Advances in Nutrition 15 (2024) 100155

journal homepage: https://advances.nutrition.org/

Nutrient Information (Invited)

Vitamin C
Jens Lykkesfeldt 1, *, Anitra C Carr 2
1 2
Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Pathology and Biomedical Science, University of
Otago, Christchurch, New Zealand

Vitamin C is a small water-soluble carbohydrate; however, its transporters. Distribution from the blood into tissues is governed
particular chemical properties have rendered it as a unique by tissue-specific SVCT2s that concentrate vitamin C further from
reducing agent in living organisms. In all but a few species, the typical 50–70 μmol/L in plasma to 0.5–10 mmol/L in tissues.
ascorbic acid—the reduced form of vitamin C—is biosynthesized The highest tissue concentrations of vitamin C are found in the
from glucose through a series of enzyme-catalyzed reactions. brain, eyes, and adrenal glands. Vitamin C is excreted through the
However, in higher-order primates, bats, guinea pigs, and some kidneys by glomerular filtration. However, if the body stores and
fish and bird species, this ability has been lost through evolution plasma concentration are low, SVCT1 in the kidneys will almost
owing to accumulation of functional mutations and deletions in quantitatively reabsorb ascorbate from the urine to prevent loss of
the gene encoding for L-gulonolactone oxidase, the enzyme vitamin C from the body. By contrast, if the vitamin C intake ex-
catalyzing the final step in the biosynthesis of ascorbate. ceeds about 400 mg/d in healthy individuals over longer periods,
Consequently, vitamin C is an essential nutrient in these species the body becomes saturated, resulting in plateau plasma steady
and must be supplied through the diet to sustain life. state concentrations of about 65–80 μmol/L, and any further
Vitamin C exists in 2 forms, the reduced form ascorbic acid and excess of vitamin C is quantitatively excreted. Thus, this dose-
its two-electron oxidation product dehydroascorbic acid. All dependent mechanism contributes to the homeostatic control of
known biological functions of vitamin C are related to its reduced the vitamin C status of the body.
form. Thus, ascorbate can donate an electron to another molecule The biological functions of vitamin C are many and can
thereby reducing it, whereas itself being oxidized to the ascorbyl roughly be separated into enzymatic and nonenzymatic re-
radical, a comparatively stable and nonharmful radical form. Two actions. The nonenzymatic reactions of ascorbate are what
ascorbyl radicals can subsequently dismutate into 1 molecule of earned it its reputation as a powerful antioxidant. Ascorbate is
ascorbate and 1 molecule of dehydroascorbic acid. Dehy- indeed capable of reducing any pathophysiologically relevant
droascorbic acid is taken up by most cell types and efficiently free radical and reactive oxygen species. Vitamin C is also
reduced to ascorbate either chemically by glutathione or enzy- capable of regenerating the lipid-soluble vitamin E from its
matically by glutathione-dependent dehydroascorbic acid re- oxidized form. Through these activities and because of its
ductases or NADPH-dependent dehydroascorbic acid reductases abundancy, vitamin C is considered to be a very important
such as thioredoxin reductase, thereby preventing metabolic loss contributor in the protection of cellular macromolecules such as
of vitamin C. This process is referred to as ascorbate recycling. DNA, proteins, and lipids from oxidative damage, although the
Similar to its chemistry, the pharmacokinetics of vitamin clinical importance of this generic antioxidant activity is difficult
C—that is, its absorption, distribution, metabolism, and to assess in vivo. Regardless, oxidative damage is believed to be
excretion—is highly complex and tightly regulated by a range of causally related to both initiation and progression of several
mechanisms [1]. Ascorbate is taken up from the intestine through chronic diseases such as cardiovascular disease and cancer.
the sodium-dependent vitamin C transporter (SVCT) 1, an active Along with its nonspecific antioxidant activity, more and
transport mechanism capable of generating a concentration more specific roles of vitamin C are being discovered. The
gradient. Dehydroascorbic acid may also be taken up from the gut longest known function of vitamin C is its role as cofactor for the
to a minor extent by facilitated diffusion through glucose ferrous and 2-oxoglutarate dependent dioxygenases that catalyze

Abbreviations: HIF-1a, hypoxia-inducible factor 1a; SVCT, sodium-dependent vitamin C transporter.

https://doi.org/10.1016/j.advnut.2023.100155
Received 17 October 2023; Received in revised form 30 October 2023; Accepted 6 November 2023; Available online 21 November 2023
2161-8313/© 2023 The Authors. Published by Elsevier Inc. on behalf of American Society for Nutrition. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
J. Lykkesfeldt, A.C. Carr Advances in Nutrition 15 (2024) 100155

the hydroxylation of lysine and proline residues in unfolded excretion and adjusted for body mass, a recommended dietary
procollagen chains to form the building blocks of the mature allowance (RDA) of 75 and 90 mg/d for females and males,
functional triple-helix collagen. Ascorbate is also a cofactor for respectively, was established in the most recent recommendation
enzymes involved in the biosyntheses of norepinephrine and by the U.S. Institute of Medicine (now National Academy of
carnitine, the amidation of peptide hormones, the metabolism of Medicine) in 2000. In addition, the RDA for pregnant and
the amino acid tyrosine, the reduction of tetrahydrobiopterin, breastfeeding females (19 y or older) was set at 85 and 120 mg/
and the denitrosylation and phosphorylation of endothelial nitric d, respectively. No RDA was established for infants; instead, the
oxide synthase. Through these actions, vitamin C facilitates a adequate intake of vitamin C was set at 40 mg/d for infants aged
wide range of physiologic processes such as immune response, younger than 6 mo and 50 mg/d for infants aged 6–12 mo. For
neurotransmission, energy metabolism, and vasorelaxation just older children, the recommendation was based on estimated
to mention a few. body mass in relation to an adult: 15 mg/d for children younger
Ascorbate is also involved in the hydroxylation of hypoxia- than 3 y, 25 mg/d for children younger than 8 y, and 45 mg/d for
inducible factor (HIF) 1α, which impacts the regulation of hun- children younger than 13 y. Moreover, the RDA for teenagers
dreds of genes and controls essential processes such as angio- was based on gender: 75 and 65 mg/d for boys and girls aged
genesis and cell proliferation. More recently, it has been 13–17 y, respectively. Smokers are known to have an increased
discovered that ascorbate is also a cofactor for the Jumonji-C turnover of vitamin C probably owing to the toxicity of the
domain–containing histone demethylases and the ten-eleven smoke and consequently an additional intake of 35 mg/d is
translocation methylcytosine dioxygenases that are known as recommended [5]. Although environmental tobacco smoke
epigenetic master regulators. These enzymes catalyze the hy- exposure has a similar effect, no recommendations have been put
droxylation of methylated lysine and arginine residues in his- forward for those exposed to smoking.
tones and methylated cytosine residues in DNA, which constitute In a more global perspective, recent reports shows that
the initial steps in demethylation that control gene expression. considerable discrepancies exist between the recommendations
Through this activity, vitamin C seems to play an important role published by national authorities. The differences are typically
in normal epigenetic regulation and may also be important in based on the health perspective underlying the recommenda-
disease prevention or treatment as acquired epigenetic changes tions. Thus, scurvy prevention can be achieved with a very small
are a hallmark of many cancers [2]. intake of vitamin C and has been the basis for the recommen-
dations by, for example, WHO of only 45 mg/d, whereas some
Deficiencies countries (Australia, New Zealand, and China) have introduced a
suggested dietary target of 200 mg/d with the aim of optimal
The ultimate clinical manifestation of vitamin C deficiency, chronic disease risk reduction [6]. Moreover, with the ongoing
scurvy, has been known for centuries from long sea voyages and obesity pandemic, evidence suggests current recommendations
expeditions and is fatal if not treated. The symptoms include are too low for a large proportion of the population and that body
impaired wound healing, gingivitis, perifollicular hemorrhages, weight should be considered in future dietary recommendations
ecchymoses, and petechiae and are largely related to impaired because vitamin C status is strongly inversely correlated with
collagen formation and possibly HIF-1α hydroxylation. Clinical body weight [4].
scurvy may be prevented with as little as 10 mg vitamin C per
day. Other less-specific symptoms of severe and prolonged Food sources
vitamin C deficiency include malaise and fatigue or lethargy and
low mood. They may result from impaired energy metabolism Most fruits and vegetables are excellent sources of vitamin C,
and decreased neurotransmitter synthesis. Judging from the although considerable variation exists. Citrus, kiwi, and mango
many specific functions of vitamin C, long-term insufficiency fruits and vegetables such as peppers and broccoli are rich in
might also increase chronic disease risk. Indeed, a considerable vitamin C, while apples, bananas, and most staple foods have low
body of epidemiologic literature has found significant inverse vitamin C content. Vitamin C content may be severely decreased
correlations between vitamin C status and risk of cardiovascular during heating and storage. Five to 9 servings of fresh, frozen, or
diseases and cancer. However, properly designed randomized minimally processed fruits and vegetables has been estimated to
controlled trials have so far not been conducted to confirm or correspond to about 200 mg of vitamin C.
reject a causal link between poor vitamin C status and increased
risk of these diseases [3]. Clinical uses
Poor vitamin C status is closely linked to a diet low in fresh
fruits and vegetables and rich in fat and carbohydrates. Addi- Although scurvy is easily prevented even by a low intake of
tional risk factors of vitamin C deficiency include smoking, vitamin C, symptoms of scurvy typically reflect a profound
pregnancy, low socioeconomic status, genetic predisposition, deficiency that requires urgent parenteral replacement therapy.
and several conditions related to cardiometabolic dysregulation Subsequently or in milder cases, oral supplementation with 500
such as hypertension, diabetes, and obesity [4]. mg/d may be adequate. Subclinical vitamin C deficiency is very
difficult to detect without blood sampling owing to the often-
Dietary recommendation unspecific symptoms. Although overt vitamin C deficiency is
rare in the general population, increased frequencies may be
Based on the vitamin C intake required to achieve near found among individuals with malnutrition, poor dietary habits,
saturation of plasma and leukocytes with minimal urinary chronic disease, intestinal disorders, or chemical dependencies.

2
J. Lykkesfeldt, A.C. Carr Advances in Nutrition 15 (2024) 100155

Clinical uses of vitamin C also include increasing nonheme iron supplementation on progression-free survival are currently
absorption because vitamin C reduces dietary iron and facilitates underway [2]. Vitamin C’s immune-modulating effect has also
its intestinal absorption. been of interest for decades for its possible ability to attenuate the
Vitamin C is currently under investigation as a therapy in common cold. More recently, more clinically important applica-
several clinical conditions such as cancers, sepsis, cardiovascular tions in relation to sepsis and serious SARS-CoV-2 infections have
disease, and coronavirus infections. However, no final conclu- been investigated but so far with mixed outcomes. However,
sion has been reached on the relevance of clinical application of numerous trials are still ongoing and may provide more definitive
vitamin C beyond that of replacement therapy during acute results.
disease. Of note, however, the doses necessary to restore normal
levels in acutely ill patients are usually many-fold higher than Author contributions
those required in healthy individuals. JL: wrote the manuscript; ACC: critically edited the manu-
script. Both authors read and approved the final manuscript.
Toxicity
Conflict of interest
Vitamin C is generally nontoxic and well tolerated even in The authors report no conflicts of interest.
large doses. The current tolerable upper intake level was set to 2
g/d by the National Academy of Medicine in 2000, but more References
recently, the European Food and Safety Administration (EFSA)
and others have removed the upper intake level for vitamin C 1 J. Lykkesfeldt, P. Tveden-Nyborg, The pharmacokinetics of vitamin C,
completely owing to a lack of evidence of toxicity. Temporary Nutrients 11 (10) (2019) 2412, https://doi.org/10.3390/nu11102412.
gastrointestinal disturbances are known to occur in some in- 2 S.U. Mikkelsen, L. Gillberg, J. Lykkesfeldt, K. Gronbaek, The role of vitamin
C in epigenetic cancer therapy, Free Radic. Biol. Med. 170 (2021)
dividuals at higher doses, and a consistent intake of several 179–193, https://doi.org/10.1016/j.freeradbiomed.2021.03.017.
grams per day has been suspected of increasing risk of kidney 3 J. Lykkesfeldt, On the effect of vitamin C intake on human health: how to
stones, but this suspicion has not been substantiated. However, (mis)interprete the clinical evidence, Redox Biol 34 (2020) 101532,
https://doi.org/10.1016/j.redox.2020.101532.
those susceptible to kidney stone formation are still recom-
4 A.C. Carr, J. Lykkesfeldt, Factors affecting the vitamin C dose-
mended to avoid vitamin C supplements. Patients at risk of iron concentration relationship: implications for global vitamin C dietary
overload should limit iron intake rather than that of vitamin C. recommendations, Nutrients 15 (7) (2023) 1657, https://doi.org/
10.3390/nu15071657.
5 Dietary reference intakes for vitamin C, vitamin E, selenium and
Recent research carotenoids: a report of the Panel on Dietary Antioxidants and Related
Compounds, Subcommitties on Upper Reference Levels of Nutrients and of
the Interpretation and Use of Dietary Reference Intakes, and the Standing
Although vitamin C has been investigated as a potential cancer Committee on the Scientific Evaluation of Dietary Reference Intakes, Food
therapy for decades, the recent identification of its involvement in and Nutrition Board, Institute of Medicine, National Academy of Sciences,
epigenetic regulation as mentioned earlier has revealed a new and National Academy Press, Washington (DC), 2000.
6 A.C. Carr, J. Lykkesfeldt, Discrepancies in global vitamin C
highly plausible mechanism by which vitamin C deficiency may
recommendations: a review of RDA criteria and underlying health
contribute to cancer progression and supports a possible thera- perspectives, Crit. Rev. Food Sci. Nutr. 61 (5) (2021) 742–755, https://
peutic potential. Studies investigating the effect of vitamin C doi.org/10.1080/10408398.2020.1744513.