The classical role of vitamins in biology and medicine was essentially centred in the prevention of deficiencies. Historically vitamins were discovered as the means to prevent diseases, which were caused by the lack of such vitamins.
The modern concept of vitamins, which we discuss in this review article, and which basically deals with the idea that taking high doses of some vitamins may be good for health is due to the influential figure Linus PaulingReference Pauling1, Reference Pauling2. Before we go any further, it is important to state that no matter whether Pauling's ideas are correct or incorrect in view of modern evidence, his influence in this field has been enormous and beneficial. Of course, the progress of science deals with testing and sometimes eventually disproving old theories with new facts, which are on many occasions obtained by new methods. But this by no means detracts from the great effort of those who have advanced the scientific progress in this area, even if their ideas were partially wrong (as they always are in science). Linus Pauling, in his books “Vitamin C, the common cold and the flu”Reference Pauling1 and “How to live longer and feel better”Reference Pauling2, displayed a great enthusiasm for the intake of high doses of one vitamin, namely vitamin C. His ideas may be now outdated. Much recent evidence suggests that taking large doses of a single vitamin may not confer beneficial effects on health. Some reports even go as far as saying that they may be harmful. Later in this article, we will provide recent scientific evidence showing that large doses of one or other vitamin do not improve the health and well-being of individuals.
But there is another point that is worth mentioning: in modern societies, not only in the poorer countries, but also in the so-called First World, large parts of the population are under-nourished. Some people may be grossly overweight but their intake of vitamins and minerals may be only marginally adequate, or even clearly deficientReference Ames, Atamna and Killilea3. In fact, large parts of the populations, both in the United States and in Europe may be deficient in one or other micronutrientReference Ames, Atamna and Killilea3. Analytical examination of great numbers of individuals may not be economically feasible. This being the case Ames has suggested that it may be advisable to propose that large parts of the population take multivitamin complexes which are harmless, and which may cover hidden sub-clinical deficienciesReference Ames, Atamna and Killilea3. Such deficiencies may cause impairment in performance and increase the susceptibility to disease. Evidence for this will also be discussed in this review paper. Finally, we will provide data showing that boosting antioxidant defences by healthy practices such as moderate physical exercise or taking phytoestrogens may be perhaps the best way of improving antioxidant status.
Pros and cons of supplementation with high doses of vitamins
Many common human diseases, including atherosclerosis, cardiovascular disease, hypertension, cataracts, Alzheimer's, diabetes, cancer as well as physiological processes such as aging, have free radical reactions as an underlying mechanism of injuryReference Valko, Leibfritz, Moncol, Cronin, Mazur and Telser4Reference Pallardo, Asensi, Garcia de la Asuncion, Anton, Lloret, Sastre and Vina5. This is the reason why, for years, many benefits have been postulated for antioxidant administration both in health and in diseaseReference Taylor, Jacques, Chylack, Hankinson, Khu, Rogers, Friend, Tung, Wolfe, Padhye and Willett6, Reference Sano, Ernesto, Thomas, Klauber, Schafer, Grundman, Woodbury, Growdon, Cotman, Pfeiffer, Schneider and Thal7.
Reactive oxygen and nitrogen species (RONS) are well recognised for playing a dual role, both unfavourable and beneficial, to the cellsReference Gomez-Cabrera, Borras, Pallardo, Sastre, Ji and Vina8. Overproduction of RONS results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures: lipid, proteins and DNAReference Halliwell9. In contrast, there is evidence that moderate changes in RONS concentrations in cells act as signals and may be beneficial to the cellsReference Valko, Leibfritz, Moncol, Cronin, Mazur and Telser4. Although supplementation with antioxidant vitamins has shown positive anti-atherogenic, anti-carcinogenic and immunomodulatory effectsReference Han, Meydani, Wu, Bender, Smith, Vina, Cao, Prior and Meydani10–Reference Naidu12, the health benefits of different antioxidants have been the subject of debate and controversy latelyReference Bjelakovic, Nikolova, Gluud, Simonetti and Gluud13.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 programmes.
The antioxidant vitamins: dose is important for health effects
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 vomitingReference Naidu12. 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.
Vitamin C
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 blood pressureReference Block, Mangels, Norkus, Patterson, Levander and Taylor14. 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 cancerReference Cameron and Pauling15, Reference Cameron, Pauling and Leibovitz16. 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 concentrationReference Khaw, Bingham, Welch, Luben, Wareham, Oakes and Day17. Similar results were also reported for men but not for womenReference Loria, Klag, Caulfield and Whelton18. 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 weekReference Fortes, Forastiere, Farchi, Rapiti, Pastori and Perucci19. 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 stomach cancerReference Drake, Davies, Mapstone, Dixon, Schorah, White, Chalmers and Axon20, Reference Block21. However, there are also studies that do not show any positive effect after supplementation with vitamin CReference Jacobs, Connell, Patel, Chao, Rodriguez, Seymour, McCullough, Calle and Thun22, Reference Creagan, Moertel, O'Fallon, Schutt, O'Connell, Rubin and Frytak23. 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 timeReference Moertel, Fleming, Creagan, Rubin, O'Connell and Ames24. 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 formedReference Lee, Oe and Blair25. 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 experimentsReference Naidu12. Finally, it has been reported that tumour cells contain large amounts of ascorbic acidReference Agus, Vera and Golde26. 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 in vivo experimentsReference Childs, Jacobs, Kaminski, Halliwell and Leeuwenburgh27. A high intake of iron along with ascorbic acid could increase in vivo lipid peroxidation of LDL and therefore could increase the risk of atherosclerosisReference Berger, Polidori, Dabbagh, Evans, Halliwell, Morrow, Roberts and Frei28. However, another study demonstrated that in iron overloaded plasma, ascorbic acid acts as an antioxidant and prevents oxidative damage to lipids in vivo Reference Chen, Suh, Carr, Morrow, Zeind and Frei29.
Clearly, the possible toxicity of large doses of vitamin C requires more experimental and clinical studies.
Vitamin E
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 and therapy. α-tocopherol, the major form of vitamin E in the human body, appears to have important health benefits; these include protection against reproductive diseases (pre-eclampsia)Reference Chappell, Seed, Briley, Kelly, Lee, Hunt, Parmar, Bewley, Shennan, Steer and Poston30, age-related eye diseases (cataract, macular degeneration)Reference Mares-Perlman, Lyle, Klein, Fisher, Brady, VandenLangenberg, Trabulsi and Palta31, Reference Belda, Roma, Vilela, Puertas, Diaz-Llopis, Bosch-Morell and Romero32, metabolic disorders (diabetes mellitus)Reference Jain, McVie and Smith33 and neurodegenerative disorders (Alzheimer's)Reference Sano, Ernesto, Thomas, Klauber, Schafer, Grundman, Woodbury, Growdon, Cotman, Pfeiffer, Schneider and Thal7.
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 effect of α-tocopherol and β-carotene, or both, on long-term cardiovascular mortality and morbidityReference Vivekananthan, Penn, Sapp, Hsu and Topol34. 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 β-carotene, as previously shown especially in smokersReference Virtamo, Pietinen, Huttunen, Korhonen, Malila, Virtanen, Albanes, Taylor and Albert35. In other studies 200 IU per day of vitamin E did not have a significant effect on lowering the incidence of respiratory tract infections in elderly nursing home residentsReference Meydani, Leka, Fine, Dallal, Keusch, Singh and Hamer36 and 600 IU of the same vitamin, taken every other day, provided no overall benefit for major cardiovascular events or cancer in healthy womenReference Lee, Cook, Gaziano, Gordon, Ridker, Manson, Hennekens and Buring37. Finally, a recent study associated β-carotene, vitamin A, and vitamin E supplementation with increased mortalityReference Bjelakovic, Nikolova, Gluud, Simonetti and Gluud13.
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 shownReference Sano, Ernesto, Thomas, Klauber, Schafer, Grundman, Woodbury, Growdon, Cotman, Pfeiffer, Schneider and Thal7. 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 AIDSReference de la Asuncion, del Olmo, Sastre, Millan, Pellin, Pallardo and Vina11. There is also a report that supplementation with vitamin E, but not other antioxidants, was effective in reducing pulmonary viral titres and preventing an influenza-mediated decrease in food intake and weight loss in miceReference Han, Meydani, Wu, Bender, Smith, Vina, Cao, Prior and Meydani10. 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 foodsReference West and Hautvast38, 39.
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 deficiency disease”Reference Ames40.
Micronutrient deficiency diseases
Micronutrients participate in the body in almost all metabolic and developmental processesReference McCann and Ames41. Inadequate intakes may result in chronic metabolic disruption. Several micronutrient deficiencies are associated with mitochondrial decay, oxidant leakage and cellular agingReference Ames42, which can be responsible for degenerative disease such as vascular dementiaReference Meydani43, DNA damage (chromosome breaks) in cultured human cells or in vivo Reference Fenech and Ferguson44, 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 decay.
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.
Fig. 1 Summary of the effects of vitamin deficiencies and supplementation.
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 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 malesReference Borras, Sastre, Garcia-Sala, Lloret, Pallardo and Vina45. 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 dismutaseReference Borras, Sastre, Garcia-Sala, Lloret, Pallardo and Vina45. 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 β receptors and the feminising effects are usually associated with the oestrogen receptor α activation)Reference Barkhem, Carlsson, Nilsson, Enmark, Gustafsson and Nilsson46. 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 cancersReference Cassidy47. 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 lineReference Borras, Gambini, Gomez-Cabrera, Sastre, Pallardo, Mann and Vina48. 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 pressureReference Mahn, Borras, Knock, Taylor, Khan, Sugden, Poston, Ward, Sharpe, Vina, Aaronson and Mann49 We 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 Temática de investigación cooperativa en envejecimiento y fragilidad (RETICEF). Instituto de Salud Carlos III” The authors have no conflict of interests to declare.
