Vitamin C, ascorbic acid is a REDOX balancer. It can donate and accept protons and electrons to facilitate all essential REDOX exchanges. [1] Ascorbic acid is birefringent. Therefore it can act as primary quantum interface to all electromagnetic radiation, natural or manmade. [2]
Yet there is ANOTHER incredible facet to this miraculous molecule that remains unexplored. This remarkable attribute will provide the answer to all these seemingly unrelated questions about Vitamin C, such as:
Am I getting smarter after taking Vitamin C?
Why is my memory better after taking Vitamin C?
Why do I have more energy and vitality after taking Vitamin C?
Why am I able to exercise longer, and require a shorter recovery time after taking Vitamin C?
Why do I seem less hungry after taking Vitamin C?
Why am I gaining weight after taking Vitamin C?
Does taking Vitamin C increase oxalate levels and increase the risk of kidney stones?
If I have G6PD deficiency, should I still take Vitamin C?
The last two questions actually hold the key that answers all the preceding questions.
Dehydroascorbic Acid (DHA)
Ascorbate can donate one electron to become semi-dehydroascorbic acid (AFR, Ascorbyl Free Radical). AFR is quite stable and our bodies use the redox pair ascorbate/AFR preferentially in most biochemical REDOX reactions. AFR can be easily regenerated by NADH. 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. The regeneration of DHA usually requires NADPH or GSH (glutathione). If it is not regenerated, DHA will degrade into various metabolites including oxalate. [3]
A paper published in 2018 showed definitely that DHA, when handled PROPERLY in blood samples, existed at extremely low to NEGLIGIBLE amounts. Improper processing and handling could increase metal ion-dependent oxidation of vitamin C in whole blood and plasma, leading to inaccurate high readings of DHA concentration in blood and plasma. [4] Heme iron and copper in plasma readily reacts with ascorbate in collected samples. Ascorbate can be further degraded when oxygen, high temperature, UV light accelerate the process. [5]
In addition to red blood cells, plasma also contains white blood cells which do not contain haemoglobin. White blood cells, similar to red blood cells [6] express GLUT transporters for DHA and glucose. [7] Let us take a look at what scientists observed in white blood cells of two subjects when they ingested 25 grams of liposomal ascorbate. [8] After three hours, ascorbate levels in white blood cells increased from 42.3 to 53.8uM in Subject 1; 37.7 to 47.7uM in Subject 2. Whereas DHA levels increased from 5.0 to 7.7uM in Subject 1, but the DHA levels did not change at all in Subject 2.
[Data source: Nina A. Mikirova, PhD, Ascorbic Acid and Dehydroascorbic Acid Concentrations in Plasma and Peripheral Blood Mononuclear Cells after Oral Liposomal-Encapsulated or Intravenous Ascorbic Acid Delivery, International Society for Orthomolecular Medicine, Volume 34, Number 2, 2019]
It appears that neither ascorbate nor DHA levels changed too much in white blood cells 3 hours after oral ingestion of 25 grams of ascorbate in the two test subjects. Is it because the liposomal ascorbate was not absorbed? The following chart tells a different story.
[Data source: Nina A. Mikirova, PhD, Ascorbic Acid and Dehydroascorbic Acid Concentrations in Plasma and Peripheral Blood Mononuclear Cells after Oral Liposomal-Encapsulated or Intravenous Ascorbic Acid Delivery, International Society for Orthomolecular Medicine, Volume 34, Number 2, 2019]
The plasma levels of ascorbate in both subjects underwent a significant increase of 7 to 8 fold respectively. 25 grams of ascorbate taken within 50 minutes (one gram every 2 minutes) will definitely overwhelm the body’s ability to regenerate ALL of the ingested ascorbate. That should mean that a considerable amount of DHA will be taken up by white blood cells which express GLUT1 and GLUT3, similar to red blood cells.
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. [9]
At this point, most of you will be thinking about people who suffer from G6PD deficiency. People who are deficient in G6PD are cautioned not to take ascorbic acid because the 2-electron oxidized form, dehydroascorbic acid, DHA, must be regenerated by glutathione (GSH) or NADPH. G6PD is the rate-limiting enzyme in the Pentose phosphate pathway that produces NADPH in red blood cells. So the reasoning is, if you are G6PD deficient, your limited source of NADPH/GSH will be depleted by DHA. Is that assumption correct?
Dehydroascorbic Acid (DHA) & the Pentose Phosphate Pathway (PPP)
One thing we need to understand about any ancient molecule or pathway is that during the course of evolution, if they survive selection pressure, these elements would inevitably be intricately linked to all related functions that evolved as organisms gain increased complexity and diversity.
The pentose phosphate pathway (PPP) is an ancient metabolic REDOX system that dates perhaps as far back as 3 billion years to when the cyanobacteria first began to produce oxygen via photosynthesis. The PPP is unique in that it does not require nor generate ATP. Yet during its non-oxidative stage, PPP can generate sugars that are precursors to nucleotides and aromatic amino acids required for the synthesis of DNA and RNA. [33]
In its oxidative phase, the pentose phosphate pathway produces the major reductant NADPH. NADPH affects the state of REDOX balance in the organism. REDOX balance is critically linked to all biological functions, as REDOX imbalance will result in oxidative stress and immune dysfunction. [10]
In cyanobacteria, their REDOX functions are tied to circadian rhythm, because oxidation and reduction fluctuated as a result of light and dark cycles. Like all ancient REDOX systems, including peroxiredoxins, the PPP has been observed to oscillate in a rhythmic cycle in sync with light and dark input in the cyanobacteria. [11] If the PPP oscillates with light dark cycles in the cyanobacterial, what do you think the PPP does in humans and other organisms?
Scientists recently discovered that in humans, the pentose phosphate pathway not only affects redox oscillations in peroxiredoxins, it directly regulates the oscillation in transcriptional clock genes. The PPP is able to remodel expression of transcription factors for circadian genes like BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. The PPP seems to regulate circadian rhythms through its NADPH metabolism. [12]
DHA, NADPH & G6PD
Red blood cells do not have mitochondria. As such, their only source for the major intracellular reductant NADPH is produced in the pentose phosphate pathway (PPP). In mammals, the PPP is found in the cytoplasm of cells, outside of the mitochondria. PPP existed in eukaryotic cells long BEFORE mitochondria was engulfed in endosymbiosis about 1.45 billion years ago. That is the reason why PPP does not require NOR generates ATP. ATP is the product of oxidative phosphorylation in mitochondria. [13]
PPP runs parallel to glycolysis and these two pathways are reversibly linked by enzymes. The pentose phosphate pathway consists of an oxidative phase that generates NADPH and a nonoxidative phase that interconverts phosphorylated sugars. [14]
Glucose-6-phosphatedehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. G6PD deficiency can lead to lower levels of NADPH. NADPH is the reductant required to regenerate oxidized glutathione (GSSG). Without adequate reduced glutathione (GSH), hemoglobin cannot be maintained in its soluble form under oxidative stress.[15, 16, 17]
So why would red blood cells, or even white blood cells risk increasing oxidative stress by taking up DHA, which will inevitably lower intracellular GSH and NADPH supply, when they can transport the reduced form ascorbate, or even the one-electron oxidized form semidehydroascorbic acid, that can be regenerated by NADH? Obviously, DHA is not meant to be used only as an antioxidant, because transporting ascorbate would be the ideal solution IF the aim is to transport a reductant.
Dehydroascorbic Acid (DHA) Increases NADPH/Glutathione in PPP
In 2000, scientists discovered that when human T lymphocytes (Jurkat cells) were treated with DHA, DHA was able to stimulate the activity of G6PD, the rate-limiting enzyme for NADPH production in the pentose phosphate pathway. This stimulation of G6PD resulted in an impressive 3.3-fold increase in glutathione, due to increased production of NADPH . Treating the cells with N-acetyl cysteine (NAC) only increased GSH by two-fold. The observed doubling in G6PD enzyme activities were accompanied by an impressive 5.9-fold increase in G6PD protein levels. [18]
Yet some questions still remain as to why DHA levels were so low in white blood cells of the two test subjects. The white blood cells of Subject 2 in the study [8] showed only a meagre increase in ascorbate and ZERO increase in DHA levels after the ingestion of 25 grams of liposomal ascorbate, even though the plasma ascorbate level in the same subject rose by a hefty 8-fold.
If cells use DHA to stimulate G6PD in PPP to increase reducing equivalents like GSH/NADPH, then why is there not a significant increase of ascorbate in those cells after the DHA is regenerated by GSH/NADPH?
Cells import DHA using GLUT transporters. Some cells like red blood cells import a large amount of DHA over glucose. After the ingestion of 25 grams of liposomal ascorbate, there would surely be a lot of DHA since the body would be unable to regenerate in such a short time all 25 g of ascorbate ingested. Yet this subject’s plasma DHA levels barely doubled. So the question is, if DHA is not reduced to ascorbate by GSH/NADPH inside the cells, where did the DHA disappear to?
DHA Metabolites as Fuel for the Pentose Phosphate Pathway
A remarkable feat was undertaken by a group of scientists who published their findings at the end of 2018 that clearly identified each and every metabolite that was created when DHA (dehydroascorbic acid) reacted with different free radicals and reactive oxygen species. They discovered that the degradation pathways of DHA varied greatly depending on the type of ROS present. Most surprising of all, was the observation that only a faint trace of oxalates was formed from DHA. [19] What are the other metabolites of DHA?
Ascorbic acid is derived from glucose. Its metabolites would naturally be sugar metabolites. [18] Products of DHA metabolism, 2,3-diketo-L-gulonate and its decarboxylation products, L-xylonate and L-lyxonate, can easily be used as substrates in the nonoxidative branch of PPP. [20]
When I wrote ‘Uric Acid & Vitamin C: Devolution of Evolution in a 5G World” [21] I could not understand how animals managed to produce ascorbic acid during the Ice Ages when carbohydrate supply was extremely low. Hominins survived by increasing uric acid. Most animals that produce ascorbic acid also retained the function of the uricase gene, and that means they cannot raise their uric acid levels to compensate for lower vitamin C levels due to shortages of glucose. How did those animals cope?
The answer to my question came in a most revealing study published in 1996 where a group of scientists showed conclusively that when ascorbate or DHA were added to hepatocytes from livers of fasted mice, there was a dose-dependent increase in glucose production and the pentose phosphate pathway intermediate xylulose 5-phosphate. [22]
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.
I am sure you are now wondering what happens to the sugar metabolites of DHA in humans. Humans and primates have lost the function of the GULO gene and can no longer synthesize ascorbic acid. Even though they can no longer produce ascorbic acid, perhaps certain aspects in the recycling of the metabolites of ascorbic acid is retained since the dominant position of ascorbic acid in all biological functions in humans and primates has not been diminished.
Ascorbate, DHA & Lactate – The Primordial Octane Fuel
It appeared that these same scientists wanted to find out the answer to our questions also. 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. [23] Now is it starting to make sense to you why erythrocytes and white blood cells hoard DHA yet show very little sign of accumulation? Both red blood cells and white blood cells are understood to show high activity in PPP. DHA was evidently used as substrates for the production of lactate in the pentose phosphate pathway. Why is lactate production so important?
One can think of lactate as the primordial octane fuel. Lactate is traditionally thought of as a ‘waste product’ of anaerobic metabolism. Current knowledge indicates that lactate is formed and used continuously under full aerobic conditions. In fact, lactate is now considered to be the critical link between anaerobic glycolysis and oxidative metabolism, such as ATP production in mitochondria during the TCA tricarboxylic acid cycle (Krebs, citric acid cycle).
Lactate – Universal Fuel Currency Accepted by ALL CELLS
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. [24]
Lactate has recently been identified as the MAJOR carbon source that fuels the mitochondrial TCA cycle in ALL types of tissues, normal and cancerous. [25] This really should not surprise you, if you consider the fact that glycolysis and the pentose phosphate pathway that runs parallel to glycolysis, are both ANCIENT pathways that probably date back to the cyanobacteria over 3 billion years ago. [26]
After the endosymbiosis of mitochondria in eukaryotes, it is easy to imagine that the addition of LDH (lactate dehydrogenase) facilitated the oxidation of lactate to produce pyruvate and NADH. Lactate dehydrogenase is an enzyme that catalyzes the reaction where lactate loses 2 electrons to form pyruvate and NAD+ gains two electrons to form NADH. [27] If lactate predates mitochondria, would there be a preference for cells to use lactate as fuel source?
Lactate – Octane for Muscles, Hearts and Brains
Lactate is now recognized to be a major source of fuel that is preferred by muscles, including the ones in the heart. [28] Ultra-endurance athletes on low-carbohydrate/high fat diets have been found to show a two-fold elevation of serum lactate in the final hour during a three-hour run training. All these athletes broke down substantially more glycogen in their muscles than the total amount of carbohydrate oxidized. If the glycogen is not oxidized for energy production, why did the body break down glycogen from muscles? Lactate can be produced from glycogen! [29]
Scientists found that in mice, the turnover flux of lactate in circulation is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice, and 2.5 fold in fasting mice. [30] Why is the level of circulating lactate so high?
Glycolysis and the TCA cycle (citric acid, Krebs cycle) are actually UNCOUPLED in peripheral tissues. Glucose is processed through glycolysis that produces lactate as the end product. This is the lactate pool that is found in circulation. 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.
ASCORBIC ACID, DHA & LACTATE: The ANLS Connection
In the brain, the uncoupling of glucose processing occurs between astrocytes and neurons. The brain is not dependent upon the peripheral lactate pool as glucose has been observed to be transported across the blood-brain barrier at 10 times above the rate of lactate in rodent brains. [31] The brain is able to modulate its own supply of lactate via the astrocyte-neuron lactate shuttle, the ANLS.
The latest understanding in brain energetics is that astrocytes are the predominant source where lactate is formed. Neurons are tightly coupled to astrocytes in that they depend on astrocytes for the supply of lactate to meet their energetic demands. Lactate is transferred to neurons via the astrocyte-neuron lactate shuttle, ANLS, where lactate can modulate neuronal functions including excitability, plasticity and memory consolidation. [32]
Lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes are tightly coupled metabolically. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal and adaptive functions, setting the ‘homeostatic tone’ of the nervous system. [34]
In vivo experiments have demonstrated the existence of an L-Lactate gradient in neurons and astrocytes. This gradient highly favors the efflux of lactate from astrocytes and the influx in neurons. [35] Lactate levels in brains are often increased during periods of stress or injury. In patients who suffered from TBI (traumatic brain injury), scientists observed significant increases in lactate production in astrocytes via glycolysis and the pentose phosphate pathway. [36]
Interestingly, some scientists noticed that there seems to be a “Metabolic Switch” from glycolysis to lactate in the presence of ascorbate or dehydroascorbate (DHA)
Metabolic Switch
The role of ascorbic acid functioning as a ‘Metabolic Switch’ was first presented in 2009, where scientists showed that ascorbate entry into neurons inhibited glucose consumption and increased lactate uptake. [37] Five years later, in 2014, another group of scientists reported that in rat brain cortical neurons, intracellular ascorbate was rapidly oxidized into DHA, due to the high oxidative environment of neurons, but DHA was able to stimulate the activity of G6PD (glucose‐6‐phosphate dehydrogenase), the rate‐limiting enzyme of the PPP to increase NADPH production. That was why even though there was a rapid decrease of GSH, the pool of reduced glutathione was spontaneously recovered. [38]
But most importantly, just before the rapid reduction of GSH was observed, the scientists also noticed an increase in the rate of glucose oxidation through the pentose phosphate pathway, and a concomitant decrease in glucose oxidation through glycolysis, leading them to conclude that DHA can modulate neuronal energy metabolism by facilitating the utilization of glucose through the PPP for antioxidant purposes. Is that the only interpretation of their findings?
We now know that lactate is the END PRODUCT of glycolysis. Technically, there is no switch in the use of end product, but there is a switch in the way the end product is produced, as glycolysis was ‘switched off’ and the pentose phosphate pathway was ‘switched on’, enhanced by DHA or oxidized ascorbate. What is the benefit of switching off glycolysis, using PPP instead to generate lactate?
GLUTs, SVCTs, Neurons and Astrocytes: The Ascorbate/DHA Connection
Glycolysis requires 2 ATP to generate a net of 2 ATP, plus the end product of lactate, whereas PPP does not require nor generate ATP, but produces NADPH and Lactate, as well as important precursors for DNA RNA synthesis. When an organism is challenged with low glucose as a result of starvation, lack of carbohydrates from food sources, or even defective glucose metabolism that is common in neurodegenerative diseases [39], lactate generated from PPP can make a huge difference in brain energetics.
Let us take a look at how Nature engineered this remarkable “Metabolic Switch” in neurons and astrocytes, using ascorbate and DHA.
The concentration of ascorbate in the brain is extremely high. [40] Under most circumstances, ascorbate is the main form of ascorbic acid present in the body. [41] Neurons require an extremely high level of energy. The high demand for ATP through oxidative metabolism creates an environment where reducing equivalents are absolutely essential in maintaining performance. [42]
This is the reason why neurons express SVCT2 (sodium-dependent Vitamin C Transporter 2), the transporter for ascorbate. Neurons use ascorbate to reduce intracellular oxidative stress, rapidly oxidizing ascorbate to dehydroascorbic acid (DHA). As we know, DHA inhibits glycolysis and activates the pentose phosphate pathway (PPP), stimulating G6PD to increase NADPH/GSH production. Thus the oxidation of ascorbate to DHA not only provides neurons with lactate (via PPP) but also additional NADPH/GSH to maintain REDOX homeostasis. Any additional DHA that neurons are incapable of processing could be effluxed via GLUT3 to astrocytes.
This is also the reason why neurons do not express GLUT1, the transporter frequently associated with DHA uptake; whereas astrocytes ONLY express GLUT1. What is more fascinating is that SVCT2 is only expressed in cultured astrocytes. [37] SVCT2 has never been detected in astrocytes in situ, as of the publication of this blog. Although the expression of SVCT2 in astrocytes has been induced under pathological conditions. [43]
The fact that astrocytes express only GLUT1 to transport glucose or DHA, and do not express SVCT2 means they do not want any ascorbate to reduce oxidative stress that is created during energy metabolism. Now isn’t that interesting. Why do you think they exhibit this odd behavior?
DHA, mtROS & Astrocytes: The Lactate Connection
The importance of astrocyte-derived lactate as neuronal energy substrate and signalling molecule has prompted researchers to explore the effects of reactive oxygen species in mitochondria on the ability of astrocytes to produce lactate.
In 2019, scientists published their discovery from a fascinating experiment where they were able to tag catalase to mitochondria of astrocytes in mice. The mice used in the experiments were bred with catalase specifically expressed in mitochondria to reduce mtROS (mCAT mice). Compared to wild-type mice, these mCAT mice produced much less lactate. In addition, increased catalase lowered NADPH levels and increased oxidized GSH levels, causing cell damage in neighboring neurons. [44]
Redox homeostasis goes beyond the concept that ROS is an undesirable element in our bodies. The naturally occurring high level of ROS in astrocyte mitochondria actually co-exists with low mitochondrial ROS in neurons. [45] The fact that astrocytes transport a huge amount of DHA via GLUT1, and not the reduced form ascorbate means that their intracellular environment needs to be maintained at a higher oxidative level. This experiment elegantly showed the dangers of manipulating antioxidants in the attempt to reduce oxidative stress without understanding context and consequence.
We need to appreciate the fact that ascorbic acid, the pentose phosphate pathway and lactate are ancient. They all predate mitochondria in eukaryotes. The relationship between Vitamin C, pentose phosphate pathway and lactate has never been truly appreciated. In the body, lactate is more than just the universal currency of energy. This ancient molecule has been found to regulate gene transcription in muscle cells that is responsible for the activation of mitochondrial biogenesis. [47]
In the brain, lactate is not only an energy substrate for neurons. Lactate is now regarded as an important signaling molecule that modulates the expression of at least 20 genes related to synaptic plasticity and neuroprotection. [46] Lactate has recently been indicated to enhance myelination in axons. [48]
Vitamin C, ascorbate and its metabolite DHA, is critical in the facilitation of lactate metabolism in neurons and astrocytes. Vitamin C is also critical in the maintenance of NADPH in erythrocytes and all other cells through its effect on the pentose phosphate pathway and G6PD. It is also important to remember that Vitamin C can perhaps even play a significant role in the contribution to circulating lactate in peripheral tissues., providing precious energy
Today’s SPECIAL EDITION answers all the questions regarding why and how Vitamin C, Ascorbic Acid, can increase energy, improve training performance, balance REDOX homeostasis, and improve mental cognition. For those who are dependent on gluconeogenesis as the result of low carbohydrate or zero carbohydrate diets, the consideration of including vitamin C supplementation is imperative. Not to mention that Vitamin C can enhance protection against electromagnetic radiation from both natural and manmade sources.
Have you had your AA today?
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