Vitamin C and Climate

David Archibald

Vitamin C and Climate

One of the predecessor animals of humans lost the ability to make vitamin C in the Eocene, 40 to 60 million years ago. The world was a lot warmer then and most land areas were covered with rain forest. There was plenty of vitamin C available all year round in the fruit of the flowering plants that had evolved not long before.

There were two evolutionary advantages for losing the ability to make vitamin C. Firstly, producing that vitamin C at the rate of 20 mg/kilo of body weight/day would have taken 0.1% of resting body energy, which is a significant advantage over time. Secondly, the antioxidant effect from the vitamin C produced by the liver is exactly offset by the oxidising effect of the hydrogen peroxide also produced in the liver in the making of the vitamin C.

While that vitamin C travels all over the body, the hydrogen peroxide has to be reduced by other antioxidants made in the liver. Because the liver is only two percent of human body weight, this is a big load on the liver and would have resulted in higher rates of liver disease and failure. In animals that do make their own vitamin C, the production of antioxidant molecules by their reducing effect is roughly one third vitamin C, one third glutathione, and one third uric acid. All glutathione production by the liver would have to go to offsetting the hydrogen peroxide resulting from making vitamin C. Not having to have the liver work so hard would have been a big driver for the mutation to lose the ability to make vitamin C.

So far, so good. Then Antarctica drifted over the South Pole, the Antarctic ice sheet appeared, and the current ice age began. The world became colder and drier. There was no longer a year-round supply of vitamin C from fruit. The human range expanded to all the climatic zones. Most of humanity now lives with a chronic vitamin C deficiency (though in places like Malaysia, there is a high rate of diabetes because people eat too much fruit).

We know how much vitamin C we need because of what other animals do. For mammals, that is shown in this graph:

Figure 1: Daily Vitamin C production in mg per kilo of body weight

In carnivores and omnivores, vitamin C production is typically near 20 mg/kg of body weight/day. Dogs have a high level because of their high metabolic rate. As omnivores, humans need about 20 mg/kg of body weight/day. For a normal person of 70 kg, that equates to 1.4 grams — equivalent to three 500 mg tablets, assuming it all gets through to the bloodstream.

Ruminants need a lot of vitamin C to cope with all the oxidative stress from fermentation. Among the ruminants, vitamin C production is proportional to how bad the country the species can survive on. So, goats produce more than twice as much as cows and seven times as much as pigs. The non-ruminant herbivores have a normal sort of production rate. Other phyla also produce vitamin C. In the fishes, bony fish produce vitamin C. Fruit flies make their own vitamin C, but crabs don’t.

The recommended daily allowance for vitamin C in Australia is 45 mg per day and we consume 110 mg per day on average. That is still less than 10% of what other omnivores use. Most of us are living our lives chronically vitamin C deficient. There is another effect we are missing out on due to our nonfunctional L-gulonolactone oxidase gene, the one that makes vitamin C. Production of vitamin C in animals reacts to stress. Infection can cause vitamin C production to increase two to five-fold, trauma can increase it three to six-fold, prolonged exertion can increase it two to four-fold, the increase due to heat stress can be up to three-fold, and crowding can increase it two-fold. So an infected 50 kg goat can produce up to 50 grams of vitamin C per day. Humans don’t get the benefit of this disease response. Our little shrew-sized ancestors back in the Eocene made a devil’s bargain on vitamin C, not expecting the climate to get colder.

This explains the effect seen in a 2020 study of the positive response of covid patients to N-acetyl cysteine (NAC) dosing. NAC is a strong anti-oxidant. Because humans live their lives chronically vitamin C-deficient, any anti-oxidant can fill the gap and produce a positive result. The US Federal Drug Administration attempted to ban NAC because they didn’t want anything to compete with the covid vaccines that were then coming.

Figure 2: Maximum daily Vitamin C production increase in response to stress

For each species, the left hand bar shows the normal daily vitamin C production rate. The right hand bar shows the maximum measured production rate when the animal is stressed.

Most mammals have the ability to significantly increase vitamin C production in response to stressors such as trauma and disease. Given what happens in animals, it is advisable for humans to increase vitamin C consumption in response to disease. For a 70 kg person, a five-fold increase from the normal level of omnivores would be seven grams per day.

We have made some adaptations to being chronically vitamin C deficient. Humans and other great apes have lost the uricase enzyme that degrades uric acid. Uric acid is a powerful extracellular antioxidant. At the high end of their concentration ranges, humans have seven times the concentration of uric acid in plasma as pigs do. This offsets about 40% of the effect of the loss of vitamin C in humans. But the effect is only in serum and uric acid does not support collagen synthesis or immune cell function. Taking up to 500 mg per day of vitamin C lowers the serum uric acid level by up to 20%.

Another human adaptation to low vitamin C levels is to concentrate it in white blood cells at 20 to 80 times the level in plasma. The brain also retains vitamin C, including during deficiency. Humans have evolved to waste almost no vitamin C, though this only works if there is an intake in the first place. In effect, humans rely heavily on secondary antioxidant systems because the primary system is missing.

All that is to provide background to the disease implications. Vitamin C is required, as in not optional, for collagen cross-linking in skin, blood vessels and joints, mitochondrial protection, immune surveillance, stem cell maintenance and suppressing cancers. Vitamin C has a big role in slowing aging by better connective tissue integrity, lower frailty and slower immune senescence. Aging in humans resembles chronic low-grade vitamin C deficiency.

Humans show rapid depletion of plasma vitamin C during infections with the concentration often falling into the scurvy range. This in turn causes capillary leaks and oxidative damage. The human vitamin C level in plasma is normally in the range of 40 to 60 µmoles per litre. During infection this falls to under 20 µmoles per litre. Scurvy starts at below 11 µmoles per litre. Relative to other animals, the human vitamin C level collapses rapidly under stress. In contrast, animals go from the 60 µmoles per litre baseline to up to 100 µmoles per litre under stress. That said, absorption of vitamin C drops sharply from oral dosing above three to five grams per day. Five grams per day will get you to about 90 µmoles per litre. There is no increase in plasma vitamin C level beyond 10 grams orally per day. Taking vitamin C intravenously bypasses the limits imposed by oral dosing. Taking one to five grams intravenously approximates what animals achieve during severe stress.

One of the things that vitamin C does during infection is to protect mitochondria from oxidation. Many hypoxic disease states are vitamin C-sensitive, not oxygen-related per se. Animals that make their own vitamin C maintain mitochondrial output during infection or exertion. Humans fatigue faster and accumulate inflammatory byproducts.

With respect to viral infection, vitamin C enhances type 1 interferon production. This slows viral load early, before viral load peaks. N-acetyl cysteine (NAC), another strong antioxidant, likely works in the same way. Vitamin C also keeps iron bound to proteins with the result that less is available for viral proteins. It also limits viral oxidative signalling cascades, capping the replication rate. In summary, viruses replicate fastest in vitamin-C depleted cells. Animals respond to viral infections by increasing vitamin C synthesis; humans experience uncontrolled inflammatory amplification instead.

Vitamin C, vitamin D, and zinc have complementary roles in controlling viral infections. Vitamin C acts within hours while vitamin D acts over days to weeks. Vitamin D controls gene transcription in making proteins, prevents immune overshoot, and reduces autoimmunity and inflammatory overshoot. Zinc is needed for making antiviral enzymes, inhibition of RNA replication, and increasing the function of the thymus. Zinc is quickly depleted during infection. Zinc works best when vitamin C keeps the oxidative state of cells stable.  This is a simpler way of putting it:

1. Vitamin C responds quickly to a viral infection.
2. Zinc slows viral replication.
3. Vitamin D prevents the immune system from burning the house down.
4. Mammals evolved to make more vitamin C while infected because timing matters.
5. Humans lost the buffer of being able to increase vitamin C production in response to the stress load and pay for it under viral stress.

The normal blood concentration of vitamin C is 12 µg/ml. Cells of the immune system concentrate vitamin C within them at 20 to 80 times higher than the plasma level. So vitamin C is important in a properly functioning immune system. Immune system impairment starts when the plasma vitamin C level falls below 8 µg/ml. Immune cells work by creating reactive-oxygen-species to kill pathogen cells. The role of vitamin C is to protect the immune cells during this oxidative burst.

With respect to cancer, a high proportion of chemotherapy drugs work by creating reactive-oxygen-species (ROS) in the mitochondria. This stresses the cancer cell so it sends signals to the cell surface to make more death receptors on the cell surface. Most antioxidants negate this effect to some extent. With vitamin C at high blood concentrations, which can only be achieved by intravenous injection, this inverts to create an anti-cancer effect. Cancers have a voracious appetite for glucose. Oxidised vitamin C looks similar to glucose to the transporter proteins that take glucose into cells. Once in the cancer cells, this overload of oxidised vitamin C creates ROS which damages it. As a cancer treatment, intravenous vitamin C is most effective in the types that have a low ability to break hydrogen peroxide into water and oxygen

The first dose in intravenous vitamin C treatment of cancer is usually 15 grams. This is to make sure that the body is not overloaded with necrotic cancer cells if too many of them die at the beginning of treatment. The next dose is 30 grams. Daily dose rates of up to 90 grams have been used. This is equivalent to what two 50 kg, infected goats might produce between them.

David Archibald is the author of The Anticancer Garden in Australia.