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The role of vitamin C at the physiological and cellular levels is indisputable. In line with this, blood level of vitamin C is inversely related to disease parameters such as risk of cancer, cardiovascular disease and mortality in prospective cohort and correlational studies. At the same time, adequately powered clinical intervention studies consistently provide no evidence for a beneficial effect of supplementing vitamin C. Here we provide a framework to resolve this apparent conflict. Besides providing an overview of the widely-known facts regarding vitamin C, we review evidence that are of potential relevance but are seldomly mentioned in the context of vitamin C. We invoke the glucose-ascorbate antagonism (GAA) theory which predicts that as a consequence of their molecular similarity glucose hinders the entry of vitamin C into cells. Integrating data coming from research at the cellular level, those from clinical, anthropological and dietary studies, in the present hypothesis paper we propose an evolutionary framework which may synthesize currently available data in the relation of vitamin C and disease. We put forward that instead of taking vitamin C as a supplement, an evolutionary adapted human diet based on meat, fat and offal would provide enough vitamin C to cover physiological needs and to ward off diseases associated with vitamin C deficiency.
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Journal of Evolution and Health
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1. Introduction
Vitamin C is one of the most widely taken nutritional supplements [1,2]. Health professionals
as well as laymen attribute a number of health benefits to vitamin C such as boosting the
immune system or preventing the common cold and cancer. Whilst the role of vitamin C in
physiologic processes is well-established, there is little or no high-grade evidence supporting
that taking vitamin C as a supplement is indeed beneficial. We will summarize existing
research data with a special emphasis on aspects that are seldomly mentioned in the context of
vitamin C. As such, we invoke the glucose-ascorbate antagonism (GAA) theory, which
proposes that availability of vitamin C for cells is determined by glucose concentration [3].
We review evidence from cellular physiology as well as dietary studies carried out in Inuit
people to support the GAA theory and the view that the source of vitamin C as well as
composition of diet is crucial for optimal vitamin C supply. In this review we propose a
concept which may be suitable for synthesizing data coming from diverse sources and/or that
are apparently conflicting. The frames of the hypothesis are formed by a major, albeit often
neglected principal: evolution. We put forward that apparent controversies regarding vitamin
C can be readily resolved by an evolutionary approach.
2. Biosynthesis and biological significance of vitamin C
In most mammals vitamin C is produced from glucose in the liver. Species that are unable to
synthesize this nutrient rely on dietary uptake from its food sources [4]. Vitamin C, in synergy
with vitamin E, is known to have a role in reducing lipid peroxidation [5]. Vitamin C also acts
as a co-factor in at least eight enzymatic reactions including those involved in the synthesis of
collagen and carnitine [6].
Vitamin C exists in two redox states: ascorbic acid (AA), and its oxidized form,
dehydroascorbic acid (DHAA). Most actions of vitamin C can be attributed to AA which acts
as a reducing agent donating electrons to various reactions [7]. The oxidised form of vitamin
C is then recycled back to AA. Both AA and DHAA are absorbed in the small intestine [7].
Absorption is almost complete at doses <200 mg but the degree of absorption decreases as
intake increases [8]. Uptake of AA from the intestine relies on an active transport mechanism
of sodium dependent vitamin C transporters (SVCT) while uptake of DHAA relies on
facilitative diffusion by facilitative glucose transporters (GLUT) [9]. Within the enterocytes,
absorbed DHAA is converted to AA thereby producing low intracellular DHAA
concentration which by a gradient facilitates further DHAA uptake. DHAA may be taken up
from the blood by several cell types that reduce it to AA. DHAA can be filtered from the
plasma by renal corpuscules and then reabsorbed in the renal tubules for subsequent reduction
[10]. Some organs accumulate vitamin C (AA) 10-50-fold higher than the blood level of it.
These include tissues of high metabolic activity such as adrenal glands, thymus, eye lens,
retina, brain, pancreas, kidney, lymph nodes and lymphocytes [11].
AA cannot penetrate the blood brain barrier thus vitamin C is taken up in its oxidised
form DHAA which is then reduced back to AA for retaining it within brain cells [12]. A
similar transport mechanism exists for vitamin C entering the mitochondria [9]. AA is
accumulated within the mitochondria where it has a role to scavange free radicals abundantly
produced by mitochondrial function [13]. Several pathological conditions have been shown to
be associated with impaired redox cycling of vitamin C. For example, conditions associated
with inflammation such as diabetes, trauma, surgery, sepsis and wound healing are also
known to be characterized by decreased AA concentrations along with elevated DHAA
concentrations in both plasma and leucocytes [10]. This is believed to be due to increased
level of oxidants such as hydroxyl radicals, peroxyl radicals and superoxide anion requiring
more AA than could be regenerated from DHAA [10].
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Clemens and Tóth: Vitamin C from the evolutionary perspective
Published by Journal of Evolution and Health, 2013
3. Shortage and overdose of vitamin C
Shortage of vitamin C causes scurvy, presenting with symptoms including malaise, gum
disease, poor wound healing, shortness of breeth and bone pain. Scurvy occurred frequenty
among salesmen in mediaeval times. In current western societies it may occur in subjects with
alcoholism where it typically presents along with deficiencies of other vitamins [14]. Oral
megadose (>1000 mg) of vitamin C may cause diarrhea, nausea, abdominal bloating and
heatburn [4]. There is evidence that vitamin C supplementation increases the risk of forming
kidney stones [4]. Megadoses of vitamin C may lead to the development of vitamin B12
deficiency [4], a phenomenon explained by redox reactions of AA converting vitamin B12
into a biologically inactive analogue [6]. As an additional side effect, in glucose-6-phosphate
dehydrogenase deficiency AA has been shown to have a hemolytic effect [6]. Intrevenous
megadose of vitamin C may result in diarrhea, nausea, headache, decreased appetite and
fatigue [16].
4. Evolutionary perspective
Vitamin C is an essential nutrient for humans who are unable to synthesize and thus have to
obtain it from its dietary sources. Loss of the ability to synthesize vitamin C is not unique
among mammals: e.g. guinea pigs, monkeys and apes also lack this ability. Non-synthesizing
species, including humans, lack the L-gulonolactone oxidase (GULO) enzyme which is
required in the last enzymatic step of synthesis of vitamin C from glucose [4]. In the genome
of humans and that of the anthropoid primates a non-functional gene is present instead of the
GULO gene. Loss of the ability to synthesize vitamin C in primates is believed to have
occurred about 60 million years ago at the time of the split of the two primate suborders:
Strepsirrhini and Haplorhini [17]. Strepsirrhine primates including lemurs, lorises, and
galagos are able to produce vitamin C while haplorhine primates such as tarsiers, monkeys
and apes obtain it from dietary sources.
In the medical literature losing the ability to synthesize vitamin C in the course of
evolution is usually interpreted as an imperfection leaving our health vulnerable. However
with an evolutionary attitude such an ”imperfection” is inconceivable given that species that
are currently living represent the highest level of adaptation to their environment. Non-human
species lacking the GULO gene are not regarded imperfect either. It would be hard to believe
that the Homo genus would have been so successful in terms of survival and spatial spread
with a deteriorating genetic mutation. We assume that in the ancestral environment, where our
hominoid predecessors lived for 2.6 million years, loss of internal synthesis of vitamin C was
not disadvantegous. As one possible explanation, Ames et al. [18] proposed that during the
primate evolution uric acid might have taken over the antioxidant function of vitamin C, a
hypothesis based on the striking paralellism between the inability to break down uric acid and
the loss of the ability of vitamin C synthesis in primates [19].
5. Dietary sources of vitamin C
Recommended Dietary Allowances (RDA) of vitamin C, as suggested by the Institute of
Medicine, is 90 mg for males and 75 for females. According to the NHANES survey between
2003 and 2004, 7% was vitamin C deficient (serum concentration <11.4 μmol/L) in an US
population where 37% of men and 47% of women was taking vitamin C supplements [20].
The estimated average requirement (EAR) is set at 75 mg/d on the basis that it will
lead to 80% saturation of neutrophil AA concentrations without substantial urinary excretion,
thereby maximizing antioxidant effects. The RDA is derived from the EAR by assuming a
coefficient of variation (CV) of 10% in nutritional needs and adding twice the CV to the EAR
to yield an RDA that presumably covers the needs of 97-98% of the population [21]. Failure
or inconclusiveness of intervention studies with vitamin C may be due to the fact that vitamin
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Journal of Evolution and Health, Vol. 1 [2013], Iss. 1, Art. 13
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DOI: 10.15310/2334-3591.1030
C in these studies was given to people who had already been meeting or nearly meeting their
requirement as defined by the RDA.
Current dietary recommendations concentrate on plant sources of vitamin C. The
WHO, for example, recommend a minimum of 400g of fruit and vegetable per day also in an
attempt to ensure other micronutrients [22]. The belief that plant sources are ideal for vitamin
C supply roots back to James Lind who in 1747 discovered that scurvy, a devasting disease of
English sailors, can be prevented and reversed by fresh fruits. In fact, several lines of
evidence indicate that people may remain free of scurvy on diets lacking fruits and vegetables.
In hunter-gatherer societies organ meats and especially liver, marrow and brain are
highly favoured. These latter organs, as also described above, accumulate high level of
vitamin C [23,24] and are rich in other vitamins too [25]. At odds with dietary
recommendations in the western world, the majority of hunter gatherer societies are subsisting
on meat based diets yet remain free of scurvy [26,27,28]. In the study of Cordain et al. [26]
168 of the 229 hunter gatherer societies subsisted on diets containing at least 55% hunted
and/or fished food. In fact the ratio of animal food may be even higher given that hunther
gatherers also eat insects, invertebrates and other small animals that are collected by gathering
[26]. If both plant and animal foods are available, hunther gatherers clearly prefer the latter
[26,27].
Traditionally living arctic people represent extreme examples of animal food relience.
Among the Inuit scurvy was not observed until the 20th century [23]. Studies show that the
traditional diets of northern populations, including the Inuit diet, provide enough amount of
vitamin C. Fediuk [23], for example, reported an average intake of 38 mg of vitamin C/day
from meat and organs. However, on special occasions such as after successful whale hunts
intake may reach 340 mg/day [23]. Animal parts with highest vitamin C content include
”muktuk”, epidermis of the beluga whale (containing 36 mg/100 mg of vitamin C) and the
liver (containing 24 mg/100 mg of vitamin C) as well as the brain (containing 15 mg/100 mg
of vitamin C) of land and sea mammals [23,24]. In the 1970th, in the study of Geraci and
Smith [29] daily intake of vitamin C in a hunting Inuit community was in the range 10-120
mg, much higher than found earlier in a national survey of Canada assessing Inuit populations
in larger settlements with transitional cultures [29]. Westernalization of native societies
brought substantial changes in life style along with a decline in the access to traditional foods.
In parallel, an increasing portion of the Inuit people became at risk for scurvy [23].
Several examples show that not only native people may subsist on meat-fat based
diets. It is known that arctic travellers of European descent living on canned Western type
food were frequently affected by scurvy but this was not the case in those who had access to
traditional foods [25]. The arctic explorer Vilhjalmur Steffanson, for example, lived on the
Inuit diet for nine years and remained completely healthy. In 1930 an experiment was set up
in which Steffanson along with a fellow explorer lived on an exclusive meat diet for one year
[30]. No sign of vitamin deficiency, including scurvy, was noticed despite of the absence of
vitamin supplementation. Voegtlin, first proponent of the human evolutionary diet, put
forward that the diet humans are evolutionary adapted to is based on animal fat, meat and
offal, and is of full nutritional value. Along with this, he argued against the usefulness of
supplementing vitamin C [25]. We would like to emphasize that those hunter gatherers
subsisting on diets containing larger amounts of fruits and vegetables, may also have access to
enough vitamin C. This may be due to the combined sources of animal and plant vitamin C
along with a carbohydrate intake being still much lower than on an average Western type diet.
Anyhow, the Kitavan islanders for example, who are known to consume much carbohydrate
as compared with other indigenous people, exhibit low blood glucose levels (on average 3.5
mmol/l in the young population) [31].
3
Clemens and Tóth: Vitamin C from the evolutionary perspective
Published by Journal of Evolution and Health, 2013
The authors of the present paper are rehabilitating patients with chronic diseases by
using a diet we refer to as the paleolithic ketogenic diet [32-36]. This is an animal fat-meat
based diet which is close to the diet originally proposed by Voegtlin [25]. The paleolithic
ketogenic diet excludes foods that were not available for preagricultural humans such as
cereal grains, milk and dairy, vegetable oils, nightshades, legumes, refined sugars and foods
with additives. It also excludes foods that may be included in the popular versions of the
paleolithic diet such as oilseeds, coconut, coconut oil, artificial sweeteners, vitamin as well as
other supplements. The paleolithic ketogenic diet also differs from the popular paleolithic diet
in that it restricts vegetables and fruits to an amount of <30% (by weight) and thus ensures
ketosis. The suggested fat:protein macronutrient ration is 2:1 (in grams). We encourage red
and fat meats and the regular intake of organ meats. Like other proponents of the paleolithic
diet [25,26] we advise patients against taking vitamin C supplements. Our clinical experience,
also shown by the example of our published cases [32-36], indicate that neither scurvy nor
other nutritional deficiency emerge in the absence of vitamin C supplementation while
adhering to the paleolithic ketogenic diet. As an important distinction, this is not the case with
the classical form of the ketogenic diet where scurvy may occur [37] likely due to limited
intake of both animal and plant sources of vitamin C.
Another potential benefit of animal derived vitamin C pertains to cooking. It is widely
known that vitamin C content of foods degrade at higher temperatures. However, cooking-
related loss of vitamin C seems to be smaller in animal-derived foods as compared with plant-
derived ones as assessed both by the analysis of the Inuit diet [29,23] and by comparison of
food items in publicly available food databases. For example, according to the USDA's
National Nutrient Database for Standard Reference in the raw spinach there is 28.1 mg/100 g
of vitamin C while cooked spinach contains only 9.8 mg/100 g of it. At the same time, raw
and cooked forms of pork liver contain comparable amounts of vitamin C: while the former
contains 25.3 mg/100 g the latter contains 23.6 mg/100 g of vitamin C.
6. Vitamin C and disease
In the following we review data from those clinical studies representing the highest grade
evidence available and have a hard clinical endpoint. In such an attempt we have searched
pubmed and google scholar databases for studies that include terms ”vitamin C” or ”ascorbic
acid” in combination with ”mortality”, "cancer”, ”cardiovascular disease”, ”stroke”,
”hypertension” and ”common cold”. We also searched for ”intravenous vitamin C therapy”.
We then reviewed search results for each of the above condition to select those studies that (1)
include the most subjects/patients, (2) have a sound methodology and (3) and assess a hard
endpoint/clinically meaningful variable. Parameters which were regarded as hard clinical
endpoint include: bivariate variables (such as death or the occurrence of specific events
including stroke or cardiovascular events, and having a diagnosis of a specific disease),
survival time, incidence of common cold, and blood pressure itself in hypertension. We
disregarded studies that rely on soft clinical endpoints of disease e.g. cholesterol level in
cardiovascular disease, the role of which in cardiovascular disease is debated. Prospective
cohort and correlational studies are presented separately from intervention studies. For
prospective and correlational studies we only included studies that assessed blood level of
vitamin C and excluded those that rely on estimated dietary intake of vitamin C. Reasons for
this include probable inadequacies in estimation of the vitamin C content of foods and the
low/variable correlation between dietary intake and the blood level of vitamin C [38]. The
low measured correlation between dietary and blood vitamin C in these studies is due to fact
that blood vitamin C not only depend on intake but on other factors including differences in
relative partitioning between plasma and intracellular concentration as well as differences in
excretion and oxidation rates [6]. From our point of view it is of upmost importance that
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Journal of Evolution and Health, Vol. 1 [2013], Iss. 1, Art. 13
http://jevohealth.com/journal/vol1/iss1/13
DOI: 10.15310/2334-3591.1030
dietary studies assessing vitamin C intake, either epidemiological or interventional studies,
limited the estimation of vitamin C to the plant sources while neglecting the animal sources of
it. The reason for selecting the conditions of common cold, cardiovascular disease and cancer
in the present manuscript lies in the fact that large studies of vitamin C (either prospective or
randomized controlled studies) are available for these conditions only. Out of the three
conditions, cancer will be in the focus, given the predominance of studies assessing cancer.
6.1. Prospective cohort and correlational studies: blood level of vitamin C and disease
For an overview of prospective cohort and correlational studies of blood level of vitamin C
and disease including mortality, cancer, cardiovascular disease, stroke and hypertension see
Table 1.
Table 1.
Major prospective cohort and correlational studies of vitamin C and disease
5
Clemens and Tóth: Vitamin C from the evolutionary perspective
Published by Journal of Evolution and Health, 2013
* number of patients in the gastric cancer group
Note that all studies indicate an inverse association between blood concentration of AA and
mortality/morbidity.
6.1.1. Mortality
In the EPIC-Norfolk prospective population study, plasma concentration of AA was inversely
related to mortality from all-causes as well as from cardiovascular disease and ischaemic heart
disease. Mortality risk in the top quintile was half the risk in the lowest quintile [39]. A study
based on an NHANES II. database found an inverse relation between dying from any cause
and low AA in men but there was no association in women [40]. In one study with elderly,
AA concentration was shown to be inversely associated with subsequent mortality in both
males and females [41] while in another study AA concentration was inversely associated
with mortality from stroke but not from coronary heart disease [42]. Male cardiovascular
mortality in the Basel Prospective Study was also inversely associated with plasma level of
vitamin C [43]. In hemodialysis patients, low level of vitamin C was shown to be a risk factor
for cardiovascular morbidity and mortality which was explained by vitamin C ameliorating
vascular dysfunction generally seen in patients with renal failure [44].
5.1.2. Cancer
In the EPIC-Norfolk study, vitamin C level was inversely related to cancer mortality in males
but not in females [40]. In an NHANES II. study, cancer risk was inversely related to AA in
males [45]. Unexpectedly, in females high level of AA was found to be associated with
increased cancer risk [45]. A case control study showed increased risk for gastric cancer for
those with low plasma level of vitamin C [46] but no association was found for dietary
vitamin C intake [46]. In hospice patients low plasma concentrations were associated with
shorter survival [47].
6.1.3. Cardiovascular disease
In an NHANES II. study, serum AA was inversely related with the prevelance of coronary
heart disease and stroke [48]. In several studies, including the Epic-Norfolk prospective
population study, low plasma concentration of vitamin C was associated with increased stroke
risk [49]. In cross-sectional studies, blood pressure in middle aged and elderly [50] as well as
in young adults [51] was found to be inversely associated with blood AA.
6.2. Intervention studies of vitamin C
6.2.1. Oral supplementation of vitamin C
For an overview of the oral vitamin C intervention studies related to mortality, common cold,
cardiovascular disease and high blood pressure see Table 2. Given the high number of
intervention studies with vitamin C available in the literature, in the present review we
concentrate on RCTs and metaanalyses.
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Table 2.
Major metaanalyses and RCTs of oral vitamin C supplementation related to mortality,
common cold, cardiovascular disease and hypertension. No study report a clinically
meaningful benefit.
CVD: cardiovascular disease; MD: missing data; SBP: systolic blood pressure
6.2.1.1. Mortality
A recent Cochrane review examining mortality as an endpoint found that supplementation of
antioxidants including vitamin C have no effect on overall mortality [52].
6.2.1.2. Common cold
The latest Cochrane review [53] concluded that vitamin C supplementation has no effect on
the incidence of common cold. However, a modest reduction of sympoms was consistently
found in the reviewed studies [53].
6.2.1.3. Cardiovascular disease
The Women's Antioxidant Cardiovascular Study, a randomized controlled study (RCT), found
no effect of vitamin C supplementation in the secondary prevention of cardiovascular disease
[54]. Another RCT, the Physicians' Health Study II., did neither find vitamin C to be
beneficial in the prevention of cardiovascular events [55]. In regards to high blood pressure, a
metaanalysis of twenty-nine trials of blood pressure indicated a statistically significant yet
clinically not meaningful decrease of 3.8 mmHg in systolic blood pressure [56].
6.2.1.4. Cancer
The idea that vitamin C may be beneficial in cancer treatment stems from Linus Pauling who
argued that high doses of vitamin C (10 g/day) given intravenously may be useful in the
treatment of cancer [57]. This assumption was based on a study of 100 patients with advanced
cancer who as compared to historical controls survived three to four times longer [57]. The
study was later criticized because of the absence of an appropriate control group. The study
was repeated with improved methodology and the authors still reported survival benefit in the
vitamin C group [58,59]. However, subsequent prospective controlled studies that were
carried out at the Mayo clinic were unable to repeat results. These studies, however, used oral
administration of vitamin C rather than intravenous administration [60,61]. Unlike the
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original study [57], Creagan et al. [60] included patients who previously received
chemotherapy while the study by Moertel et al. [61] included cancer patients with no prior
chemotherapy.
Prospective RCTs, like the Physicians’ Health Study II., did not find vitamin C
supplementation to be effective in the prevention of total cancers, prostate and in other solid
tumors [62]. No effect of vitamin C supplementation on cancer incidence and mortality was
seen in another randomized trial, the Women's Antioxidant Cardiovascular Study [63]. A
metaanalysis by Coulter et al. [64] also concluded that vitamin C provide no prevention of
cancer.
For an overview of the oral vitamin C intervention studies related to cancer see Table
3.
Table 3.
Cancer-related intervention studies of oral vitamin C.
a patients received IVC therapy for 10 days followed by oral vitamin C
b besides oral vitamin C some patients received IVC therapy too
c number of patients in the vitamin C group
* Number of patients treated with vitamin C
RCT: randomised controlled trial; NA: not applicable
6.2.2. High dose intravenous vitamin C (IVC) therapy in cancer
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Vitamin C is known to poorly absorb when administered orally at higher doses: immune cells
saturate at 100 mg daily, and renal excretion of AA increases above this dose [8]. Therefore, it
was claimed that blood concentrations of vitamin C in the Mayo Clinic studies [60,61] might
not have reached a concentration producing the cytotoxic effect to tumor cells seen in in vitro
studies [65]. With intravenous administration, the tightly regulated absorption and transport of
vitamin C is bypassed and therefore result in a much (30- to 70-fold) higher than
physiological blood level of vitamin C [66]. Cytotoxicity of AA to cancer cells was based on
in vitro studies which suggested that AA in concentrations higher than physiological in the
extracellular space act as a pro-oxidant and through the formation hydrogen peroxide kill
cancer cells [67]. However, in a recent study the cytotoxic effect was abolished at
physiological concentrations of iron which prevented the accumulation of hydrogen peroxide
[68]. It was suggested that previous studies disregarding in vivo concentration of iron had
significantly overestimated the anticancer effect of AA [68].
Currently, no more than a single RCT is available that assessed the effect of IVC
therapy in cancer patients [69]. This indicated a reduction of chemotherapy induced side
effects in ovarian cancer patients but no significant effect in terms of survival was found [69].
In an uncontrolled study of metastatic pancreatic cancer patients, Monti et al. [70] reported
minor decrease in the size of the tumor without evidence of prolonged survival. In another
study, of the 16 patients with solid tumors no one experienced an objective tumor response
[71]. In a study by Mikirova et al. [72], decreased level of inflammatory markers was seen
following IVC therapy but no positive effect was reported on disease progression and
survival. Clearly, no antitumor effect was evident in phase I. clinical trials studies including
studies by Welsh et al. [73] and Hoffer et al. [74]. Two other clinical group studies by
Riordan [75] and Yeom et al. [76] did neither provide evidence for an anticancer effect. A
more recent phase I-II. clinical study by Hoffer et al. [77] reported transient (lasting for 3-13
months) stable disease in 3 out of the 16 patients in the study. Actually all the existing group
studies have failed to provide evidence for a benefit in hard clinical endpoints such as
survival. At the same time, it is important to mention that except for the seminal study of
Cameron and Pauling [57] all the above IVC studies included patients with prior or
concurrent chemotherapy. Thus the possibility suggested by Creagan et al. [60] that cancer
patients with no chemotherapy may benefit more from IVC therapy cannot be entirely
excluded.
Currently only case reports are available describing survival benefit following IVC
therapy [78,17]. Overall, from the available group studies it only seems that high dose IVC
therapy is relatively safe, reduces chemotherapy induced side effects but provide no benefit in
terms of hard clinical endpoints including survival in cancer patients also receiving
chemotherapy.
For an overview of the IVC studies related to cancer see Table 4.
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Table 4.
IVC therapy studies in cancer. Except for a small RCT (Ma et al. 2014) all studies contain
only a single group. Each study included patients with prior or concurrent chemotherapy. No
study reported an apparent benefit in terms of survival.
ICV: intravenous vitamin C; RCT: randomized controlled trial
6.3. Summary of the prospective cohort and intervention studies of vitamin C
Prospective cohort studies unequivocally found an inverse relation with the blood level of
vitamin C for mortality, cancer and cardiovascular disease for each of the specific disease
populations. Two prospective studies [40,45] when assessing males and females separately,
reported the inverse association in males only. We assume that the absence of an inverse
association in females may be due to differential habits of males and females in taking
supplements. Although in the two studies it was not possible to retrieve data on supplement
use, females are known to be more prone to take vitamin C supplements [20], and thus a
higher serum level of AA in females may reflect the effect of supplementation which may not
be preventive. Overall results from prospective studies are in sharp contrast with the
intervention studies where none of the studies reported a clinically meaningful benefit as
regards mortality, incidence of common cold, cardiovascular events, and prevention or
treatment of cancer.
7. The glucose-ascorbate antogonism theory
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The glucose-ascorbate antagonism (GAA) theory was first proposed by John Ely as early as
the 1970s [3]. The theory postulates that given the structural similarity between glucose and
vitamin C, the two molecules compete for same transport system to enter cells [10]. It has
been shown that cellular uptake of both AA and DHAA may be competitively antagonized by
elevated glucose levels. Specifically, AA uptake by the small intestine enterocytes was shown
to be inhibited by elevated glucose concentration [9]. DHAA transport into cells was shown
to be impaired by high blood glucose concentration in most cell types including adipocytes,
erythrocytes, granulosa cells, neutrophils, osteoblasts and smooth muscle cells [10].
A potential limitation of the GAA theory pertains to the lack of in vivo studies in
animals and in humans. Diabetes, however, can be regarded as a natural model to study
interaction between blood glucose and vitamin C in vivo in humans. Studies with diabetic
patients are in line with the GAA therory. Two studies in type 2 diabetes [79,80] indicated
that in spite of similar dietary intake of vitamin C, patients have decreased levels of plasma
AA as compared to normal controls. Furthermore, serum level of AA inversely correlated
with glucose levels [80] and in another study with glycated hemoglobin of diabetic patients
[81]. Diabetes is also known to be associated with impaired renal reabsorption of AA [82]
which likely contributes to the low level of AA in patients.
Uptake of glucose and DHAA also share the feature of insulin-dependency on the
GLUT4 glucose transporter primarily found in muscle and adipose tissue [83]. In type 1
diabetes, deficiency of insulin has been shown to impair DHAA uptake of lymphoblasts [84].
Such a decreased DHAA uptake, through impaired AA accumulation, may lead to
compromized immune system function in type 1 diabetes patients [84]. The effect of glucose
seems to be immediate on intracellular AA given that intravenous glucose administration
results in a prompt decrease in the AA concentration of leukocytes [85]. Also consistently
with the GAA theory, blood level of vitamin C is inversely related with obesity [86] a
correlate of increased carbohydrate intake.
Controlling hyperglycemia has also been suggested as an adjunct to cancer therapy
[87]. Hyperglycemia in cancer patients is known to be associated with reduced intracellular
AA concentration. Such a decrease results in impaired actions of AA, including a decreased
activity of the hexose monophosphate shunt, a patway important in optimal immune cell
functioning [87]. In cardiovascular disease, the association of high blood glucose and low AA
concentration is also consistent with the GAA mechanism, and may plausibly explain
functional impairments such as lipid peroxidation and endothelial dysfunction which are
known to contribute to the generation of atherosclerosis [87].
As an additional parallelism, the study by Johnstone et al. [88] compared the effect of
two high protein diets: one with low (in fact ketogenic) and another with medium
carbohydrate content. To the surprise of the investigators, higher concentration of blood
vitamin C was found on the low carbohydrate diet. Yet, the difference was explained by other
factors.
AA is known to have a role in scavenging reactive oxygen species within the
mitochondria. Reactive oxygen species within the mitochondria have been suggested to have
a role in the development of degenerative disorders including cancer [89]. Given the fact that
carbohydrate based Western type nutrition is associated with increased production of reactive
oxygen species in the mitochondria [89], it is plausible to speculate that the need for AA
would be decreased when on a low carbohydrate diet.
In human brush border membrane vesicles evaluated ex vivo, AA uptake is
competitively antagonized by glucose [9] coming abundantly from carbohydrate based diets
may explain why according to a metaanalysis dietary intake and plasma level of AA were
only moderately correlated [38]. Importantly, estimation of AA intake in this study relied on
plant sources only. Negligation of animal sources of vitamin C is typical in the case of the
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other dietary studies too. This fact together with the loose association between the intake
estimate and blood level indicate that plants are not ideal sources of vitamin C. Additionally,
flavonoids abundantly found in fruits and vegetables were also shown to inhibit vitamin C
uptake by enterocytes [90]. We are not aware of studies assessing the relation between animal
sources of vitamin C and blood level of it. The striking dissociation between epidemiological
and intervention studies, as revealed in this review for mortality, cardiovascular disease and
cancer, may be regarded as an indication that vitamin C taken as a supplement may not be an
optimal way to obtain this nutrient.
Chronic diseases such as obesity, diabetes, neurodegenerative diseases, cancer and
cardiovascular diseases being associated by the cluster of carbohydrate overconsumption [91],
mitochondrial dysfunction [92], increased production of reactive oxygen species [92] and
decreased blood level of vitamin C also point to the GAA as a common mechanism beyond
these pathologic conditions. It can be speculated that increased dietary intake of carbohydrates
and resulting low level of blood AA are important factors contributing to the development of
chronic degenerative disorders.
As a further parallelism, the hypothesis proposed in the present paper also fits well
with the Warburg theory postulating that cancer is originating from a metabolic dysfunction
including insufficient mitochondrial oxidative phosphorylation and compensatorily enhanced
glycolysis [93]. Cancer cells are highly dependent on glucose and are unable to use fat or
ketones for energy [94], a metabolic failure ketogenic diets are aimed to exploit. We suggest
that an animal based, low carbohydrate high fat diet (instead of the currently used ketogenic
diets) may provide vitamin C not only in sufficient amounts but also in a bioavailable form,
and thus may be more appropriate for the treatment of cancer as compared with the versions
of the classical ketogenic diets that are currently used in clinical trials e.g. [95].
8. Conclusion
From the prospective cohort and correlational studies it is clear that higher blood level of AA
is associated with lower mortality and morbidity in several chronic conditions. At the same
time, high-grade evidence from clinical intervention studies indicate that vitamin C taken as a
supplement provide little or no benefit in the prevention or treatment of chronic diseases.
Indeed, apart from intervention studies of common cold where minor benefit was reported, no
single RCT is available that found a clinically meaningful benefit in hard clinical endpoints of
chronic diseases including cancer and cardiovascular diseases. We put forward that the
discrepancy between correlational and interventional studies, as regards the role of vitamin C,
is only apparent and may be resolved by introducing the GAA theory. As detailed above,
metabolism of vitamin C, including absorption and its uptake by several cell types, is
inhibited by increasing glucose concentration. Western type diets resulting in carbohydrate
overconsumption and high blood level of glucose may inhibit utilization of vitamin C also
when taken as a supplement. Current dietary guidelines, instead of animal sources,
concentrate on plant sources of vitamin C, thereby also increasing carbohydrate load and
intake of polyphenols which both inhibit vitamin C utilization. By contrast, studies of
contemporary hunter-gatherer societies as well as documentations of the arctic people from
the 18th and 19th century indicate no signs of scurvy despite subsisting on diets predominated
by foods of animal origin and using no vitamin supplements. Our own clinical experience
with the paleolithic ketogenic diet also shows improving health parameters and long-term
sustainability of meat-fat based diet in the absence of vitamin C supplementation. It may be
anticipated that supplementing vitamin C while on a Western type diet may not reproduce the
biochemical and physiological complexity of the evolutionary adapted way to utilize vitamin
C. Even though the amount of dietary vitamin C consumed on an animal meat-fat based diet
may be lower as compared to dietary intake from some fruits and vegetables, the former may
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ensure a higher bioavailability of vitamin C. We believe that loss of vitamin C synthesis was
not deleterious in the ancestral environment humans are evolutionary adapted to. Rather, a
mismatch between our current diet and ancestral physiology may explain why deficient levels
of vitamin C are associated with disease. Instead of supplementing vitamin C, changing our
nutrition as a whole and adopting a meat-fat based diet, even if it may sound a radical
solution, may be a better choice to support vitamin C homeostasis. Bearing in mind that
nothing in biology makes sense except in the light of evolution” [96] this concept is in
accordance with the major organizing principle of the living world: evolution.
Conflict of interest
The authors declare that there are no conflicts of interest.
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... Vitamin C is also associated in reduction of a number of diseases, being a good anti-oxidant it reduces the cancer incidence. [24] Ascorbic acid or Vitamin C also helps in maintenance and development of connective tissues, healing of wounds, healthy gums maintenance, and also in formation of bones. Ascorbic acid also helps in metabolic activities like Vitamin B activation, cholesterol conversation to the bile acids, folic acid, amino acid conversion, serotonin, neurotransmitter, and tryptophan. ...
... [34] Vitamin C in banana, being a good anti-oxidant, reduces the cancer incidence. [24] Role in enzymatic activities ...
Article
Products from natural sources are being used from thousands of years. Banana is famous for its traditional, medicinal, and nutritional uses. It is rich in carbohydrates (22.84 g/100 g), provides energy about 370 kJ/100 g and it is considered to be one of the best sources of potassium (358 mg/100 g) that fulfils 8% of the daily recommended value. Along with the unique nutritional profile, banana possesses excellent medicinal properties. Banana is one of those fruits whose all parts could be processed, including its flesh and peel like banana chips, banana powder, banana biscuits, and most commonly banana juice.
... The 275 reason for this is unknown, but it may be due to vitamin C's interaction with glucose. Glucose 276 appears to compete with the oxidized form of vitamin C for entry into cells and mitochondria 277 (116)(117)(118)(119) . Once inside the cell, glutathione, which is increased during a LCKD, appears to recover 278 the function of vitamin C (120-122) . ...
... Once inside the cell, glutathione, which is increased during a LCKD, appears to recover 278 the function of vitamin C (120-122) . Vitamin C is also found in meat, so it may be possible that the requirement is simply sufficiently met (116) . However, there is a case report of a child developing 280 scurvy while on a classical ketogenic diet for epilepsy, indicating a potential for deficiency when 281 combined with epileptic medications or proprietary ketogenic formulas (123) . ...
Article
Full-text available
The purpose of this review is to describe how human physiology at very low carbohydrate intakes relates to the criteria for nutritional essentiality. Although we did not limit ourselves to one particular type or function of carbohydrates, we did primarily focus on glucose utilization as that function was used to determine the Recommended Daily Allowance. In the general population, the human body is able to endogenously synthesize carbohydrates, and does not show signs of deficiency in the absence of dietary carbohydrates. However, in certain genetic defects, such as glycogen storage disease type I, absence of dietary carbohydrates causes abnormalities that are resolved with dietary supplementation of carbohydrates. Therefore, dietary carbohydrates may be defined as conditionally essential nutrients because they are nutrients that are not required in the diet for the general population but are required for specific subpopulations. Ketosis may be considered a physiological normal state due to its occurrence in infants in addition to at very low carbohydrate intakes. Although sources of dietary carbohydrates can provide beneficial micronutrients, no signs of micronutrient deficiencies have been reported in clinical trials of low carbohydrate ketogenic diets. Nonetheless, more research is needed on how micronutrient requirements can change depending on the dietary and metabolic context. More research is also needed on the role of dietary fiber during a low carbohydrate ketogenic diet as the beneficial effects of dietary fiber were determined on a standard diet and several studies have shown beneficial effects of decreasing non-digestible carbohydrates.
... Vitamin C is non-enzymatic antioxidant and is a class of essential nutrient vitamins that is essentially required for many biochemical and physiological functions in humans body and animals including immune functions, as a cofactor, as a reducing agent, the synthesis of collagen, L-carnitine, and sparing action of other vitamins (like vitamin E, A) from oxidation (Clemens and Tóth, 2013, Grosso et al., 2013, Omidi et al., 2015, and Pacier and Martirosyan, 2015. There are several studies showed that vit. ...
Article
Full-text available
Thyroid hormones are the body’s primary regular of normal development of organs. High and low levels of Thyroid hormones alter the balance of metabolism of oxygen in human cells and stimulate the over production of free radicals which associated with many biochemical abnormalities. The study conducted on (40) newly diagnosed hypothyroidism females (Group 1), (40) treated hypothyroidism with L-Thyroxin for more than six months (Group 2), (40) newly diagnosed hyperthyroidism females (Group 3), and (40) treated hyperthyroidism with carbamizole for more than six months (Group 4). The patient’s biochemical parameters were compared with that for (40) apparently healthy control. Fasting blood samples were taken from all participant and analyzed for peroxynitrite, ceruloplasimin (CP), vitamins C (vit. C), Albumin (Alb), and glutathione (GSH). The levels of peroxynitrite increased significantly in all patients, pre and post treatment compared to healthy control. Ceruloplasimin, in all patients, pre and post treatment, showed no significant differences from that of control group. Albumin was found to be compatible with control group apart from untreated hypothyroidism (Group 1) who showed significantly lower value. The level of vitamin C showed significantly low levels pretreatment for both patient groups. The level showed no significant differences from control after treatment, while, serum Glutathione concentration showed a significant decrease in all groups in comparison with the control.
... The available data also confirm the hypothesis that KDs are generally safe for cancer patients. In fact, nutritional ketosis is a physiological condition that probably was highly prevalent during human evolution [115,116], providing little a priori reason to believe that nutritional ketosis per se is unsafe or even dangerous. Again, a fundamentalist skeptic would reject the prior assumption of the safety of a diet appearing extreme compared to dietary guidelines and could point to putative side effects that have been mostly observed in the pediatric population treated with very strict and partially outdated forms of KDs [117]. ...
Preprint
Full-text available
Background Ketogenic diets (KDs) have gained popularity among patients and researchers alike due to their putative anti-tumor mechanisms. However, the question remains which conclusions can be drawn from the available human data thus far concerning the safety and efficacy of KDs for cancer patients. Methods A realist review utilizing a matrix-analytical approach was conducted according the RAMEsEs publication standards. All available human studies were systematically analyzed and supplemented with results from animal studies. Evidence and confirmation were treated as separate concepts. Results 29 animal and 24 human studies were included in the analysis. The majority of animal studies (72%) yielded evidence for an anti-tumor effect of KDs. Evidential support for such effects in humans was weak and limited to individual cases, but a probabilistic argument shows that the available data strengthen the belief in the anti-tumor effect hypothesis at least for some individuals. Evidence for pro-tumor effects was lacking completely. Conclusions Feasibility of KDs for cancer patients has been shown in various contexts. The probability of achieving an anti-tumor effect seems greater than that of causing serious side effects when offering KDs to cancer patients. Future controlled trials would provide stronger evidence for or against the anti-tumor effect hypothesis.
... We are embarrassed because we need to refer to our own study on vitamin C again, which, apparently, slipped your attention (Clemens and Tóth, 2016). Vitamin C is another good example of how the role of nutrients cannot be interpreted without the food environment as a whole. ...
Data
Full-text available
One should only grab a pen or, in this case, a keyboard and write an open letter if they want to make a clear and meaningful point. Competence in the subject is an advantage. We hope we meet both criteria. First of all, please let us express our appreciation for your work in the field of human nutrition science. We particularly appreciate your work as we have learned a lot from you. We are convinced that the changes your work has triggered will result in a considerable shift in nutrition science and help return to a reasonable and healthy diet which conforms to human evolution, or at least it will help with its scientific and exact description. As you suggest, there must be a single, optimal diet for all Homo Sapiens: an authentic Paleolithic Diet. We are writing this open letter because we want to respond to the recent criticism you expressed regarding Ketogenic Diets. We chose to publish an open letter, because thus we can inform laypeople about a professional debate which may be of public interest. You are a distinguished professional in the field of nutrition science and recently have expressed opinions on Ketogenic Diets, which have reached a wide range of people.
... So, their food supplement should contain necessary amount of vitamin C for maintenance of good health. Due to the shortage of vitamin C not only scurvy, but also symptoms including malaise, gum disease, poor wound healing, and shortness of breath and bone pain [22] are cause to happen in people of different age groups. Recommended Dietary Allowances (RDA) of vitamin C, as suggested by the Institute of Medicine, is 90 mg for males and 75 for females [23]. ...
Article
Full-text available
As part of shelf life analysis of vitamin C enriched amla candy, which was prepared form fruits Phyllanthus emblica, the present work was under taken to analysis the proximate microbial load, protein, iron and some other heavy metal content of the product over a six months period. The candy was prepared by applying osmotic dehydration method. Iron was observed 0.34 mg/100g; heavy metals like Hg, As, Pb, and Cd were below the limit of detection at AAS. The candy and raw amla were found to contain protein 4.29%& 4.53%; ascorbic acid (550.20-535.83) mg/100g & (593.22-553.74) mg/100g respectively. From the microbial point of view, screening results of microbial load test confirmed the safety of prepared amla candy over six months period. The present study results revealed that the prepared amla candy is a good source of vitamin (Ascorbic Acid) and mineral (Fe) having shelf life over six months.
... So, their food supplement should contain necessary amount of vitamin C for maintenance of good health. Due to the shortage of vitamin C not only scurvy, but also symptoms including malaise, gum disease, poor wound healing, and shortness of breath and bone pain [22] are cause to happen in people of different age groups. Recommended Dietary Allowances (RDA) of vitamin C, as suggested by the Institute of Medicine, is 90 mg for males and 75 for females [23]. ...
Article
Full-text available
As part of shelf life analysis of vitamin C enriched amla candy, which was prepared form fruits Phyllanthus emblica, the present work was under taken to analysis the proximate microbial load, protein, iron and some other heavy metal content of the product over a six months period. The candy was prepared by applying osmotic dehydration method. Iron was observed 0.34 mg/100g; heavy metals like Hg, As, Pb, and Cd were below the limit of detection at AAS. The candy and raw amla were found to contain protein 4.29%& 4.53%; ascorbic acid (550.20-535.83) mg/100g & (593.22-553.74) mg/100g respectively. From the microbial point of view, screening results of microbial load test confirmed the safety of prepared amla candy over six months period. The present study results revealed that the prepared amla candy is a good source of vitamin (Ascorbic Acid) and mineral (Fe) having shelf life over six months.
... We believe that the paleolithic ketogenic diet by excluding "non-paleolithic" food components normalizes the pathological permeability of the intestines as also seen in a published case of Crohn's disease [22], and likely through the normalization of intestinal permeability results in lowering inflammatory factors (as also showed in our previous case reports). In addition, ketosis, based on animal meat and fat may ensure optimal supply and bioavailability of vitamins, including vitamin C [33] the high blood level of which is important for the proper functioning of the immune system and also convey antitumor effects [34]. ...
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... The higher blood level of Vitamin C is associated with lower mortality and morbidity in several chronic conditions [23]. Metabolism of vitamin C, including absorption and its uptake by several cell types, is inhibited by increasing glucose concentration. ...
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We recently reported that Metadichol ® [1] brings about a three to four-fold increase in Vitamin C levels in patients without the use of Vitamin C supplementation. In this study of 6 patients who experienced a 5-12 fold increase in plasma Vitamin C levels higher than 80-100 u mol/L level which is the highest reported to date by oral supplementation at high doses of Vitamin C. Metadichol improved in these patients TSH levels, normalized High Blood pressure, fasting glucose levels, reduced eosinophil count, high triglycerides, body fat reduction and increased bone mass, normalized sodium levels, reducing high insulin levels, increased creatinine output in urine and also reducing of Red Cell Distribution width %. Metadichol thus serves as a surrogate for Vitamin C at doses of 5 mg per day as opposed to mega doses that are currently used.
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This paper explores the role of vitamin C (ascorbic acid) in the foodways of hunter-gatherers—both ethnohistoric and Paleolithic—whose diet seasonally or over much of the year, of necessity, was comprised largely of animal foods. In order to stave off scurvy, such foragers had to obtain a minimum of about 10 mg per day of vitamin C. However, there is little to no vitamin C in muscle meat, being concentrated instead in various internal organs and brain. Even ruminant stomach contents, despite the abundance of partially digested plants, contains almost none. Moreover, many of the “meatiest” anatomical units in a carcass, such as the thigh muscles or “hams” associated with the femur, are extremely lean in most wild ungulates, making them nutritionally much less valuable to northern foragers than archaeologists commonly assume (for example, Inuit and other indigenous peoples of the arctic and subarctic commonly use the thigh meat as dog food). Vitamin C is also the most unstable vitamin, rapidly degrading or disappearing when exposed to water, air, light, heat, and pH levels above about 4.0. As a consequence, common methods of preparing meat for storage and consumption (e.g., drying, roasting, boiling) may lead to significant loss of vitamin C. There are two effective methods of minimizing such loss: (1) eating meat raw (fresh or frozen); and (2) eating the meat after it has been putrefied. Putrefaction has distinct advantages that make it a common, if not essential, way of preparing and preserving meat among northern latitude foragers and, for the same reasons, very likely also among Paleolithic foragers in the colder climes of Pleistocene Eurasia. Putrefaction “pre-digests” the meat (including the organs), making it much less costly to ingest and metabolize than raw meat; and it lowers the pH, greatly increasing the stability of vitamin C. These observations offer insights into critical nutritional constraints that likely had to be addressed by Neanderthals and later hominins in any context where their diet was heavily meat-based for a substantial part of the year.
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Purpose: Although the classical ketogenic diet is an effective treatment in childhood epilepsy, it is difficult to maintain on the long term due to side-effects and dislike. Methods: Here we report a case of a child with frequent epileptiform discharges confined to non-rapid-eye-movement (NREM) sleep and extensive cortical malformation. The child was started on a modified version of the classical ketogenic diet we refer to as the paleolithic ketogenic diet. Results: Subsequent follow-up electroencephalograms showed complete normalization of brain electric activity along with cognitive improvement. Neither antiepileptic medication nor vitamin supplements were used. The child strongly adhered to the diet as assessed by regular urinary ketone tests and laboratory work ups. Currently she is on the diet for 17 months. Neither side effects nor clinical signs of nutrient deficiency were observed. Conclusion: We conclude that the paleolithic ketogenic diet was effective, safe and feasible in this case.
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Gilbert’s syndrome (GS) is a common hyperbilirubinaemia syndrome caused by reduced conjugation of serum bilirubin by the liver. Although it is considered as a common and harmless condition not requiring treatment symptoms associated with GS may be unfavorable. Here we present a case of GS where high level of total and direct bilirubin, yellowish discoloration of the sclera as well as associated symptoms including migraine, fatigue and granulomatosus dermatitis were reversed following a shift toward the popular paleolithic and then toward the paleolithic ketogenic diet.
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Authors' conclusions The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them. Further therapeutic RCTs are warranted. AVAILABLE AT: http://www.mv.helsinki.fi/home/hemila/CC/CC.htm
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Introduction: Metabolic syndrome is a major public health problem affecting at least 20% of the world’s adult population. Components of the metabolic syndrome include obesity, impaired glucose metabolism, hypertension and altered lipid profile. Currently, medical treatment relies on drugs. A major problem is that patients with long-standing disease are excessively medicated because of an increase in the number of symptoms over time. A few clinical studies indicate that low-carbohydrate diets, including the paleolithic as well as the ketogenic diet, may be beneficial in the treatment of conditions associated with the metabolic syndrome. Case Report: Herein, we present a case of patient with metabolic syndrome successfully treated with the paleolithic ketogenic diet. While on the diet the patient was able to discontinue eight medicines, lost weight, showed a continuous improvement in glucose parameters and her blood pressure normalized. Currently, the patient is on the paleolithic ketogenic diet for 22 months, free of symptoms and side effects. Conclusion: We conclude that the paleolithic ketogenic diet was safe, feasible and effective in the treatment of this patient with metabolic syndrome.
Chapter
Ascorbic acid (vitamin C) is classified as a water-soluble vitamin. It is a powerful reducing agent and is sensitive to transition metals, light, oxygen, and heat. As a strong antioxidant, ascorbic acid is used as a preservative in the food industry. Humans depend on ascorbic acid for many physiological and biochemical functions such as collagen, carnitine, and neurotransmitter biosynthesis, which is crucial to the maintenance of bones, teeth, and blood vessels. A deficiency in ascorbic acid can lead to scurvy. Unlike most plants, animals, and single-cell organisms, humans cannot synthesize their own supply of ascorbic acid due to lack of the enzyme responsible for the final step in its conversion - gulonolactone oxidase. It must be obtained from dietary sources including fruits, vegetables and supplements. Good dietary sources of vitamin C include citrus fruits, green vegetables, bell peppers, papaya, and tomatoes. However, vitamin C level is reduced in storage and processing. Generally, the US recommended dietary allowance (RDA) for ascorbic acid is from 100 - 120 mg/per day for adults. Ascorbic acid is an antioxidant that can help neutralize free radicals. Many health benefits have been attributed to ascorbic acid such as protection from viral infections, anti-atherogenesis, anti-carcinogenesis, and immune-modulation. A new study indicates that it has a complex protective role against toxic compounds formed from oxidized lipids, preventing genetic damage and inflammation. The amount of ascorbic acid to cause overdose symptoms in humans varies among individuals, and overdose is generally characterized by diarrhea and possibly indigestion. Ascorbic acid has been implicated with increasing the susceptibility to Vitamin B12 deficiency, and also has shown to be contraindicative in cancer chemotherapy. High doses of ascorbic acid may have prooxidant effects and have also been implicated in the development of kidney stones. In vitro and animal studies have shown that fruit and vegetable components, such as flavonoids and other matrix compounds, might reduce ascorbic acid intestinal uptake. The role of ascorbic acid in human biology and health is still controversial. The health benefits of ascorbic acid have been the subject of much debate. More mechanisms of action and human in vivo studies are needed to understand and elucidate the molecular mechanisms of ascorbic acid in health functions. The purpose of this chapter is to review the health benefits and adverse effects of ascorbic acid based on a review of the literature.
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The biomedical significance of human vitamin C (VC) metabolism is reviewed in the light of polymorphisms in xenobiotic enzymes deduced from genetic, biochemical, and epidemiological results to estimate optimal nutrition. VC comprises both ascorbic acid (AsA) and dehydroascorbic acid (DAsA). AsA is oxidized to DAsA via short-lived monodehydroascorbate radicals in a series of xenobiotic reactions and by reactive oxygen species (ROS). DAsA is reversibly reduced by glutaredoxin, but is also irreversibly hydrolyzed into 2,3-diketo-L-gulonate by dehydroascorbatase [EC 3.1.1.17] and non-enzymatic reactions. VC is a cofactor in reactions catalyzed by Cu+-dependent monooxygenases [EC 1.13.12.-] and Fe2+-dependent dioxygenases [EC 1.13.11.-]. VC plays a protective role against oxidative stress by ROS and xenobiotics, via monodehydroascorbate radicals. The Vitamin Society of Japan has re-evaluated old data because of the development of life science. The recommended dietary allowance (RDA) of VC is 100 mg/day for adults in Japan to prevent scurvy. RDA is defined as EAR+2SD, i.e. estimated average requirement (EAR) and the standard deviation (SD) obtained by short-term depletion-repletion studies. However, based on VC synthetic rates in rat, Pauling proposed that the optimum intake is 2.3 g/day. This is the problem of RDA vs. optimal nutrition. Optimal nutrition is wider in scope than RDA that covers genetic polymorphisms, long-term health outcome during the lifespan, and xenobiotics. Humans (VC auxotrophs) have relatively low plasma AsA levels and high serum uric acid levels compared to most VC-synthesizing mammals (VC autotrophs) due to gene defects in L-gulonolactone oxidase (GLO [EC 1.1.3.8]) and uricase (urate oxidase) [EC 1.7.3.3], respectively. Extrapolation of metabolic data of VC autotrophs to estimate human optimal nutrition is limited because of the compensatory mechanism for the GLO defect in VC auxotrophs, including DAsA transport by GLUT1, and specific mutations in uricase and dehydroascorbatase. Beneficial effects of long-term VC supplementation remain controversial, perhaps because of 1. genetic heterogeneity in study populations, and 2. the balance of antioxidant and pro-oxidant activities of VC depending on the xenobiotic conditions. Thus, in addition to the biochemical studies on AsA and DAsA, human genetic analysis on VC-loading experiments and epidemiological survey are needed. There are marked interindividual differences (coefficient of variation >45%) in the metabolism of VC. This difference is evident during oral loading with 1 mmol AsA or DAsA in subjects consuming a diet low in VC (less than 5 mg/day) for 3 days before loading in the cross-over experiment. Since tubular maximum reabsorption of AsA (TmAsA) and glomerular filtration rate (GFR) are similar among subjects, degradation steps of VC may be involved in the personal difference. The metabolisms of three most important water-soluble antioxidants in mammals i.e. VC, urate and glutathione are different in humans and other animals. The effects of polymorphism A313G (Ile105Val) in the gene for glutathione S-transferase P1 (GSTP1) [EC 2.5.1.18], one of the most active xenobiotic enzymes in the second phase of detoxification, on human VC metabolism were thus studied. In an epidemiologic survey of Mongolians (n = 164) with very low VC intake, serum VC concentration was only 28%, and the level of reactive oxygen metabolites was 128%, when compared with those in Japanese. The variant frequency of GSTP1 among Japanese subjects (n = 210) was AA, 71.0%; GA, 27.0% and GG, 1.9%. In Mongolian subjects (n = 93), it was AA, 62.4%; GA, 36.6%; and GG, 1.1%.In VC loading experiments, at 24 h after administration of 1 mmol of VC to young women (n = 17; age, 21.0 ± 1.1 y, glomerular filtration rate, GFR = 90 ml/min), total VC excretion (46.7 ± 18.1 mg) by AA homozygotes of GSTP1 was greater (p < 0.0069) than that (28.2 ± 14.0 mg) by GA heterozygotes. One hour after administration of VC, blood total VC levels were also significantly different (p < 0.0036) between the homozygotes and heterozygotes. The results of background experiments were as follows: (1) the VC level in 24-h urine after VC loading did not differ between the two orally administered C forms (AsA and DAsA); (2) VC excretion between 0 and 3 h after VC loading was significantly higher (p < 0.05) for DAsA, while those between 3 and 6, 6 and 9, 9 and 12, and 12 and 24 h after VC loading were significantly higher (p < 0.05 or p < 0.01) for AsA; and (3) blood VC concentrations and the increase in VC at 1 h after VC loading were significantly higher (p < 0.05 and p < 0.01, respectively) in the DAsA group than in the AsA group. The difference between AsA and DAsA dynamics in (2) and (3) may be explained by the sodium-dependent active transport of AsA by SVCT1 and 2, and passive transport of DAsA by glucose transporters (GLUTs) in the presence of glutathione. The large species differences in DAsA metabolism are partly explained by the low activity of human dehydroascorbatase, which has a unique structure, as deduced by X-ray crystallography, and a unique sequence of 299 amino acids. The anti-oxidant and anti-xenobiotic roles of monodehydroascorbate radicals both in vivo and in vitro are important. ROS are generated mainly in mitochondria but DAsA transported through GLUT1 into mitochondria is converted into AsA and prevents oxidative stress. Finally RDA and optimal nutrition are discussed from the standpoint of human specific metabolism of VC including prevention against ROS produced by exercise and pathological conditions.
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Ascorbic acid (vitamin C) is classified as a water-soluble vitamin. It is a powerful reducing agent and is sensitive to transition metals, light, oxygen, and heat. As a strong antioxidant, ascorbic acid is used as a preservative in the food industry. Humans depend on ascorbic acid for many physiological and biochemical functions such as collagen, carnitine, and neurotransmitter biosynthesis, which is crucial to the maintenance of bones, teeth, and blood vessels. A deficiency in ascorbic acid can lead to scurvy. Unlike most plants, animals, and single-cell organisms, humans cannot synthesize their own supply of ascorbic acid due to lack of the enzyme responsible for the final step in its conversion - gulonolactone oxidase. It must be obtained from dietary sources including fruits, vegetables and supplements. Good dietary sources of vitamin C include citrus fruits, green vegetables, bell peppers, papaya, and tomatoes. However, vitamin C level is reduced in storage and processing. Generally, the US recommended dietary allowance (RDA) for ascorbic acid is from 100 - 120 mg/per day for adults. Ascorbic acid is an antioxidant that can help neutralize free radicals. Many health benefits have been attributed to ascorbic acid such as protection from viral infections, anti-atherogenesis, anti-carcinogenesis, and immune-modulation. A new study indicates that it has a complex protective role against toxic compounds formed from oxidized lipids, preventing genetic damage and inflammation. The amount of ascorbic acid to cause overdose symptoms in humans varies among individuals, and overdose is generally characterized by diarrhea and possibly indigestion. Ascorbic acid has been implicated with increasing the susceptibility to Vitamin B12 deficiency, and also has shown to be contraindicative in cancer chemotherapy. High doses of ascorbic acid may have prooxidant effects and have also been implicated in the development of kidney stones. In vitro and animal studies have shown that fruit and vegetable components, such as flavonoids and other matrix compounds, might reduce ascorbic acid intestinal uptake. The role of ascorbic acid in human biology and health is still controversial. The health benefits of ascorbic acid have been the subject of much debate. More mechanisms of action and human in vivo studies are needed to understand and elucidate the molecular mechanisms of ascorbic acid in health functions. The purpose of this chapter is to review the health benefits and adverse effects of ascorbic acid based on a review of the literature.
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During the spring and summer months the diet of three Inuit families living in a seal hunting camp south of Holman, N.W.T., was studied. A total of 13 food items including the most commonly eaten mammal, bird and plant species were analysed for Vitamin C in both the raw and cooked state. A daily intake of ascorbic acid of between 11 and 118 mg and a mean dose of at least 30 mg is indicated. This is well above the levels documented in larger transitional culture villages by a recent Nutrition Canada report. - Authors
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Food supplements, if not properly used, may lead to potentially harmful nutrient intake. The purpose of this survey was to examine vitamin intake from food supplements. Taking into account the intake from food, as obtained from the National Nutrition Survey, it was determined whether the tolerable upper intake levels (ULs) were exceeded via supplements alone, or in combination with food. Data from 1070 supplement users (18 - 93 years) was available. The dietary and supplemental vitamin intakes of three groups were analyzed: average intake (50th percentile food + 50th percentile supplements), middle-high intake (50th + 95th ) and high intake (95th + 95th ). Vitamin C (53 %), vitamin E (45 %) and B vitamins (37 - 45 %) were consumed most frequently. Few subjects (n = 7) reached or exceeded the ULs through supplements alone. The UL for vitamin A and folate was reached by a few men in the middlehigh group, and by a few men and women in the high intake group. Otherwise, even in the high intake group, the recommended vitamin D intake of 20 μg/day (in case of insufficient endogenous synthesis) could not be achieved. The use of food supplements was not associated with excessive vitamin intake in this survey, except in a small number of cases. Vitamin A intake above the UL was the result of high dietary intake which also included the intake of β-carotene, rather than the result of overconsumption of food supplements. Diets mainly included folate from natural sources, which has no associated risk.