Recently three papers appeared in the medical literature (1,2,3) by Bruce Ames, a respected and very well known professor of biochemistry from the University of California at Berkeley and the Children's Hospital Oakland Research Institute, suggesting that low levels of micronutrients (vitamins and minerals in particular) at the cellular level may actively promote DNA and protein damage and cause disease to a larger extent than is generally realized. Thus certain micronutrients may play both a prophylactic and therapeutic role in a number of disorders related to damaged cellular components. The general term used to describe this phenomenon is genome instability. This view has also been actively promoted by Michael Fenech of the Australian CSIRO (4) and is backed, not only by extensive literature, but also by a recent paper (5) of unusual length (46 pages) in the American Journal of Clinical Nutrition where Ames and coworkers document the role of vitamins and minerals critical to enzyme reactions which at therapeutic doses could correct for reduced enzyme activity. Over 40 genetically related diseased states are discussed.

The multiplicity of critical functions of vitamins and minerals at the cellular level, and especially their role as companion molecules (cofactors) in enzyme reactions that protect genes from mutations and repair gene damage, is probably unrecognized or unappreciated by all but specialists in this field. The Metabolic Tune- Up suggested by Professor Ames makes a compelling case for vitamin/mineral supplements to avoid problems associated with micronutrient deficiency. Ames also promotes taking several antioxidants that do not appear to be in common use. The Metabolic Tune-Up relates to many health issues, including the potential for cancer prevention and the slowing of aging and related degenerative diseases.

Biochemists and nutritional scientists who study the role of vitamins in human biochemistry can list innumerable cellular processes that are vitamin dependent, where a vitamin acts as an essential factor. In fact, it can be argued that the true importance of vitamins in human biochemistry is far from fully elaborated, simply due to the almost incomprehensible complexity of cellular processes. After all, there are approximately 30,000 human genes and over 3800 enzymes currently catalogued, at least 22% of which require a cofactor, in many cases a vitamin, to function.

What is also perhaps not fully appreciated by the general public, and perhaps some physicians, is the essential role that various minerals play in human biochemistry. Critical enzymes require such metals as copper, zinc, manganese, selenium, etc. as an integral part of their molecular structure or mechanism of action, i.e. no metal, no enzyme activity! Deficiencies are thought to produce a broad spectrum of health problems. Minerals of course must come from food and water, air pollution or out of a bottle. It is also true that overloads of some minerals can be disastrous, leading to excessive and potentially harmful oxidative stress, i.e. the metal acts as a center for oxidation by being reduced as it oxidizes an adjacent molecule, in some cases an important cellular constituent, and then, if re-oxidized, is ready to repeat the process. Iron overload is a good example.

The almost complete absence in North America of patients who present with recognized deficiency diseases such as pellagra, rickets, scurvy, acute night-blindness, or beriberi has probably led to a false sense of security and the belief that almost everyone gets enough vitamins from food. Vitamins and minerals have seemingly fallen off the screen for many health care professionals and supplementation viewed as a fad. Interest now seems obsessively focused on toxicity. However, a significant fraction of the North American population appears to not get even the Recommended Daily Allowance (RDA) of some critical nutrients from their diet or supplements (3). In the view of Ames and others, levels of deficiencies that fall between the RDA and the levels that produce recognized deficiency diseases can have serious consequences in connection with what has come to be called our genome integrity.

Ames and others argue that vitamin and mineral deficiencies are common, present a serious health risk and can be corrected by supplementation. Human studies are exceedingly difficult when the goal is to establish evidence based arguments for or against taking supplements, establish a hierarchy of supplements, i.e. which are the most important, and determine what are the optimum amounts of each micronutrient. This is especially true if the goal is to investigate their impact on all aspects of health, from in utero to old age. There are too many variables, too much human variability, too many important endpoints, too many confounding factors, and too few cellular level biomarkers. Financing for intervention studies can be difficult to obtain since pharmaceutical companies, which typically assist in financing large clinical trials, have little or nothing to gain— vitamins and minerals cannot be patented. Also, because of inherent difficulties in achieving good design, execution and statistical power, studies that attempt to connect micronutrients with disease or health have proved to be very easy to criticize or dismiss as inconclusive.

In this review it will be argued that understanding the key role of certain vitamins, minerals and antioxidants in the context of protecting nuclear and mitochondrial DNA, cellular proteins and enzymes from damage may assist in the process of establishing a hierarchy of supplements. The focus of this review will only be on certain micronutrients.

DNA, CHROMOSOMES, GENES, ENZYMES AND COFACTORS - A VERY BRIEF OVERVIEW

The human genome consists of large amounts of deoxyribonucleic acid (DNA), the macromolecule with the famous double helix structure. DNA contains within its structure the genetic information a living organism needs to develop and function, from conception to death. The human genome consists of about 30,000 genes which are the units of genetic information. Genes are encoded in the DNA that makes up a number of rod-shaped cellular constituents called chromosomes that are collected in the nucleus or mitochondria of each cell. The encoding involves the sequence of four organic molecules (bases) that are linked together to form the two long chains that make up the double helix. Only recently has this sequence problem been solved. It is a monumental achievement that will profoundly influence medical genetics for the foreseeable future.

Genes control cellular functions responsible for maintaining the multitude of biochemical processes that characterize a living organism. They serve as blueprints for the cellular production of proteins which include cell receptors, enzymes, hormones, and cytokines (hormone-like proteins which regulate immune responses and are involved in cell-to-cell communication), etc. The functions carried out by these proteins include cell growth, differentiation, metabolism and cell death. Genes are selectively activated or suppressed when molecules such as neurotransmitters, hormones or growth factors bind to and activate cell surface receptors, initiating a cascade of biochemical reactions within the cell in which enzymes play a central role.

Enzymes play a critical role in regulating the rates of most of the multitude of biochemical reactions in living organisms. They act as catalysts and are in general not consumed. The critical nature of the proper functioning of enzymes can be appreciated by the obvious necessity of biochemical reactions in living organism being in balance and occurring at appropriate rates, since otherwise either negligible or huge amounts of a given product could be produced, with either result having serious or perhaps even fatal consequences. That an individual is alive and well is in a large part due to thousands of exquisitely controlled biochemical reactions that occur at the right place and time and to the appropriate extent.

Many enzymes require the presence of other compounds, called cofactors, before their catalytic activity is enabled. Thus there is a protein portion plus the cofactor which can be a vitamin or other organic molecule or a metal ion (i.e. the charged form of iron, copper, zinc, magnesium, etc). In what follows, the essential role that metal ions or vitamins play as cofactors will be shown to directly relate to the role of micronutrients in many aspects of both health and disease. It is also well established that DNA, enzymes and other proteins and fatty acids can be damaged by reactive species such as reactive oxygen and nitrogen compounds and other free radicals, and thus antioxidants, which neutralize these reactive species, also play a critical role in maintaining normal cellular functions and providing protection from damage.

There are a large number of mitochondria in each cell and their proper functioning is critical to health. A popular theory of aging involves mitochondrial damage from free radical attacks such as oxidative damage. It is well known that it is in the mitochondria that cells make ATP, a chemical that is involved in energy generation, and at the same time chemical reactions in the mitochondria generate large amounts of reactive oxygen species and free radicals which can attack and damage nearby molecules and mitochondrial DNA. As might be expected, there are elegant defense mechanisms to minimize the oxidative damage that could result. Otherwise, living organisms would presumably have self-destructed a long time ago. As will be discussed below, micronutrient deficiencies can severely impact these defense mechanisms and thus are thought to lead to accelerated aging and other health problems.

We can't prevent the gene mutations with which we are born. Serious inherited mutations can sometimes be dealt with by significant lifestyle changes (e.g. phenylketonuria can generally be controlled by dietary intervention), while others inevitably lead to early death or lifelong disability. Some are innocuous. Mutations also occur throughout ones lifetime. There are repair mechanisms for gene mutations induced by natural, cosmic or diagnostic radiation, mutagens, toxic substances, etc., and anything that interferes with the proper operation of these repair processes puts the individual at increased risk for diseases related to genetic damage. Enzymes play a central role in these repair processes and thus enzymes with impaired activity due, for example, to low concentrations of cofactors or oxidative damage, may be unable to adequately carry out this essential function.

WHAT CAN GO WRONG THAT IS AMENABLE TO INTERVENTION?

The thesis of Professor Bruce Ames and coworkers, as will as other researchers in this field is that much metabolic damage occurs at micronutrient levels between those generated by the recommended daily allowances (RDAs) and those that cause acute deficiency disease. When one component in the metabolic- micronutrient network is inadequate, repercussions are experienced in a specific biochemical process or even in a large number of processes, and can lead to deficiency related diseases. For example, cancer may result from DNA damage, cognitive dysfunction from neuron decay, and accelerated aging and Alzheimer's disease from mitochondrial functional decay. The focus on cellular micronutrient deficiency is illustrated by the established role in genomic stability of abnormally low levels of the following specific micronutrients (1,2,3,4).

• Vitamins C and E. These prevent the oxidation of DNA and lipids (fats). The consequences of deficiency are increased DNA strand breaks, chromosome breaks, oxidative DNA lesions and lipid peroxide adducts to DNA, all of which are well know to be undesirable (6,7).
• Folate (folic acid) and vitamins B2, B6, and B12. These are involved in the maintenance of DNA methylation, synthesis of critical phosphate compounds, and efficient recycling of folate. Deficiency consequences—uracil misincorporation in DNA with increased chromosome breaks and DNA hypermethylation. Both single and double strand breaks are induced by excessive uracil binding to DNA, and excesses of up to a million uracil molecules per cell are seen with folate deficiency (8).
• Niacin (Nicotinic acid). This is a required substrate (substance with which an enzyme reacts in the process of generating a product). Involved in DNA repair and telomere (chromosome end chains) length maintenance. Deficiency results in an increased level of unrepaired nicks in DNA, increased chromosome breaks and rearrangements, and mutagen sensitivity, all undesirable (9).
• Zinc. Required as a cofactor for over 200 enzymes and for the DNA binding capability of over 400 nuclear regulatory processes. Deficiency results in increased DNA oxidation, DNA breaks and an elevated rate of chromosome damage. Zinc adequacy appears necessary for maintaining DNA integrity and preventing DNA damage, cancer, age related macular degeneration and infertility (10,11,12,13).
• Iron. Required in a critical enzyme. Deficiency results in reduced DNA repair capacity and the potential for increased oxidative damage to mitochondrial DNA (14). Plays an essential role in mitochondrial maintenance through two functional forms, heme and iron-sulfur clusters. Effect of deficiency—massive oxidative damage to mitochondria, tissues and cells if the iron dependent biosynthetic pathway of heme or iron- sulfur clusters is corrupted (15,16).
• Magnesium. Required as a cofactor in a number of enzymes involved in the function of DNA as well as in DNA repair mechanisms. Deficiency results in reduced fidelity of DNA replication, reduced DNA repair ability and chromosome errors (17).
• Manganese. Required in a critical mitochondrial enzyme. Deficiency results in susceptibility to oxidative damage of mitochondrial DNA and reduced resistance to nuclear DNA damage (18).

The above discussion illustrates the connection between cellular micronutrient deficiencies and metabolic and genetic problems. The mechanisms involve: [1] DNA damage in general, [2] reduced reactivity of damaged enzymes and [3] oxidative damage to DNA and other cellular components which has a particularly serious impact on the components of the mitochondria and induces what Ames and others call mitochondrial oxidative decay (2). It is highly significant that deficiencies in folic acid, vitamins B12, B6, C and E and the metals iron and zinc appear, according to Ames, to mimic radiation damage to DNA by causing single- and double-strand breaks, oxidative lesions, or both (3). The reduction of enzyme efficiency in DNA repair process is also a critical aspect of the micronutrient deficiency syndrome.

The deficiency levels at which these various deleterious processes become significant are not easily studied except in human cell cultures. As Michael Fenech points out (4), "To date our knowledge on optimal micronutrient levels for genomic stability is scanty and disorganized." Extensive research by Ames and coworkers (5) suggests that the danger point occurs somewhere at or below about one-half the RDA, and that a significant fraction of the populations of the developed world has a deficiency of this magnitude in at least one of the above micronutrients, and multiple deficiencies are far from uncommon (3). The potential for profound deficiencies among the malnourished seems clear. Thus there is not only a significant personal health issue here, but also a public health issue of considerable magnitude that extends throughout the world.

DEFICIENCIES IN VITAMINS AND MINERALS - A CANCER RISK?

This question is the title of a review in 2002 by Ames and Wakimoto (19) which followed a review in 2001 by Ames addressing the connection between DNA damage from micronutrient deficiencies and cancer (20). The essence of the argument is that micronutrient deficiency can mimic radiation or chemical damage to DNA causing both single and double strand breaks and oxidative damage (lesions) or both. The double strand chromosomal aberration is a strong predictive factor for human cancer (21). Deficiencies in the micronutrients listed above all show laboratory (i.e. cell culture) evidence of mimicking radiation damage with the evidence ranging from likely to compelling (20). The percentage of the US population that is deficient, i.e. an intake of <50% of the RDA for each of these micronutrients ranges from 2% to greater than 20%. Similar or more serious deficiencies may be present in a significant portion of many populations (20). However, as mentioned above, the human in vivo cellular threshold level of each micronutrient where the rate of DNA or other damage becomes significant, in the context of cancer risk, remains in most cases unknown, and definitive studies may be impossible given the natural history of the disease as well as ethical concerns. Thus it is reasonable to turn to epidemiologic studies to seek further evidence, i.e. a diet-cancer link. However, the micronutrients in question are rather widely distributed in the foods we eat. Consider the richest sources for the following micronutrients (19):

• Folate (folic acid). Fortified cereals, citrus fruits and vegetables, including dried beans and dark green vegetables, liver and whole grains
• Vitamin B12. Fortified cereals, meat, shellfish, and milk products
• Vitamin B6. Fortified cereals, whole grains, meat
• Niacin. Meat, fish, legumes, cereals, nuts, asparagus, and green leafy vegetables
• Vitamin C. Citrus fruits and vegetables
• Iron. Meat
• Zinc. Meat, eggs, nuts
• Magnesium. Shellfish, nuts, legumes, beans, some fruits
• Manganese. Grains, cereals, tea and drinking water. Severe air pollution can cause excessive, toxic exposure.

Furthermore, epidemiologic studies of the link between diet and cancer are difficult to interpret because each food item can contain dozens and perhaps even hundreds of different micronutrients, making it difficult to correlate a given food item with a given micronutrient and correct for confounding. In addition, many studies may have lacked the statistical power necessary to provide meaningful results. It is also possible that the upper end of the range for intake of a given food class, e.g. fruits and vegetables, may not be high enough to influence cancer risk in a significant fraction of the particular population studied (22). It is not surprising that studies tend to be inconsistent. Bingham and Riboli (23) believe that prospective cohort studies of the diet-cancer link should involve at least 500,000 initially healthy subjects (about 5-8 times the cohort size in large studies already in the literature) who should be followed for at least ten years in order to observe sufficient cancer cases at the common sites. Such a study, involving a large number of European countries, which includes some genetic typing and extensive examination of serum markers (the EPIC Study) is now in the data analysis stage (23).

Nevertheless, more than two hundred studies have examined the question of the connection between diets high or low in fruits and vegetables and the risk of developing cancer. The accumulated evidence supports the conclusion that eating large amounts of fruits and vegetables lowers the risk of developing some but not all cancers. In his recent bookEat, Drink and Be Healthy (24) (review published in IHN issue #136, April 2003), Dr. Walter Willett lists seven cancer sites and the associated fruit and vegetable types where epidemiologic research has found anticancer effects, a list that emphasizes the apparent lack of a "blanket anticancer effect."

A recent study employed a new approach to this question. In a case-control study the relationship between gastric cancer risk and the total dietary antioxidant potential was examined (25). Total antioxidant potential of dietary plant food was found to be significantly inversely associated with the risk of gastric cancer. The relative benefit was enhanced in individuals exposed to high oxidative stress on the gastric mucosa (long-term smokers and subjects exposed to H. pylori). This study used only 12 dietary items. Very recently, Wu et al reported the results of a large study where the total antioxidant capacity (fat- and water-soluble antioxidants) of individual food items was measured. This benchmark study should facilitate studies attempting to correlate total dietary antioxidant power and specific fruits and vegetables (26). The top 15 food sources of water-soluble antioxidants were small red beans, blueberries (wild), red kidney beans, pinto beans, blueberries (cultivated), cranberries, artichoke hearts, blackberries, prunes, strawberries, raspberries, apples (red delicious and Granny Smith). For the fat-soluble antioxidants, the top 15 foods were avocado, navy beans, pinto beans, black eye peas, broccoli, black beans, raspberries, cranberries, russet potatoes, spinach, oat cereal and Brazil nuts. Pecans, walnuts and hazelnuts were also high in total antioxidants.

The strength of the association between cancer risk and the consumption of fruits and vegetables, when not stratified by antioxidant power, seems to be diminishing somewhat as recent prospective cohort studies are reported, and in a review published in 2004, the authors (including Willett) now use the word probably in describing the inverse association (27). The huge range of antioxidant power found by Wu et al (26) suggests that just lumping fruits and vegetables together in one category in studies may underestimate their effectiveness. The study on gastric cancer appears to be the first where total antioxidant power was a parameter.

However, no one appears to be suggesting that fruits and vegetables are unimportant. In fact, the study of Wu et al (26) provides a useful guide to selecting fruits and vegetables to emphasize in the diet for maximum antioxidant protection. An inverse correlation of fruits and vegetables with cancer is of course consistent with the action of folic acid and vitamin C in the context of DNA damage, but clearly as outlined above, other food classes (e.g. meat and whole grains, etc.) contribute micronutrients thought as well to be critical, and these foods by and large have not stood out in epidemiologic correlations with cancer, either as good or bad. The possible connection between cancer and specific micronutrients as well as multivitamin/mineral intake will be discussed below.

FOLIC ACID: A MAJOR PLAYER

In the model of Ames for chromosome breaks and the associated risk of cancer, folic acid (folate) is a major player. The form of folic acid in food differs in molecular structure and bioavailability from the synthetic compound found in supplements and used in the fortification of flour and cereals, with the synthetic version being almost twice as bioavailable. However, there appears to be an upper limit on the metabolism of the synthetic form, with intakes of more than about 400 µg/d resulting in serum levels of free folic acid which do not appear to be utilized. Concern has been expressed (28,29) regarding this since it appears unknown if there are dangers associated with long-term high levels of free serum folic acid which might build up as a consequence of both supplementation and eating fortified foods. Special concerns have been raised in connection with children who may be given supplements and eat large amounts of prepared cereals (28,29). Some estimates of potential daily intake exceed the upper limit for children by 300-400%. There does not appear to be a problem with metabolism of the natural form found in food, except that some individuals may have genetic defects which reduce the bioavailability and this can result in deficiencies. Government mandated fortification in the US and Canada started in 1998. Spot checks of the level of fortification indicate that it is common for foods to contain considerably more folic acid than indicated on the label. In the US the upper limit for the daily intake of the synthetic form is 1 mg. There is now concern that this may be exceeded in an unknown but significant fraction of the population. Note the big gap between the 400µg/d above which unmetabolized folic acid appears in the blood and the 1000µg/d considered to be the safe upper limit. Also, therapeutic doses as high as 5 mg/d are used (29). There are obviously unresolved issues.

One of these issues involves folate therapy after coronary stenting with plain metal stents. Folate therapy was found to increase in-stent restenosis (recurrent blockage) and the need for target-vessel revascularization. This adverse result was observed in a cohort that had undergone successful coronary stenting, although it was absent in the subgroups consisting of women, patients with diabetes and those with homocysteine levels over 15 µmol/L at baseline. This result was inconsistent with earlier folate trials aimed at reducing restenosis (30).

A well-validated concern with high levels of folic acid intake is related to the possibility of masking a vitamin B12 deficiency and related megaloblastic anemia. It is well known that folic acid reverses the evidence revealed by blood tests, i.e. it eliminates the anemia, but does not eliminate the B12 deficiency, which can go on to cause neurological damage which can be severe, reach the point of irreversibility and mimic Alzheimer's disease. Since the elderly can have problems with the metabolism of B12 from food because they are unable to separate the vitamin from its natural, protein-bound form, B12 deficiencies in this age group are common and a real reason for concern. Also, a deficiency in what is called intrinsic factor prevents normal absorption of any form of B12, but this is rare (31). Because of the potential for high intakes of folic acid, there have been calls for fortification with significant amounts of B12 to accompany folic acid. The B12 present in supplements or as a food additive is generally metabolized easily and normally leads to increased serum and tissue levels of B12, although larger amounts may be needed than found in some multivitamin pills. Individuals with a severe deficiency generally need therapeutic doses given by injection. There appears to be only one study reported that addresses the question of an increase in untreated or masked B12 deficiency since folic acid fortification (32). The study found no increase in B12 deficiency in the absence of anemia over the period 1990 to 2001 in the age group 60-80. This result would argue against the suggestion that there is a B12 deficiency problem masked by the over consumption of folic acid in the elderly due to fortification.

The fortification of cereal products and flour was motivated by the fact that a folate deficiency in the first few weeks of pregnancy can result in birth defects, in particular neural tube defects. As a preventive measure, the folic acid supplement must be taken prior to conception. In the mid 90s there was a campaign to motivate women of child-bearing age to take folic acid supplements, but with 50% of pregnancies unplanned and problems in general associated with convincing a large population to take supplements, this program was a failure. After mandated fortification in 1998, a few studies now indicate a drop in neural tube defects, and in one particularly careful study done in Nova Scotia (33), which included aborted fetus data, over a 50% decrease was found. Finally, there is little doubt that in the post-fortification era, there has been a dramatic increase in average serum and red blood cell folate levels and a modest drop in homocysteine levels (34). Whether this latter change will translate into decreased adverse cardiovascular events remains to be seen. It is of interest that the growing popularity of low-carbohydrate diets, as judged by the lamentations of the processed food industry, may result in reduced effectiveness of the folate fortification program. However, the major advocates of low-carb diets all strongly recommend supplements as a vital and essential part of the program (see Research Report "The Diet Zoo" published in IHN issues #143 and #144).

In epidemiologic studies that specifically focused on folate and cancer, some have found an inverse relationship between folate intake and the risk of adenomatous polyps and colorectal cancer. In the Nurses' Health Study, a high intake of folate from fruits and vegetables was found to lower the risk of colorectal cancer, and supplementation with a multivitamin containing folate was found to offer even greater risk reduction (35). Such a result can be viewed as evidence that even a high level of fruit and vegetable consumption may not provide optimum cellular levels of folate. There have in fact been a large number of studies regarding the role of folic acid in colorectal cancer (see (36) for references), but only about half produced statistically significant evidence of reduced risk. In view of the problems with such studies, perhaps this should be viewed in a positive light.

An interesting chapter in the folic acid story involves its relationship to breast cancer. In the Nurses' Health Study (37) no risk reduction was observed for folic acid except for a very weak inverse association for postmenopausal women. However, there was a strong protective effect found for women who consumed over 15g/d (about one drink) or more of alcohol. Alcohol is known to interfere with the absorption and metabolism of folic acid. This suggests that the cohort of non-drinkers had folic acid levels above the threshold for observing increased breast cancer risk, and alcohol consumption put those with low or moderate dietary folate intake below the threshold.

Other studies that show an inverse disease risk relationship with folate consumption could be discussed. For example, it is well known that a folate deficiency is associated with elevated serum homocysteine, and there now seems to be general agreement that high homocysteine levels are a risk factor for cardiovascular disease and perhaps Alzheimer's and Parkinson's disease. Incidentally, vitamin B12 is also directly involved in the folate- homocysteine chemistry (38). There is also growing evidence that homocysteine per se is implicated in chromosome damage (39), and lower serum homocysteine has been found to correlate with lower risk of colorectal adenoma recurrence (36).

At this point, it seems sufficient to conclude that the epidemiology is very suggestive and provides support for the Ames model. The interested reader is referred to reviews by Ames (20), Fenech (4) and Ames and Wakimoto (19) for detailed information on the epidemiologic and cell culture evidence associated with the important micronutrients in the context of both cancer (19,20) and other health issues (4). References are also provided in the item-by-item list given above. A full discussion would result in a 30-40 page review!

References

1. Ames, B. N., "The metabolic tune-up: metabolic harmony and disease prevention," J Nutr, vol. 133, no. 5 Suppl 1, pp. 1544S-1548S, May2003.
2. Ames, B. N., "Delaying the mitochondrial decay of aging-a metabolic tune-up," Alzheimer Dis.Assoc.Disord., vol. 17 Suppl 2 pp. S54-S57, Apr.2003.
3. Ames, B. N., "A role for supplements in optimizing health: the metabolic tune-up," Arch Biochem.Biophys., vol. 423, no. 1, pp. 227-234, Mar.2004.
4. Fenech, M., "Nutritional treatment of genome instability:a paradigm shift in disease prevention and in setting of recommended diatary allowances," Nutritional Research Reviews, vol. 16 pp. 109-122, 2003.
5. Ames, B. N., Elson-Schwab, I., and Silver, E. A., "High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms," American Journal of Clinical Nutrition, vol. 75, no. 4, pp. 616-658, Apr.2002.
6. Halliwell, B., "Vitamin C and genomic stability," Mutat.Res, vol. 475, no. 1-2, pp. 29-35, Apr.2001.
7. Claycombe, K. J. and Meydani, S. N., "Vitamin E and genome stability," Mutat.Res, vol. 475, no. 1-2, pp. 37-44, Apr.2001.
8. Fenech, M. and Ferguson, L. R., "Vitamins/minerals and genomic stability in humans," Mutat.Res, vol. 475, no. 1-2, pp. 1-6, Apr.2001.
9. Hageman, G. J. and Stierum, R. H., "Niacin, poly(ADP-ribose) polymerase-1 and genomic stability," Mutat.Res, vol. 475, no. 1-2, pp. 45-56, Apr.2001.
10. Ho, E., Courtemanche, C., and Ames, B. N., "Zinc deficiency induces oxidative DNA damage and increases p53 expression in human lung fibroblasts," J Nutr, vol. 133, no. 8, pp. 2543-2548, Aug.2003.
11. Dreosti, I. E., "Zinc and the gene," Mutat.Res, vol. 475, no. 1-2, pp. 161-167, Apr.2001.
12. Ho, E. and Ames, B. N., "Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line," Proc.Natl Acad Sci U.S.A, vol. 99, no. 26, pp. 16770- 16775, Dec.2002.
13. Wood, J. P. and Osborne, N. N., "Zinc and energy requirements in induction of oxidative stress to retinal pigmented epithelial cells," Neurochem.Res, vol. 28, no. 10, pp. 1525-1533, Oct.2003.
14. Walter, P. B., Knutson, M. D., Paler-Martinez, A., Lee, S., Xu, Y., Viteri, F. E., and Ames, B. N., "Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats," Proc.Natl Acad Sci U.S.A, vol. 99, no. 4, pp. 2264-2269, Feb.2002.
15. Atamna, H., Walter, P. B., and Ames, B. N., "The role of heme and iron-sulfur clusters in mitochondrial biogenesis, maintenance, and decay with age," Arch Biochem.Biophys., vol. 397, no. 2, pp. 345-353, Jan.2002.
16. Atamna, H., Killilea, D. W., Killilea, A. N., and Ames, B. N., "Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging," Proc.Natl Acad Sci U.S.A, vol. 99, no. 23, pp. 14807-14812, Nov.2002.
17. Hartwig, A., "Role of magnesium in genomic stability," Mutat.Res, vol. 475, no. 1-2, pp. 113-121, Apr.2001.
18. Ambrosone, C. B., Freudenheim, J. L., Thompson, P. A., Bowman, E., Vena, J. E., Marshall, J. R., Graham, S., Laughlin, R., Nemoto, T., and Shields, P. G., "Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer," Cancer Res, vol. 59, no. 3, pp. 602-606, Feb.1999.
19. Ames, B. N. and Wakimoto, P., "Are vitamin and mineral deficiencies a major cancer risk?," Nat.Rev.Cancer, vol. 2, no. 9, pp. 694-704, Sept.2002.
20. Ames, B. N., "DNA damage from micronutrient deficiencies is likely to be a major cause of cancer," Mutat.Res, vol. 475, no. 1-2, pp. 7-20, Apr.2001.
21. Bonassi, S., Hagmar, L., Stromberg, U., Montagud, A. H., Tinnerberg, H., Forni, A., Heikkila, P., Wanders, S., Wilhardt, P., Hansteen, I. L., Knudsen, L. E., and Norppa, H., "Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. European Study Group on Cytogenetic Biomarkers and Health," Cancer Res, vol. 60, no. 6, pp. 1619-1625, Mar.2000.
22. Slattery, M. L., Curtin, K. P., Edwards, S. L., and Schaffer, D. M., "Plant foods, fiber, and rectal cancer," American Journal of Clinical Nutrition, vol. 79, no. 2, pp. 274-281, Feb.2004.
23. Bingham, S. and Riboli, E., "Diet and cancer--the European Prospective Investigation into Cancer and Nutrition," Nat.Rev.Cancer, vol. 4, no. 3, pp. 206-215, Mar.2004.
24. Willett, W. C., Eat, Drink and be Healthy. The Harvard Medical School Guide to Healthy Eating Simon & Schuster (Fireside), 2001.
25. Serafini, M., Bellocco, R., Wolk, A., and Ekstrom, A. M., "Total antioxidant potential of fruit and vegetables and risk of gastric cancer," Gastroenterology, vol. 123, no. 4, pp. 985-991, Oct.2002.
26. Wu, X., Beecher, G. R., Holden, J. M., Haytowitz, D. B., Gebhardt, S. E., and Prior, R. L., "Lipophilic and hydrophilic antioxidant capacities of common foods in the United States," J Agric.Food Chem, vol. 52, no. 12, pp. 4026-4037, June2004.
27. Key, T. J., Schatzkin, A., Willett, W. C., Allen, N. E., Spencer, E. A., and Travis, R. C., "Diet, nutrition and the prevention of cancer," Public Health Nutr, vol. 7, no. 1A, pp. 187-200, Feb.2004.
28. Kelly, P., McPartlin, J., Goggins, M., Weir, D. G., and Scott, J. M., "Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements," American Journal of Clinical Nutrition, vol. 65, no. 6, pp. 1790-1795, June1997.
29. Lucock, M., "Is folic acid the ultimate functional food component for disease prevention?," BMJ, vol. 328, no. 7433, pp. 211-214, Jan.2004.
30. Lange, H., Suryapranata, H., De Luca, G., Borner, C., Dille, J., Kallmayer, K., Pasalary, M. N., Scherer, E., and Dambrink, J. H., "Folate Therapy and In-Stent Restenosis after Coronary Stenting," The New England Journal of Medicine, vol. 350, no. 26, pp. 2673-2681, June2004.
31. Ho, C., Kauwell, G. P., and Bailey, L. B., "Practitioners' guide to meeting the vitamin B-12 recommended dietary allowance for people aged 51 years and older," J Am Diet.Assoc., vol. 99, no. 6, pp. 725-727, June1999.
32. Mills, J. L., Von, K., I, Conley, M. R., Zeller, J. A., Cox, C., Williamson, R. E., and Dufour, D. R., "Low vitamin B- 12 concentrations in patients without anemia: the effect of folic acid fortification of grain," American Journal of Clinical Nutrition, vol. 77, no. 6, pp. 1474-1477, June2003.
33. Persad, V. L., Van den Hof, M. C., Dube, J. M., and Zimmer, P., "Incidence of open neural tube defects in Nova Scotia after folic acid fortification," CMAJ., vol. 167, no. 3, pp. 241-245, Aug.2002.
34. Quinlivan, E. P. and Gregory, J. F., III, "Effect of food fortification on folic acid intake in the United States," American Journal of Clinical Nutrition, vol. 77, no. 1, pp. 221-225, Jan.2003.
35. Giovannucci, E., Stampfer, M. J., Colditz, G. A., Hunter, D. J., Fuchs, C., Rosner, B. A., Speizer, F. E., and Willett, W. C., "Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study," Annals of Internal Medicine, vol. 129, no. 7, pp. 517-524, Oct.1998.
36. Martinez, M. E., Henning, S. M., and Alberts, D. S., "Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence," American Journal of Clinical Nutrition, vol. 79, no. 4, pp. 691-697, Apr.2004.
37. Zhang, S., Hunter, D. J., Hankinson, S. E., Giovannucci, E. L., Rosner, B. A., Colditz, G. A., Speizer, F. E., and Willett, W. C., "A prospective study of folate intake and the risk of breast cancer," JAMA: The Journal of the American Medical Association, vol. 281, no. 17, pp. 1632-1637, May1999.
38. Mattson, M. P., Kruman, I. I., and Duan, W., "Folic acid and homocysteine in age-related disease," Ageing Res Rev., vol. 1, no. 1, pp. 95-111, Feb.2002.
39. Fenech, M., Aitken, C., and Rinaldi, J., "Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults," Carcinogenesis, vol. 19, no. 7, pp. 1163-1171, July1998.
40. Willett, W. C. and Stampfer, M. J., "Clinical practice. What vitamins should I be taking, doctor?," The New England Journal of Medicine, vol. 345, no. 25, pp. 1819-1824, Dec.2001.
41. Packer, L. and and Colman, C., The Antioxidant Miracle New York: John Wiley & Sons, 1999.
42. Lipoic Acid in Health and Disease New York: Marcell Dekker, 1997.
43. Berkson, B. M., "A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories," Med Klin.(Munich), vol. 94 Suppl 3 pp. 84-89, Oct.1999.
44. Hargreaves, I. P., "Ubiquinone: cholesterol's reclusive cousin," Ann Clin Biochem., vol. 40, no. Pt 3, pp. 207- 218, May2003.
45. Krum, H. and McMurray, J. J., "Statins and chronic heart failure: do we need a large-scale outcome trial?," J Am Coll Cardiol., vol. 39, no. 10, pp. 1567-1573, May2002.
46. Shults, C. W., "Coenzyme Q10 in neurodegenerative diseases," Curr Med Chem, vol. 10, no. 19, pp. 1917- 1921, Oct.2003.
47. Marriage, B., Clandinin, M. T., and Glerum, D. M., "Nutritional cofactor treatment in mitochondrial disorders," J Am Diet.Assoc., vol. 103, no. 8, pp. 1029-1038, Aug.2003.
48. Muller, T., Buttner, T., Gholipour, A. F., and Kuhn, W., "Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease," Neurosci.Lett., vol. 341, no. 3, pp. 201-204, May2003.
49. Battino, M., Bullon, P., Wilson, M., and Newman, H., "Oxidative injury and inflammatory periodontal diseases: the challenge of anti-oxidants to free radicals and reactive oxygen species," Crit Rev.Oral Biol.Med, vol. 10, no. 4, pp. 458-476, 1999.
50. Stampfer, M. J., Hennekens, C. H., Manson, J. E., Colditz, G. A., Rosner, B., and Willett, W. C., "Vitamin E Consumption and the Risk of Coronary Disease in Women," The New England Journal of Medicine, vol. 328, no. 20, pp. 1444-1449, May1993.
51. Rimm, E. B., Stampfer, M. J., Ascherio, A., Giovannucci, E., Colditz, G. A., and Willett, W. C., "Vitamin E Consumption and the Risk of Coronary Heart Disease in Men," The New England Journal of Medicine, vol. 328, no. 20, pp. 1450-1456, May1993.
52. Jialal, I. and Devaraj, S., "Antioxidants and Atherosclerosis: Don't Throw Out the Baby With the Bath Water," Circulation, vol. 107, no. 7, pp. 926-928, Feb.2003.
53. Azzi, A., Breyer, I., Feher, M., Ricciarelli, R., Stocker, A., Zimmer, S., and Zingg, J. M., "Nonantioxidant Functions of {{alpha}}-Tocopherol in Smooth Muscle Cells," Journal of Nutrition, vol. 131, no. 2, pp. 378S-381, Feb.2001.
54. Meydani, S. N. and Beharka, A. A., "Recent developments in vitamin E and immune response," Nutr Rev., vol. 56, no. 1 Pt 2, pp. S49-S58, Jan.1998.
55. Chow, C. K., "Vitamin E regulation of mitochondrial superoxide generation," Biol.Signals Recept., vol. 10, no. 1- 2, pp. 112-124, Jan.2001.
56. Traber, M. G. and Packer, L., "Vitamin E: beyond antioxidant function," American Journal of Clinical Nutrition, vol. 62, no. 6 Suppl, pp. 1501S-1509S, Dec.1995.
57. Vatassery, G. T., Lai, J. C., DeMaster, E. G., Smith, W. E., and Quach, H. T., "Oxidation of vitamin E and vitamin C and inhibition of brain mitochondrial oxidative phosphorylation by peroxynitrite," J Neurosci.Res, vol. 75, no. 6, pp. 845-853, Mar.2004.
58. Willis, M. S. and Wians, F. H., "The role of nutrition in preventing prostate cancer: a review of the proposed mechanism of action of various dietary substances," Clin Chim.Acta, vol. 330, no. 1-2, pp. 57-83, Apr.2003.
59. Kikuchi, S., Shinpo, K., Takeuchi, M., Yamagishi, S., Makita, Z., Sasaki, N., and Tashiro, K., "Glycation--a sweet tempter for neuronal death," Brain Res Brain Res Rev., vol. 41, no. 2-3, pp. 306-323, Mar.2003.
60. Baynes, J. W., "The role of AGEs in aging: causation or correlation," Exp.Gerontol., vol. 36, no. 9, pp. 1527- 1537, Sept.2001.
61. Vlassara, H. and Palace, M. R., "Glycoxidation: the menace of diabetes and aging," Mt.Sinai J Med, vol. 70, no. 4, pp. 232-241, Sept.2003.
62. Cherniske, S., The Metabolic Plan New York: Ballantine Books, 2003.
63. Kowald, A., "The mitochondrial theory of aging," Biol.Signals Recept., vol. 10, no. 3-4, pp. 162-175, May2001.
64. Berdanier, C. D. and Everts, H. B., "Mitochondrial DNA in aging and degenerative disease," Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol. 475, no. 1-2, pp. 169-183, Apr.2001.
65. Liu, J., Atamna, H., Kuratsune, H., and Ames, B. N., "Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites," Ann N Y.Acad Sci, vol. 959 pp. 133-166, Apr.2002.
66. Liang, F. Q. and Godley, B. F., "Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration," Exp.Eye Res, vol. 76, no. 4, pp. 397-403, Apr.2003.
67. Sastre, J., Pallardo, F. V., and Vina, J., "The role of mitochondrial oxidative stress in aging," Free Radic.Biol.Med, vol. 35, no. 1, pp. 1-8, July2003.
68. Snellen, E. L., Verbeek, A. L., Van Den Hoogen, G. W., Cruysberg, J. R., and Hoyng, C. B., "Neovascular age- related macular degeneration and its relationship to antioxidant intake," Acta Ophthalmol.Scand., vol. 80, no. 4, pp. 368-371, Aug.2002.
69. "A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8," Arch Ophthalmol., vol. 119, no. 10, pp. 1417-1436, Oct.2001.
70. Zandi, P. P., Anthony, J. C., Khachaturian, A. S., Stone, S. V., Gustafson, D., Tschanz, J. T., Norton, M. C., Welsh-Bohmer, K. A., and Breitner, J. C., "Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study," Arch Neurol., vol. 61, no. 1, pp. 82-88, Jan.2004.
71. Heilbronn, L. K. and Ravussin, E., "Calorie restriction and aging: review of the literature and implications for studies in humans," American Journal of Clinical Nutrition, vol. 78, no. 3, pp. 361-369, Sept.2003.
72. Weindruch, R. and Sohal, R. S., "Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging," The New England Journal of Medicine, vol. 337, no. 14, pp. 986-994, Oct.1997.
73. Walford, R. L., Mock, D., Verdery, R., and MacCallum, T., "Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period," J Gerontol.A Biol.Sci Med Sci, vol. 57, no. 6, pp. B211-B224, June2002.
74. Willcox, B. J., Willcox, D. C., and Suzuki, M., The Okinawa Program New York: Clarkson Potter, 2001.
75. Koubova, J. and Guarente, L., "How does calorie restriction work?," Genes and Development, vol. 17, no. 3, pp. 313-321, Feb.2003.
76. Giovannucci, E., Stampfer, M. J., Colditz, G. A., Hunter, D. J., Fuchs, C., Rosner, B. A., Speizer, F. E., and Willett, W. C., "Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study," Annals of Internal Medicine, vol. 129, no. 7, pp. 517-524, Oct.1998.
77. Jacobs, E. J., Connell, C. J., Patel, A. V., Chao, A., Rodriguez, C., Seymour, J., McCullough, M. L., Calle, E. E., and Thun, M. J., "Multivitamin use and colon cancer mortality in the Cancer Prevention Study II cohort (United States)," Cancer Causes Control, vol. 12, no. 10, pp. 927-934, Dec.2001.
78. White, E., Shannon, J. S., and Patterson, R. E., "Relationship between vitamin and calcium supplement use and colon cancer," Cancer Epidemiol Biomarkers Prev, vol. 6, no. 10, pp. 769-774, Oct.1997.
79. Zhang, S., Hunter, D. J., Hankinson, S. E., Giovannucci, E. L., Rosner, B. A., Colditz, G. A., Speizer, F. E., and Willett, W. C., "A prospective study of folate intake and the risk of breast cancer," JAMA: The Journal of the American Medical Association, vol. 281, no. 17, pp. 1632-1637, May1999.
80. Rimm, E. B., Willett, W. C., Hu, F. B., Sampson, L., Colditz, G. A., Manson, J. E., Hennekens, C., and Stampfer, M. J., "Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women," JAMA: The Journal of the American Medical Association, vol. 279, no. 5, pp. 359-364, Feb.1998.
81. Muntwyler, J., Hennekens, C. H., Manson, J. E., Buring, J. E., and Gaziano, J. M., "Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality," Arch Intern Med, vol. 162, no. 13, pp. 1472-1476, July2002.
82. Holmquist, C., Larsson, S., Wolk, A., and de Faire, U., "Multivitamin supplements are inversely associated with risk of myocardial infarction in men and women--Stockholm Heart Epidemiology Program (SHEEP)," J Nutr, vol. 133, no. 8, pp. 2650-2654, Aug.2003.
83. Watkins, M. L., Erickson, J. D., Thun, M. J., Mulinare, J., and Heath, C. W., Jr., "Multivitamin use and mortality in a large prospective study," Am J Epidemiol, vol. 152, no. 2, pp. 149-162, July2000.
84. Mark, S. D., Wang, W., Fraumeni, J. F., Jr., Li, J. Y., Taylor, P. R., Wang, G. Q., Guo, W., Dawsey, S. M., Li, B., and Blot, W. J., "Lowered risks of hypertension and cerebrovascular disease after vitamin/mineral supplementation: the Linxian Nutrition Intervention Trial," Am J Epidemiol, vol. 143, no. 7, pp. 658-664, Apr.1996.
85. Earnest, C. P., Wood, K. A., and Church, T. S., "Complex multivitamin supplementation improves homocysteine and resistance to LDL-C oxidation," J Am Coll Nutr, vol. 22, no. 5, pp. 400-407, Oct.2003.
86. Church, T. S., Earnest, C. P., Wood, K. A., and Kampert, J. B., "Reduction of C-reactive protein levels through use of a multivitamin," Am J Med, vol. 115, no. 9, pp. 702-707, Dec.2003.
87. Botto, L. D., Mulinare, J., and Erickson, J. D., "Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps," Am J Med Genet., vol. 121A, no. 2, pp. 95-101, Aug.2003.
88. Correa, A., Botto, L., Liu, Y., Mulinare, J., and Erickson, J. D., "Do multivitamin supplements attenuate the risk for diabetes-associated birth defects?," Pediatrics, vol. 111, no. 5 Part 2, pp. 1146-1151, May2003.
89. Botto, L. D., Olney, R. S., and Erickson, J. D., "Vitamin supplements and the risk for congenital anomalies other than neural tube defects," Am J Med Genet., vol. 125C, no. 1, pp. 12-21, Feb.2004.
90. Olshan, A. F., Smith, J. C., Bondy, M. L., Neglia, J. P., and Pollock, B. H., "Maternal vitamin use and reduced risk of neuroblastoma," Epidemiology, vol. 13, no. 5, pp. 575-580, Sept.2002.
91. Preston-Martin, S., Pogoda, J. M., Mueller, B. A., Lubin, F., Holly, E. A., Filippini, G., Cordier, S., Peris-Bonet, R., Choi, W., Little, J., and Arslan, A., "Prenatal vitamin supplementation and risk of childhood brain tumors," Int J Cancer Suppl, vol. 11 pp. 17-22, 1998.
92. Chandra, R. K., "Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects," Lancet, vol. 340, no. 8828, pp. 1124-1127, Nov.1992.
93. Whelan, R. L., Horvath, K. D., Gleason, N. R., Forde, K. A., Treat, M. D., Teitelbaum, S. L., Bertram, A., and Neugut, A. I., "Vitamin and calcium supplement use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia," Dis.Colon Rectum, vol. 42, no. 2, pp. 212-217, Feb.1999.
94. Fawzi, W. W., Msamanga, G. I., Spiegelman, D., Wei, R., Kapiga, S., Villamor, E., Mwakagile, D., Mugusi, F., Hertzmark, E., Essex, M., and Hunter, D. J., "A Randomized Trial of Multivitamin Supplements and HIV Disease Progression and Mortality," The New England Journal of Medicine, vol. 351, no. 1, pp. 23-32, July2004.
95. Fletcher, R. H. and Fairfield, K. M., "Vitamins for chronic disease prevention in adults: clinical applications," JAMA: The Journal of the American Medical Association, vol. 287, no. 23, pp. 3127-3129, June2002.
96. Fairfield, K. M. and Fletcher, R. H., "Vitamins for chronic disease prevention in adults: scientific review," JAMA: The Journal of the American Medical Association, vol. 287, no. 23, pp. 3116-3126, June2002.
97. U.S.Preventive Services Task Force*, "Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale," Annals of Internal Medicine, vol. 139, no. 1, pp. 51- 55, July2003.
98. Alonso-Aperte, E. and Varela-Moreiras, G., "Drugs-nutrient interactions: a potential problem during adolescence," Eur.J Clin Nutr, vol. 54 Suppl 1 pp. S69-S74, Mar.2000.
99. Desouza, C., Keebler, M., McNamara, D. B., and Fonseca, V., "Drugs affecting homocysteine metabolism: impact on cardiovascular risk," Drugs, vol. 62, no. 4, pp. 605-616, 2002.
100. Westphal, S., Rading, A., Luley, C., and Dierkes, J., "Antihypertensive treatment and homocysteine concentrations," Metabolism, vol. 52, no. 3, pp. 261-263, Mar.2003.
101. Morrow, L. E. and Grimsley, E. W., "Long-term diuretic therapy in hypertensive patients: effects on serum homocysteine, vitamin B6, vitamin B12, and red blood cell folate concentrations," South.Med J, vol. 92, no. 9, pp. 866-870, Sept.1999.
102. Seelig, M. S. and Rosanoff, A., The Magnesium Factor New York: Avery (Penguin Group), 2003.
103. Navarro, M. and Wood, R. J., "Plasma changes in micronutrients following a multivitamin and mineral supplement in healthy adults," J Am Coll Nutr, vol. 22, no. 2, pp. 124-132, Apr.2003.
104. Abudu, N., Miller, J. J., Attaelmannan, M., and Levinson, S. S., "Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E," Clin Chim.Acta, vol. 339, no. 1-2, pp. 11-25, Jan.2004.
105. Feskanich, D., Singh, V., Willett, W. C., and Colditz, G. A., "Vitamin A intake and hip fractures among postmenopausal women," JAMA: The Journal of the American Medical Association, vol. 287, no. 1, pp. 47-54, Jan.2002.
106. Jiang, R., Manson, J. E., Meigs, J. B., Ma, J., Rifai, N., and Hu, F. B., "Body Iron Stores in Relation to Risk of Type 2 Diabetes in Apparently Healthy Women," JAMA: The Journal of the American Medical Association, vol. 291, no. 6, pp. 711-717, Feb.2004.
107. Neuzil, J., "Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity," Br.J Cancer, vol. 89, no. 10, pp. 1822-1826, Nov.2003.
108. Challem, J. J., "Toward a new definition of essential nutrients: is it now time for a third 'vitamin' paradigm?," Med Hypotheses, vol. 52, no. 5, pp. 417-422, May1999.
109. Millen, A. E., Dodd, K. W., and Subar, A. F., "Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey results," J Am Diet.Assoc., vol. 104, no. 6, pp. 942-950, June2004.
110. Shrimpton, R., Shrimpton, R., and Schultink, W., "Can supplements help meet the micronutrient needs of the developing world?," Proc.Nutr Soc., vol. 61, no. 2, pp. 223-229, May2002.
111. West, K. P., Jr., Katz, J., Khatry, S. K., LeClerq, S. C., Pradhan, E. K., Shrestha, S. R., Connor, P. B., Dali, S. M., Christian, P., Pokhrel, R. P., and Sommer, A., "Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS-2 Study Group," BMJ, vol. 318, no. 7183, pp. 570-575, Feb.1999.