Steven Bussinger
Member
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:
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.
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?
Maybe humans lost the ability to synthesize AA because the sugar metabolites from DHA produce lactate?
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.
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]
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:
[1] Ascorbate And The Copper Hand-Off
[2] Energy, structure, and carbon dioxide: A realistic view of the organism – Functional Performance Systems (FPS)
[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
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.
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]
[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