British Journal of Nutrition
have been postulated for antioxidant administration both in
health and in disease
Reactive oxygen and nitrogen species (RONS) are well
recognised for playing a dual role, both unfavourable and beneficial,
to the cells
8. Overproduction of RONS results in oxidative
stress, a deleterious process that can be an important
mediator of damage to cell structures: lipid, proteins and
9. In contrast, there is evidence that moderate changes
in RONS concentrations in cells act as signals and may be
beneficial to the cells
4. Although supplementation with antioxidant
vitamins has shown positive anti-atherogenic, anti-carcinogenic
and immunomodulatory effects
10 – 12, the health
benefits of different antioxidants have been the subject of
debate and controversy lately
13.We consider that the contradictory
data can be explained by taking into account several
aspects: the type of antioxidant vitamins used as dietary supplements,
the doses, the antioxidant and the health status in the
supplemented individuals and the duration of the intervention
The antioxidant vitamins: dose is important for health
There are several enzyme systems within the body that effectively
scavenge free radicals (see below). In addition, the cell
has many low molecular weight antioxidants. Prominent
amongst these are the main antioxidant vitamins, C and
E. In large doses some vitamins show undesirable side effects
and these tend to increase in severity with increasing dosage.
The likelihood of consuming too much of any vitamin from
food is remote, but overdosing from vitamin supplementation
does occur. At high enough doses some vitamins cause side
effects, such as nausea, diarrhoea, or vomiting
12. When vitamin
side effects emerge, recovery is often achieved by reducing
the dosage. Furthermore, the concentrations of vitamins
that an individual can tolerate vary widely, and appear to be
related to age and state of health.
Several studies have pointed to an association between vitamin
C intake and chronic diseases. For instance, it was
reported that vitamin C supplementation lowered arterial
14. On the other hand, the role of vitamin C
in cancer prevention remains controversial in spite of a
number of studies that have been conducted over the last 30
years to clarify this point. Nobel laureate Pauling and his colleague
Cameron recommended the use of high doses of
ascorbic acid to cure and prevent the common cold infections
as well as to prevent the onset of cancer
15,16. In a 4-y prospective
study with 30,466 men and women, the risk of mortality
due to all causes for those in the highest quintile of plasma
ascorbate concentration was about one-half that of those in
the lowest quintile of plasma ascorbate concentration
results were also reported for men but not for women
Another study indicated that free-living elderly who consumed
citrus fruits twice a week had adjusted risks of dying that
were half those of elderly who consumed citrus fruit less
than once a week
19. Considerable biochemical and physiological
evidence suggests that ascorbic acid functions as a
free radical scavenger and inhibits the formation of
potentially carcinogenic N-nitroso compounds from nitrates,
including nitrites stomach and thus offers protection against
20,21. However, there are also studies that do
not show any positive effect after supplementation with
22,23. Clinical studies on cancer patients carried out
at the Mayo Clinic showed no significant differences between
vitamin C and placebo groups with particular regard to survival
24. Moreover Lee et al. reported that lipid hydroperoxides
can react with ascorbic acid to form products that could
potentially damage DNA, suggesting that genotoxic metabolites
from lipid hydroperoxides might be formed
25. In this
scenario, ascorbic acid could enhance mutagenesis and risk
of cancer. However the physiological relevance of these
results is yet to be established in
in vivo experiments12.
Finally, it has been reported that tumour cells contain large
amounts of ascorbic acid
26. It has been speculated that high
levels of ascorbic acid in cancer cells may interfere with chemotherapy
or radiation therapy since these therapies induce
cell death by oxidative mechanisms. Thus, ascorbic acid supplementation
might make cancer treatment less effective.
More studies are needed to understand the role of ascorbic
acid in tumour cells and the speculative contraindication of
ascorbic acid for cancer chemotherapy.
Another important aspect that should be taken into account
when supplementing with vitamin C is the possibility that it
acts as a pro-oxidant
in vivo. These pro-oxidative reactions
of vitamin C readily occur
in vitro and recently it has been
demonstrated that they can also have relevance in
27. A high intake of iron along with ascorbic
acid could increase
in vivo lipid peroxidation of LDL and
therefore could increase the risk of atherosclerosis
another study demonstrated that in iron overloaded
plasma, ascorbic acid acts as an antioxidant and prevents oxidative
damage to lipids
Clearly, the possible toxicity of large doses of vitamin C
requires more experimental and clinical studies.
Numerous epidemiological studies have shown that a high
intake of vitamin E is related to a lower risk of age-related
and chronic diseases. Experimental studies have suggested
substantial health benefits from vitamin E in disease prevention
a-tocopherol, the major form of vitamin E
in the human body, appears to have important health benefits;
these include protection against reproductive diseases (preeclampsia)
, age-related eye diseases (cataract, macular
31,32, metabolic disorders (diabetes mellitus)33
and neurodegenerative disorders (Alzheimer’s)
However recent data show unfavourable, rather than beneficial,
effects after supplementation with this antioxidant vitamin.
In 2003, a meta-analysis was performed to assess the
a-tocopherol and b-carotene, or both, on long-term
cardiovascular mortality and morbidity
34. No positive effect
of high doses of vitamins in different populations was
shown. Due to the lack of data for the efficacy of vitamin E,
the main conclusion derived from this study was that its supplementation
should be discontinued because of its risks.
The authors did not support the routine use of
previously shown especially in smokers
35. In other studies
200 IU per day of vitamin E did not have a significant effect
Up-regulation of antioxidant genes by nutrients S37
British Journal of Nutrition
on lowering the incidence of respiratory tract infections in
elderly nursing home residents
36 and 600 IU of the same vitamin,
taken every other day, provided no overall benefit for
major cardiovascular events or cancer in healthy women
Finally, a recent study associated
b-carotene, vitamin A, and
vitamin E supplementation with increased mortality
Thus, the overall conclusion that can be drawn from these
studies is that the general population should not be advised to
take supplements with vitamin E. This, however, does not
mean that vitamin E supplements should not be indicated in
cases of vitamin E deficiency, or prevention of deficiency.
As mentioned previously, Sano
et al. published a seminal
paper in which the efficacy of vitamin E in delaying the physical
deterioration associated with advanced forms of Alzheimer’s
disease was shown
7. Our research group reported that high
doses of vitamin C and E prevented muscle damage associated
with the intake of anti-retroviral drugs which are commonly
used to treat AIDS
11. There is also a report that supplementation
with vitamin E, but not other antioxidants, was effective in reducing
pulmonary viral titres and preventing an influenzamediated
decrease in food intake and weight loss in mice
The fact that other antioxidants were not effective led to the conclusion
that, in addition to its effect as an antioxidant, vitamin E
might be acting via other mechanisms which might not be related
to its antioxidant properties.
The concept of micronutrient malnutrition and deficiency
Micronutrient malnutrition is a term commonly used to refer
to vitamin and mineral nutritional deficiency diseases. Diets
which lack adequate amounts of essential vitamins and minerals
lead to such diseases. Vitamin A deficiency, iron
deficiency anaemia and iodine deficiency disorders are
among the most common forms of micronutrient malnutrition.
Other micronutrients found in food, including vitamins such as
thiamine, niacin, riboflavin, folate, vitamins C and D, and
minerals such as calcium, selenium and zinc can also significantly
affect health when dietary deficiencies exist. As stated,
these deficiencies cause diseases. Well-known human vitamin
deficiencies involve thiamine (beriberi), niacin (pellagra), vitamin
C (scurvy) and vitamin D (rickets). In much of the developed
world, such deficiencies are rare; this is due to (1) an
adequate supply of food; and (2) the addition of vitamins
and minerals, often called fortification, to common foods
Micronutrient deficiency is a term used to refer to the situation
where the levels of micronutrients are lower than
requirements, but are high enough to prevent the development
of diseases mentioned.
Ames stated, “our daily intake of the 40 essential micronutrients
is commonly thought to be adequate” but “the optimum
amount of vitamins, minerals, and essential biochemicals is
the amount that maximizes a healthy life span, and is likely
to be higher than the amount needed to prevent acute
Micronutrient deficiency diseases
Micronutrients participate in the body in almost all metabolic
and developmental processes
41. Inadequate intakes may result
in chronic metabolic disruption. Several micronutrient
deficiencies are associated with mitochondrial decay,
oxidant leakage and cellular aging
42, which can be responsible
for degenerative disease such as vascular dementia
damage (chromosome breaks) in cultured human cells or
44, or late onset diseases such as cancer.
It is crucial for the understanding of micronutrient deficiency
diseases to distinguish them from micronutrient malnutrition.
The former occurs when the micronutrient intake is lower than
the levels we need for metabolic processes, but are high
enough to prevent the development of the diseases that result
from the latter (e.g. rickets, scurvy, etc.).
Diseases related to micronutrient deficiency, such as degenerative
diseases or cancer, are caused mainly by the chronic
metabolic disruption which is translated into a mitochondrial
Simple preventive measures like increasing the uptake of
relatively low doses of multivitamin and multimineral supplements
may be instrumental in lowering the incidence of
age-associated degenerative diseases. These ideas are summarised
in the Fig. 1.
Increasing endogenous antioxidant defences versus
increasing the uptake of antioxidant vitamins
The cell possesses a number of extremely powerful mechanisms
to counteract the harmful effects of the inevitable free
radicals which are formed as a consequence of aerobic
metabolism. Of critical importance among these are the enzymatic
systems which catalytically detoxify free radicals and
other reactive oxygen species. For instance, the superoxide
dismutase – glutathione peroxidase system serves to detoxify
superoxide which is formed in the mitochondrial respiratory
chain and to convert it to water via the intermediary formation
of hydrogen peroxide. Other critically important
enzymes exist, for instance catalase which is present in peroxisomes
and which detoxifies hydrogen peroxide very effectively,
converting it to water. Moreover, the importance of
other enzyme systems, such as thioredoxin, glutaredoxin
or sestrins amongst other has been emphasised. From a
Summary of the effects of vitamin deficiencies and supplementation.
S38 Jose Vin˜a
British Journal of Nutrition
nutritional and physiological standpoint, it may be advisable
to increase the expression and activity of these antioxidant
enzyme systems as a way to improve the overall antioxidant
defence capacity of the cells. Thus, we, as well as other laboratories,
have searched for mechanisms which could
increase the activity of critical antioxidant enzymes. In
recent times, we have been considering the observation that
females in many species including humans, live longer than
45. We concluded that this is due to the beneficial
effect of oestradiol which is effective at up-regulating the
expression of the genes coding for antioxidant enzymes
such as glutathione peroxidase and superoxide dismutase
Obviously, oestrogens cannot be used as nutritional supplements
because they have many disadvantages, particularly
in males where they are powerfully feminising. Phytoestrogens,
on the other hand, lend themselves as possible candidates
for supplementation to increase the endogenous
antioxidant defences of cells, animals, and eventually
human beings. Phytoestrogens are not feminising (because
they bind quite specifically to oestrogen
b receptors and
the feminising effects are usually associated with the oestrogen
a activation)46. Moreover, no reports of the carcinogenic
effect of phytoestrogens have been published. They
also have a number of beneficial effects like increasing bone
density, lowering hot flushes associated with menopause and
even partially preventing the incidence of breast cancers
We have found that genistein has beneficial effects in that
it increases the expression and activity of longevity-associated
genes particularly superoxide dismutase and glutathione
peroxidase in a human cell line
48. Moreover, in in vivo experiments,
in which blood pressure was measured in rats using
telemetric methods, administration of phytoestrogens in the
form of a soya-enriched diet lowered blood pressure
found that this was due to the up-regulation of the expression
of genes such as the endothelial nitric oxide synthase. Therefore,
evidence is gathering that increasing the expression of
antioxidant and other longevity-related genes by the ingestion
(in the form of dietary modifications or of supplementation)
of phytoestrogens or by increased physical activity in the
form of leisurely sport activities that do not cause exhaustion,
increases the expression and activity of longevity-related
genes and may be the ideal ways of improving endogenous
antioxidant defences rather than trying to increase them by
supplementation with antioxidant vitamins.
Conflict of interest statement
The authors work was supported by grants SAF 2004-03 755
and BFU2007-65 803/BFI to J. V., GV06/289 to M. C. G-C
and by grant (ISCIII2006-RED13-027) from the “Red Tema´-
tica de investigacio´n cooperativa en envejecimiento y fragilidad
(RETICEF). Instituto de Salud Carlos III” The authors
have no conflict of interests to declare.
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