Growing up, I spent much of my free time reading the accounts of great explorers and inspired novels. Mental pictures of Gulliver’s Travels, Robinson Crusoe, and Sindbad the Sailor made up much of my childhood adolescent day and night dreams. I am safe to assume that many of you dear readers share these fantasies and still wonder how it was like traveling the high seas, venturing into the unknown, looking for adventure, fame, and great bounties. If you are anything like me, you still feel slightly disappointed looking at the gapless world map of our time, leaving no place for wannabe explorers. I can also safely bet that your seafaring fantasies, as diverse and unexpected as they might be, never or rarely included bleeding gums, falling teeth, and bleeding sores.

Vitamin C, a great friend to keep away the scourge of sea

Yet this was the daunting reality of the majority of high-ocean sailors: long expeditions lost on average half of their crews, with larger losses also being recorded, like the case of Vasco de Gama losing 117 out of his 170 in his first voyage to India. It was Scurvy, the scourge of the sea, much worse than wars and pirates combined, claiming over 2 million sailor lives between the 16th and 18th centuries.

This all changed with a remarkable English lad, named James Cook. A navy officer and a meticulous cartographer, Cook was very methodical and disciplined and known to take good care of his crew. Upon his first circumnavigation, Cook made sure to load his ship with sauerkraut, based on his observation that Dutch sailors, who regularly consumed it, rarely developed scurvy. Indeed, Captain Cook managed his circumnavigation of the globe without losing a single sailor to scurvy.

Later on, this knowledge became commonplace among navies and completely validated the earlier findings of James Lind that fresh foods in general, especially citrus fruits, were really good at preventing and reversing scurvy.

Collagen; connecting tissues, and vitamin C to its anti-scurvy role

What was it though, in fresh fruits that prevented the scurvy scourge? That question had to wait almost 2 centuries to first be answered by Albert-Saint-Georgiy to isolate the molecule in 1928, which was later termed Vitmain C by Charles Glen King, and its chemical structure resolved by Normal Howarth in 1933.

The importance of Vitamin C to healthy human physiology was later explained by the remarkable discoveries of Linus Pauling that uncovered the structure and biosynthesis of collagen, and vitamin C role in that process. Collagen is the universal main building block of connective tissues, in the healthy connective tissue collagen is constantly broken down and replenished. Vitamin C is essential to this process as it stabilizes and prevents the oxidative inactivation of two key enzymes for collagen biosynthesis. By this, vitamin C prevents the degeneration of the connective tissues, and its absence these tissues decay, what has been long known as Scurvy.

Humans and Vitamin C; enigmatic evolutionary history that still eludes

With that explained, the intriguing history of vitamin C predates the age of sailing by over 61 million years, namely the time when our primate ancestors lost the ability to biosynthesize vitamin C from a natural precursor called glucoronate that is absorbed by the natural gut bacteria. Unlike us humans, other primates, and a few other mammals, including bats, most mammals and other members of the animal kingdom retain the ability to biosynthesize vitamin C and are hence immune to scurvy. In other words, for most animals, vitamin C is not really a vitamin, as they can make it from scratch without having to source it from their diet.

This loss of the biosynthesis ability of vitamin C happened due to a mutation in a key enzyme for this pathway called GLO. While the long form name of the enzyme is totally boring, what is more interesting is the evolutionary mystery we have at hand here. Normally, disadvantageous mutations are dropped by evolution, as the carrying individuals are selected against; hence, the loss of the ability to synthesize vitamin C must have bestowed some advantages on our ancestors for it to be evolutionarily permitted. This remains an open question up to date, with various intriguing theories trying to explain it. While not definitive, these theories are an interesting way of showcasing the uniqueness of vitamin C to human metabolism.

All the theories around this revolve around the main chemical characteristic of vitamin C and the core of all its biological roles, namely that vitamin C is an essential antioxidant and free radical scavenger that protects the membranous structures in the cell from oxidative damage, in addition to maintaining molecules and ions in their functionally desired reduced form, like reducing ferrous to ferric, which is the absorbable and bioactive form of iron. Likewise, the cell can also recycle the oxidized vitamin C, known as DHA, back to its reduced form with the help of cellular redox modulators like glutathione, which is essential for cellular homeostasis, including protein redox modulation affecting protein structures and xenobiotic oxidative metabolism in the liver.

The interdependency between vitamin C and glutathione goes beyond them being direct redox partners; one of the likely reasons that made losing vitamin C biosynthesis advantageous is the fact that the biosynthesis pathway of vitamin C requires the oxidization of a glutathione molecule, making it more efficient to source vitamin C directly from the diet. Early primate and human diets were rich in fresh fruits, which provided enough dietary vitamin C, hence making the ability to make the molecule obsolete, so cells could do without this pathway and save their energy costs for more urgent processes.

Another counterintuitive theory postulates that vitamin C biosynthesis has been lost, especially because it is not a free radical scavenger. An improved understanding of cellular redox biology has established free radicals as naturally occurring byproducts that play an essential role in cell signaling, including the regulation of gene expression. This “destigmatization” of reactive oxygen species has been a milestone in shedding the old, oversimplified theories regarding aging being a simple direct byproduct of accumulated oxidative damage. But this is a wider topic worthy of its own article.

Vitamin C and Cancer; my personal experience and take on the controversy

Linus Pauling’s discovery of the collagen structure prompted his strong conviction that the molecule was a health and wellness panacea. This went as far as claiming that vitamin C is an essential nutrient for both the prevention and effective treatment of cancer. One of his postulated mechanisms was that, by preserving collagen, vitamin C kept the connective tissues tight enough to prevent the spread of cancerous cells. He and Ewan Cameron advocated for the use of vitamin C in cancer patients and oversaw an iconic clinical trial demonstrating an advantage for vitamin C supplementation in extending the survival time of terminal cancer patients, but with no cure effect on the outcome. Mayo Clinic weighed into the topic with a subsequent study that failed to show an advantage of vitamin C supplementation in cancer patients. Consequently, skepticism surrounded the concept, and the potential of vitamin C went neglected for the better part of three decades.

Two shortcomings in the earlier studies signified the remaining hope for vitamin C in helping cancer patients. The original study from Pauling and Cameron was limited to 10 grams daily, while the Mayo Clinic study used the oral route to administer vitamin C. Meaning that both studies did not even get close to the maximal tolerable plasma concentrations of vitamin C. As highlighted in the works of Mark Levin and others, large doses of Vitamin C are limitedly absorbed in the intestines, severely capping the achievable plasma concentrations via oral supplementation, which enables us to dismiss the failure of Vitamin C in the Mayo Clinic study as a failure to achieve the necessary concentrations achieved in the earlier Cameron and Pauling trial.

While the intravenous dosing does achieve full and quick bioavailability, the kidneys quickly clear the excessive vitamin C to maintain its plasma concentrations within the physiological limits. To achieve high supraphysiological (pharmacological) concentrations in patients, high doses of vitamin C should be given continuously for several hours. Recent clinical studies established the safety, tolerability, and feasibility of flushing the circulation with a vitamin C infusion containing a daily dose of up to 100 grams of vitamin C over several hours. While some case studies and small trials show some efficacy, an improved understanding of the mechanisms in various types of cancers is essential to translating this potential into real interventions, in which vitamin C anti-cancer effects can be harnessed in combination with established and emerging lines of therapy.

To that end, the return of this subject has been largely driven by conceptual animal and in-vitro studies showing that vitamin C specifically targets cancer cells due to their metabolic and oxidative vulnerability. I was personally drawn into this field of research by a high-profile report on vitamin C specifically eliminating cancer cells with specific mutations, based on the increased uptake of the oxidized form via the amplified glucose transporters that are preferentially used by cancer cells to boost their metabolism. I therefore led a research project to improve the molecular and cellular understanding of the effects of vitamin C on breast cancer cells in culture. Which also uncovered mechanisms in which vitamin C specifically targeted cancer cells redox homeostasis, leading to oxidative damage, collapse of key metabolic functions, and accumulated DNA damage. While in-vitro and animal studies can help uncover new mechanisms and lead the way in exploring the potential of vitamin C supplementation in cancer treatment and prevention, clinical trials have the final say in validating these mechanisms and translating them into potential therapies.

While it is unlikely that large doses of vitamin C will ever be proven to fully cure cancer, there is abundant molecular, cellular, pre-clinical, and clinical evidence that warrants a serious consideration of pharmacological vitamin C supplementation or infusion as a complementary measure for treating cancer and improving patient outcomes. This is substantiated by the unique safety profile of this molecule, making it an attractive add-on choice to therapy regiments.

Vitamin C in wellness and longevity

If you are anything like me, a fizzy, sour, refreshing drink is an invariable part of your cold-recovery ritual. The use of vitamin C supplementation for the common cold has also been advocated and pushed by Linus Pauling and others. While many, including me, do feel better, vitamin C has no proven mechanism for improving the common cold per se. With that said, if you also feel that vitamin C helps you stay energized and active through a common cold, there are several universal mechanisms of vitamin C activity that can help explain and justify this feeling, other than the placebo effect.

Vitamin C is a universal reactive oxygen species scavenger; the release of reactive oxygen species is a hallmark of all inflammation. Vitamin C helps get rid of the excess of reactive oxygen species, reducing inflammation and potentially allowing the immune cells to sustain a longer response without being neutralized by excessive oxidation. Moreover, vitamin C, via its reductive qualities, can modulate the stability and effects of transcriptional factors that influence gene expression. This includes an effect on the expression of inflammatory cytokines that could also have a role in reducing inflammation.

Beyond the common cold, reducing inflammation is a highly desirable effect for preserving health into the later decades of life, as increased inflammation, or "inflammaging,” is a hallmark of aging that contributes to the increase in the risk and incidence of cardiovascular, cancer, neurodegenerative, and autoimmune diseases, among others.

Vitamin C also inhibits a particular transcriptional factor that is involved in cancer development and progression, called the hypoxia-inducible factor. Vitamin C reduces its stability and limits its effects on promoting tumor growth.

Conversely, vitamin C stabilizes and substantiates the effects of pluripotency factors, essential for maintaining stem cell populations that are vital to preserving the integrity and function of organs and tissues as we grow older. Consistently, vitamin C is used as a component of the “cocktails” used for making and preserving stem cells in the lab, also called induced pluripotent stem cells (iPSCs).

On the metabolic side, vitamin C competes with glucose at the absorption and cell entry levels, and hence large doses of vitamin C have a lowering effect on the blood glucose, independent of the insulin effects, and hence are still useful for patients with reduced insulin sensitivity, also known as increased insulin tolerance.


In short, vitamin C is a marvelous molecule with a unique and intimate influence on our evolution and history as a species. As with such omnipresent molecules, their abundant roles in the cells are very intricate, sometimes to the level of contradiction, where they seem to support pathways or mechanisms with opposing roles. Studying and improving our understanding of the physiological roles and pharmacological potential of such essential molecules always brings new insights that improve our understanding of our cells and bodies. In a sense, Vitamin C continues to participate in writing history, but now from research labs, hospitals, and the wellness and longevity communities, who are all contributing pieces to understand its ever-evolving puzzle.


1 Sauerkraut, sugar, and salt pork – the diet on board Cook’s 'Resolution'.
2 Pauling L. Evolution and the need for ascorbic acid. Proc Natl Acad Sci U S A. 1970 Dec;67(4):1643-8. doi: 10.1073/pnas.67.4.1643. PMID: 5275366; PMCID: PMC283405.
3 Bánhegyi, G et al. “Ascorbate synthesis-dependent glutathione consumption in mouse liver.” FEBS letters vol. 381,1-2 (1996): 39-41. doi:10.1016/0014-5793(96)00077-4.
4 Hornung TC, Biesalski HK. Glut-1 explains the evolutionary advantage of the loss of endogenous vitamin C-synthesis: The electron transfer hypothesis. Evol Med Public Health. 2019 Aug 28;2019(1):221-231. doi: 10.1093/emph/eoz024. PMID: 31857900; PMCID: PMC6915226.
5 Kalinina, Elena, and Maria Novichkova. “Glutathione in Protein Redox Modulation through S-Glutathionylation and S-Nitrosylation.” Molecules (Basel, Switzerland) vol. 26,2 435. 15 Jan. 2021, doi:10.3390/molecules26020435.
6 Zhitkovich A. Ascorbate: antioxidant and biochemical activities and their importance for in vitro models. Arch Toxicol. 2021 Dec;95(12):3623-3631. doi: 10.1007/s00204-021-03167-0. Epub 2021 Oct 1. PMID: 34596731; PMCID: PMC8541910.
7 Pauling L, Corey Rb. ,The structure of fibrous proteins of the collagen-gelatin group. Proc Natl Acad Sci U S A. 1951 May;37(5):272-81. doi: 10.1073/pnas.37.5.272. PMID: 14834150; PMCID: PMC1063353.
8 Pauling, L, and C Moertel. “A proposition: megadoses of vitamin C are valuable in the treatment of cancer.” Nutrition reviews vol. 44,1 (1986): 28-32. doi:10.1111/j.1753-4887.1986.tb07553.x.
9 Cameron, E. “Protocol for the use of vitamin C in the treatment of cancer.” Medical hypotheses vol. 36,3 (1991): 190-4. doi:10.1016/0306-9877(91)90128-l.
10 Padayatty, Sebastian J et al. “Vitamin C pharmacokinetics: implications for oral and intravenous use.” Annals of internal medicine vol. 140,7 (2004): 533-7. doi:10.7326/0003-4819-140-7-200404060-00010.
11 Malo, C, and J X Wilson. “Glucose modulates vitamin C transport in adult human small intestinal brush border membrane vesicles.” The Journal of nutrition vol. 130,1 (2000): 63-9. doi:10.1093/jn/130.1.63.
12 Yun, Jihye et al. “Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.” Science (New York, N.Y.) vol. 350,6266 (2015): 1391-6. doi:10.1126/science.aaa5004.
13 Ghanem, Ali et al. “Ascorbate kills breast cancer cells by rewiring metabolism via redox imbalance and energy crisis.” Free radical biology & medicine vol. 163 (2021): 196-209. doi:10.1016/j.freeradbiomed.2020.12.012.
14 Miles SL, Fischer AP, Joshi SJ, Niles RM. Ascorbic acid and ascorbate-2-phosphate decrease HIF activity and malignant properties of human melanoma cells. BMC Cancer. 2015 Nov 7;15:867. doi: 10.1186/s12885-015-1878-5. PMID: 26547841; PMCID: PMC4636772.
15 Gao, Yuan et al. “Vitamin C facilitates pluripotent stem cell maintenance by promoting pluripotency gene transcription.” Biochimie vol. 95,11 (2013): 2107-13. doi:10.1016/j.biochi.2013.08.001.