of humans is left unexplained. The thread is picked up and then immediately put down, and when/if it resurfaces I don't recognize it. I don't know, maybe later it's tied into uric acid?

During the experiment, if ascorbate oxidation was increased, or the reduction of DHA inhibited (meaning DHA was prevented from being reduced or regenerated back into ascorbate), it would be followed by an increase in the production of glucose. Whereas if the pentose phosphate pathway was inhibited, there was a decrease in glucose production, with a concomitant elevation in the accumulation of xylulose 5-phosphate, the sugar metabolite of DHA. [22]

The results from this study showed how animals that synthesize ascorbic acid can obtain glucose generated by the recycling of ascorbate oxidation products from the pentose phosphate pathway, and how DHA under oxidative stress environments play a distinct role in the generation of antioxidants and energy substrates; as well as the regeneration of ascorbic acid in a cycle that involves the pentose phosphate pathway, gluconeogenesis and the hexuronic acid pathway in those animals.

Maybe humans lost the ability to synthesize AA because the sugar metabolites from DHA produce lactate?

The next year, in 1997, they published a ground-breaking paper that showed that in human liver cells (HepG2), the addition of ascorbate or DHA produced a high amount of glucose. Whereas in erythrocytes, MCF7 cells (model cell lines used in breast cancer research), ascorbate and DHA were also metabolized at a high rate; but unlike the liver cells, erythrocytes and MCF7 did not produce glucose from the added ascorbate or DHA. Instead, they produced lactate. [23]

When the scientists added an oxidizing agent to ascorbate, lactate production was doubled. That means oxidizing ascorbate generated more sugar metabolites from DHA that could enter the pentose phosphate pathway, producing lactate.

...Lactate is then oxidized by LDH (lactate dehydrogenase) to form pyruvate and NADH that is used in the TCA cycle by most tissues. [31] It has been demonstrated that in mammals, mitochondria contain their own lactate dehydrogenase that can easily oxidize lactate into pyruvate for use in the TCA cycle. [32] This uncoupling of TCA and lactate is observed in most tissues except muscles and brain. In muscles, lactate could be oxidized without ever leaving the muscle or even the producing cell.[30] In the brain, the story is quite different.

For a moment, I thought I was making progress when I understood that lactate is used in the Pentose Phosphate Pathway, and the PPP is needed to make NADPH. NADPH is important for good redox status. However, it appears the true significance of lactate role here is lactate.

For quite a long time, science regarded pyruvate as the end product of glycolysis. This misconception has now been corrected to the understanding that LACTATE, not pyruvate, is THE end product of glycolysis and related pathways such as the pentose phosphate pathway, possibly under all metabolic conditions in most cells. Lactate is now recognized as the primary element that links glycolysis to oxidative phosphorylation. This understanding effectively translates to the realization that in the absence of lactate, mitochondria will not be able to generate ATP.

I looked at the paper Loh cited for this paragraph, and I don't feel like it proved any of those statements. [4] I did a ctrl-F operation for "mitochondria" and in virtually every instance only the transport of lactate is mentioned, nothing about ATP. The paper found that lactate was virtually always produced by PPP and so therefore we can kick pyruvate out of the throne and install lactate as regent. This kind of simpleton logic can be seen in another paper [5]

Even higher serum lactate concentrations may be seen after surgery. More than 20 years ago Drake et al. (1980) showed that the uptake of lactate by the heart in vivo is directly proportional to its serum concentration.

This is supposed to be taken as evidence that lactate is really, really important -- fundamental, critical, integral. All it shows is that the heart takes what fuel is available to it, and the available fuel is determined by the circumstances of the body.

I don't profess to fully understand everything I've read. I've really been stretching the limits of my knowledge, and my ability to comprehend biology texts at 2AM. There are actually some interesting paths for me to research, even if Loh's grand theory isn't so grand.

However, if vitamin C is seen as beneficial under the gothic 21st century paradigm [6], then under the bioenergetic paradigm I should treat it as suspect as a precaution. A kind of heuristic.

In fact, I realize now that it was probably completely unnecessary to read all of this and better to instead just poke around Google Scholar for some studies on vitamin C and lactate. Loh's piece was just strings-on-a-wall speculation like Kruse and I didn't even realize it. I kind of regret this now. All I needed to know was this:

Intracellular ascorbic acid was able to stimulate lactate transport in both cell types. Extracellular ascorbic acid did not affect this transport. Our data show that ascorbic acid inhibits glucose transport and stimulates lactate transport in neuronal and non-neuronal cells.[8]

iu



[1] Ascorbate And The Copper Hand-Off
[2] Energy, structure, and carbon dioxide: A realistic view of the organism – Functional Performance Systems (FPS)
The question of biological energy is usually handled in the manner of the cosmologist who explained that the earth rests on the back of an elephant; when asked what the elephant stood on, the cosmologist replied that “it’s elephants all the way down.” Several decades ago, it was discovered that ATP mediates many processes in the energized cell, but there is still fundamental disagreement on the question of how ATP is synthesized, and how its energy is used to produce movement, to control the movement of water in cells and organs and to regulate the ionic balance of cells and fluids, and even why its absence produces rigor mortis.

When people actually try to examine the question of how the “high energy bond” of ATP can be transformed into usable energy, they sometimes find that it is easier to propose fundamental changes in the laws of physics than to find an explanation within ordinary physics and chemistry. (For example, Physiologie 1986 Jan-Mar;23(1):65-8, “The non-conservation of parity in the domain of elementary particles and a possible mechanism for the delivery of energy from the ATP molecule,” Portelli, C.) More often, biologists simply prefer not to go beyond the first or second elephant.
[3] Vitamin C - SPECIAL EDITION - Primordial Octane Fuel - EvolutaMente.it
[4] Lactate is always the end product of glycolysis
[5] Lactate – the forgotten fuel!
[6]
[7] https://www.linkedin.com/pulse/vitamin-c-mitochondria-part-1-redox-5g-world-doris-loh/
[8] Ascorbic acid participates in a general mechanism for concerted glucose transport inhibition and lactate transport stimulation. - PubMed - NCBI

Thanks for the post. My introduction to Doris Loh. Very interesting read. So, to clarify, what 'is' your current thinking on vitamin C supplementation, do you agree with Morley or Doris on their differing views, and what level of supplementation, if any, do you subscribe to?
 
OP
Steven Bussinger
Joined
Oct 8, 2016
Messages
464
Location
Colorado, USA
Thanks for the post. My introduction to Doris Loh. Very interesting read. So, to clarify, what 'is' your current thinking on vitamin C supplementation, do you agree with Morley or Doris on their differing views, and what level of supplementation, if any, do you subscribe to?

I might be wrong, but it seems like Doris Loh's protocol is to take 1 or more grams of AA several times a day, if not hourly. Used in that way, I think AA is being used as an antioxidant. At the moment, I think that it's better to simply support the body's natural redox system. Introducing exogenous antioxidants has very mixed results, most likely due to the fact that redox balance is homeostatic and your body will regulate it, just like how it regulates blood pH. I'm still studying that idea. You can look up a paper called "The neglected significance of 'antioxidative stress'" as an introduction to the nuances of the redox situation.

Some other uses for AA are as a gut biome cleanser (look up "bowel tolerance" or Dr. Jaffe's protocol). That can be done annually or however often you see fit. It can be used to control the vaginal biome, too. It can even be used as a contraceptive.

Regarding Morley, I've become more skeptical of what he says over the past six months. He has said some nutty things like "ceruloplasmin is the god molecule" and "sugar is just sweet iron". I enjoy evidence or theories that upset received opinions, but I think this just suggests derangement.

To him, copper is infallible. Therefore, anything that might oppose copper is bad. That's why he is against zinc supplementation. Zinc is required for the synthesis of metallothionein (MT). MT scoops up heavy metals in the blood like copper. Morley sees that as bad, because copper is an absolute good. Yet, many diseases will present with elevated levels of copper in the blood.

He is basically out in the desert of unipolar grand theorizing with Garrett Smith (Vitamin A toxicity). It's not holistic. In the Jan 2019 newsletter, Ray quotes A. N. Whitehead: "Seek simplicity and distrust it."

I'm evaluating how vitamin C supplementation works for me right now. Currently I put AA in OJ with aspirin and baking soda. This is contrary to the conclusion I had in the past. In the post I wrote in 2018, I recommended not taking AA with food. I think it may be better to take a synthetic or refined supplement with foods that are already good sources of that vitamin. So AA with OJ, zinc with an oyster, any fat soluble vitamin with an egg yolk, etc. These foods will have co-factors for the vitamin in question.
 

Dave Clark

Member
Joined
Jun 2, 2017
Messages
1,978
I might be wrong, but it seems like Doris Loh's protocol is to take 1 or more grams of AA several times a day, if not hourly. Used in that way, I think AA is being used as an antioxidant. At the moment, I think that it's better to simply support the body's natural redox system. Introducing exogenous antioxidants has very mixed results, most likely due to the fact that redox balance is homeostatic and your body will regulate it, just like how it regulates blood pH. I'm still studying that idea. You can look up a paper called "The neglected significance of 'antioxidative stress'" as an introduction to the nuances of the redox situation.

Some other uses for AA are as a gut biome cleanser (look up "bowel tolerance" or Dr. Jaffe's protocol). That can be done annually or however often you see fit. It can be used to control the vaginal biome, too. It can even be used as a contraceptive.

Regarding Morley, I've become more skeptical of what he says over the past six months. He has said some nutty things like "ceruloplasmin is the god molecule" and "sugar is just sweet iron". I enjoy evidence or theories that upset received opinions, but I think this just suggests derangement.

To him, copper is infallible. Therefore, anything that might oppose copper is bad. That's why he is against zinc supplementation. Zinc is required for the synthesis of metallothionein (MT). MT scoops up heavy metals in the blood like copper. Morley sees that as bad, because copper is an absolute good. Yet, many diseases will present with elevated levels of copper in the blood.

He is basically out in the desert of unipolar grand theorizing with Garrett Smith (Vitamin A toxicity). It's not holistic. In the Jan 2019 newsletter, Ray quotes A. N. Whitehead: "Seek simplicity and distrust it."

I'm evaluating how vitamin C supplementation works for me right now. Currently I put AA in OJ with aspirin and baking soda. This is contrary to the conclusion I had in the past. In the post I wrote in 2018, I recommended not taking AA with food. I think it may be better to take a synthetic or refined supplement with foods that are already good sources of that vitamin. So AA with OJ, zinc with an oyster, any fat soluble vitamin with an egg yolk, etc. These foods will have co-factors for the vitamin in question.
Thanks for your perspective on this. I have similar opinions. I tend to think that dose can be the poison with some of these nutrients. It is interesting to see people show higher zinc levels when they stop zinc supplementation, maybe indicating that the MT may of prevented zinc levels to go up. And, mega gram doses of ascorbic acid may very well throw off ceruloplasmin, copper, etc. I think keeping the doses low enough, and like you said, taking them with similar nutrient profile foods, may be a better way to utilize these nutrients without upsetting other metabolic processes. I believe I had read, or heard Doris say that it was acceptable to take vitamin C twice/day to keep ascorbate levels up. I also wonder about nutrients like dehydroquercetin (taxifolin), which helps recycle ascorbate and keeps levels up.
Flavonoid boosts antioxidant power of Vitamin C - - Life Extension
This is a very intriguing subject. Doris may be right that we need to have higher ascorbate levels, but at what expense? Appreciate you digging into this

_
 

RealNeat

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Messages
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This (carnovire) article talks about uric acid somewhat.

Do Humans Need Vitamin C? | Kevin Stock

Some Qs that come to mind:

So do we suppose that vitamin C is somewhat antagonistic to glucose? One or the other? How is it selected/ preferred and at what "ratios?" Do amino acids play a role in this too considering insulin is also involved?
 

RealNeat

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Messages
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T

TheBeard

Guest
Previously, I have been a proponent of ascorbic acid supplementation.[1] However, due to some personal experiments and what I am about discuss, I have begun to reconsider my level of support.

TL;DR:
Intracellular ascorbic acid was able to stimulate lactate transport in both cell types. Extracellular ascorbic acid did not affect this transport. Our data show that ascorbic acid inhibits glucose transport and stimulates lactate transport in neuronal and non-neuronal cells.[8]

Doris Loh is arguably the pre-eminent expert on vitamin C and ascorbic acid. When most people discuss vitamin C, they are very vague and nebulous. She is not. While she does get deep into the weeds, she's the first source I've seen that brings clarity to many of the positive actions attributed to vitamin C. On her forum, she debunks a couple of the warnings about AA that have become popular with health bloggers (ie, AA "blows up" ceruloplasmin, "whole food C").

Unfortunately for me, she drinks from the same pool of knowledge as Jack Kruse, Rhonda Patrick, Joseph Mercola, etc: everything is about blue light, cold, melatonin, vitamin D, circadian rhythms, insulin, low carb, EMFs (the new term is EMR, please note), and fish oil! Their theories are supported by cutting edge science and they can explain mechanisms at a very deep level, but to paraphrase Peat himself, they have only gone "a few elephants down".[2]

Doris Loh has advanced an hypothesis where lactate is the octane, no -- PRIMORDIAL octane fuel of the cell (emphasis mine). Lactate fuels the "ANCIENT pathways" (emphasis not mine) of glycolysis and the pentose phosphate pathway. She asks "If lactate predates mitochondria, would there be a preference for cells to use lactate as fuel source?"[3]

Krusisms aside, I have just realized that the aim of the theories advanced by this intellectual vanguard seems to be to return to the origin of the universe. Only there will we find refuge from our perverse modernity. The deeper into biological history that one can dig, the more one's theories are imbued with the unassailable gravitas of incomprehensible lengths of time. That is what they do. Out of a labyrinth of byzantine mechanisms, they construct a gothic fortress. A fortress that is highly resistant to the arrows of pedestrian inquiry.

It's ironic what these people are doing. They are so focused on understanding evolutionary biology but only to wind the clock back, to devolve. I wonder if they ever thought of what they're doing in such naked terms. Probably not. Narratives tend to overtake your own personal sense of direction without you being conscious of it.

For those that don't know, DHA = Dehydroascorbic Acid. "When ascorbate loses two electrons, it becomes dehydroascorbic acid (DHA), a highly unstable form with a half-life of only 6 minutes under physiological conditions."

If I understand correctly what Doris Loh has written, then taking AA will increase lactate production.

DHA has been shown conclusively to be taken up by red blood cells via GLUT1 transporters. In red blood cells, glucose and DHA have been observed to be mutually competitive for binding to GLUT1. However, it appears that humans, because they are unable to synthesize ascorbic acid, have evolved special adaptive mechanisms.

Human red blood cells have the highest number of GLUT1 transporters among all cells in the body. During the formation of red blood cells in erythropoiesis, expression of GLUT1 is significantly raised. However, transport of glucose decreased while that of DHA is dramatically elevated.

The special adaptive mechanism of humans is left unexplained. The thread is picked up and then immediately put down, and when/if it resurfaces I don't recognize it. I don't know, maybe later it's tied into uric acid?

During the experiment, if ascorbate oxidation was increased, or the reduction of DHA inhibited (meaning DHA was prevented from being reduced or regenerated back into ascorbate), it would be followed by an increase in the production of glucose. Whereas if the pentose phosphate pathway was inhibited, there was a decrease in glucose production, with a concomitant elevation in the accumulation of xylulose 5-phosphate, the sugar metabolite of DHA. [22]

The results from this study showed how animals that synthesize ascorbic acid can obtain glucose generated by the recycling of ascorbate oxidation products from the pentose phosphate pathway, and how DHA under oxidative stress environments play a distinct role in the generation of antioxidants and energy substrates; as well as the regeneration of ascorbic acid in a cycle that involves the pentose phosphate pathway, gluconeogenesis and the hexuronic acid pathway in those animals.

Maybe humans lost the ability to synthesize AA because the sugar metabolites from DHA produce lactate?

The next year, in 1997, they published a ground-breaking paper that showed that in human liver cells (HepG2), the addition of ascorbate or DHA produced a high amount of glucose. Whereas in erythrocytes, MCF7 cells (model cell lines used in breast cancer research), ascorbate and DHA were also metabolized at a high rate; but unlike the liver cells, erythrocytes and MCF7 did not produce glucose from the added ascorbate or DHA. Instead, they produced lactate. [23]
When the scientists added an oxidizing agent to ascorbate, lactate production was doubled. That means oxidizing ascorbate generated more sugar metabolites from DHA that could enter the pentose phosphate pathway, producing lactate.
...Lactate is then oxidized by LDH (lactate dehydrogenase) to form pyruvate and NADH that is used in the TCA cycle by most tissues. [31] It has been demonstrated that in mammals, mitochondria contain their own lactate dehydrogenase that can easily oxidize lactate into pyruvate for use in the TCA cycle. [32] This uncoupling of TCA and lactate is observed in most tissues except muscles and brain. In muscles, lactate could be oxidized without ever leaving the muscle or even the producing cell.[30] In the brain, the story is quite different.

For a moment, I thought I was making progress when I understood that lactate is used in the Pentose Phosphate Pathway, and the PPP is needed to make NADPH. NADPH is important for good redox status. However, it appears the true significance of lactate role here is lactate.

For quite a long time, science regarded pyruvate as the end product of glycolysis. This misconception has now been corrected to the understanding that LACTATE, not pyruvate, is THE end product of glycolysis and related pathways such as the pentose phosphate pathway, possibly under all metabolic conditions in most cells. Lactate is now recognized as the primary element that links glycolysis to oxidative phosphorylation. This understanding effectively translates to the realization that in the absence of lactate, mitochondria will not be able to generate ATP.

I looked at the paper Loh cited for this paragraph, and I don't feel like it proved any of those statements. [4] I did a ctrl-F operation for "mitochondria" and in virtually every instance only the transport of lactate is mentioned, nothing about ATP. The paper found that lactate was virtually always produced by PPP and so therefore we can kick pyruvate out of the throne and install lactate as regent. This kind of simpleton logic can be seen in another paper [5]

Even higher serum lactate concentrations may be seen after surgery. More than 20 years ago Drake et al. (1980) showed that the uptake of lactate by the heart in vivo is directly proportional to its serum concentration.

This is supposed to be taken as evidence that lactate is really, really important -- fundamental, critical, integral. All it shows is that the heart takes what fuel is available to it, and the available fuel is determined by the circumstances of the body.

I don't profess to fully understand everything I've read. I've really been stretching the limits of my knowledge, and my ability to comprehend biology texts at 2AM. There are actually some interesting paths for me to research, even if Loh's grand theory isn't so grand.

However, if vitamin C is seen as beneficial under the gothic 21st century paradigm [6], then under the bioenergetic paradigm I should treat it as suspect as a precaution. A kind of heuristic.

In fact, I realize now that it was probably completely unnecessary to read all of this and better to instead just poke around Google Scholar for some studies on vitamin C and lactate. Loh's piece was just strings-on-a-wall speculation like Kruse and I didn't even realize it. I kind of regret this now. All I needed to know was this:

Intracellular ascorbic acid was able to stimulate lactate transport in both cell types. Extracellular ascorbic acid did not affect this transport. Our data show that ascorbic acid inhibits glucose transport and stimulates lactate transport in neuronal and non-neuronal cells.[8]

iu



[1] Ascorbate And The Copper Hand-Off
[2] Energy, structure, and carbon dioxide: A realistic view of the organism – Functional Performance Systems (FPS)
The question of biological energy is usually handled in the manner of the cosmologist who explained that the earth rests on the back of an elephant; when asked what the elephant stood on, the cosmologist replied that “it’s elephants all the way down.” Several decades ago, it was discovered that ATP mediates many processes in the energized cell, but there is still fundamental disagreement on the question of how ATP is synthesized, and how its energy is used to produce movement, to control the movement of water in cells and organs and to regulate the ionic balance of cells and fluids, and even why its absence produces rigor mortis.

When people actually try to examine the question of how the “high energy bond” of ATP can be transformed into usable energy, they sometimes find that it is easier to propose fundamental changes in the laws of physics than to find an explanation within ordinary physics and chemistry. (For example, Physiologie 1986 Jan-Mar;23(1):65-8, “The non-conservation of parity in the domain of elementary particles and a possible mechanism for the delivery of energy from the ATP molecule,” Portelli, C.) More often, biologists simply prefer not to go beyond the first or second elephant.
[3] Vitamin C - SPECIAL EDITION - Primordial Octane Fuel - EvolutaMente.it
[4] Lactate is always the end product of glycolysis
[5] Lactate – the forgotten fuel!
[6]
[7] https://www.linkedin.com/pulse/vitamin-c-mitochondria-part-1-redox-5g-world-doris-loh/
[8] Ascorbic acid participates in a general mechanism for concerted glucose transport inhibition and lactate transport stimulation. - PubMed - NCBI


She advocates a combination of high dose AA + Melatonin.
Never tried AA, but melatonin sure makes me severely depressed.
 

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