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ABSTRACT
Poor nutrition has been linked to an increased risk of many diseases, including cancer, heart disease, and diabetes. The human diet requires both macronutrients, which are the main source of calories, and micronutrients (≈40 essential minerals, vitamins, and other biochemicals), which are required for virtually all metabolic and developmental processes. The leading dietary sources of energy in the United States are abundant in carbohydrates and fats (1) but deficient in micronutrients (i.e., they are energy-dense and nutrient-poor) (2). Such foods are inexpensive and tasty and as a consequence are consumed excessively, particularly by the poor (3). Thus, even in the United States (4), inadequate intake of some vitamins and minerals is. Suboptimal consumption of micronutrients (4) often accompanies caloric excess (6, 88) and may be the norm among the obese and contribute to the pathologies associated with obesity.
Significant chronic metabolic disruption may occur when consumption of a micronutrient is below the current Recommended Dietary Allowance (RDA) (7–10) but above the level that causes acute symptoms. When one component of the metabolic network is inadequate, there may be a variety of repercussions in metabolism, including acceleration of degenerative diseases. The optimum intake of each micronutrient necessary to maximize a healthy lifespan remains to be determined and could even be higher than the current RDA, particularly for some populations (7, 10). For example, folic acid intakes above the RDA appear to be necessary to minimize chromosome breaks (10, 11).
MICRONUTRIENT DEFICIENCIES MAY ACCELERATE MITOCHONDRIAL DECAY AND DEGENERATIVE DISEASES OF AGING, SUCH AS CANCER
Mitochondrial decay appears to be a major contributor to aging and its associated degenerative diseases, including cancer and neural decay (12). Mitochondria from old rats compared with those from young rats generate increased amounts of oxidant by-products (13) and have decreased membrane potential, respiratory control ratio, cellular oxygen consumption, and cardiolipin (a key lipid found only in mitochondria). Oxidative damage to DNA, RNA, proteins, and lipids in mitochondrial membranes contributes to this decay (9, 13–16) and leads to functional decline of mitochondria, cells, tissues, and eventually organs such as the brain with an accompanying loss of ambulatory activity (9, 13–16).
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Magnesium Deficiency.
Magnesium intakes for ≈56% of adults in the United States are below the Estimated Average Requirement (EAR) (Table 1). In humans, magnesium deficiency has been associated with colorectal and other cancers (25–28), hypertension, osteoporosis, diabetes, and the metabolic syndrome (5, 29, 89). In a study of 4,035 men followed for 18 years, the highest quartile with serum magnesium at baseline compared with the lowest had a 40% decrease in all-cause mortality and cardiovascular disease and a 50% decrease in cancer deaths (30). In primary human cells in culture, magnesium deficiency leads to mitochondrial DNA damage, accelerated telomere shortening, activation of cell-cycle arrest proteins, and premature senescence (D. W. Killilea, B.N.A., unpublished observations). Magnesium deficiency in rats leads to chromosome breaks (31) and cancer (25). A standard multivitamin–mineral (MVM) supplement does not contain sufficient magnesium (or calcium) because it would make the supplement too bulky.
Vitamin D Deficiency.
Vitamin D deficiency has been estimated to account for 29% of cancer mortality in males (38) and has been strongly associated with colon, breast, pancreatic, and prostate cancer (38–44). It also has been associated with a variety of diseases with long latency periods, including cardiovascular disease (45–51). A study of independent, community-dwelling elderly people reported that nursing home admissions, and possibly mortality, were strongly associated with vitamin D inadequacy (52). A large prospective study (50) in women reported that intakes of ≥400 I.U. of vitamin D per day from supplements was associated with a 41% lower risk of multiple sclerosis compared with women that did not consume vitamin D from supplements. It was not possible to definitively attribute the effect to vitamin D, because it was mostly consumed in MVM supplements, which were also associated with lower risk; the authors concluded that vitamin D was the most likely explanation. Some evidence in humans and rodents suggests that vitamin D deficiency is associated with cognitive dysfunction (90, 91). Numerous authors have suggested that efforts to improve vitamin D status by supplementation could reduce disease incidence and mortality at low cost with few or no adverse effects (39, 41, 49, 53). Many experts suggest the current RDA for vitamin D should be raised (54, 55).
Other Micronutrient Deficiencies Associated with Chronic Degenerative Diseases.
Calcium deficiency is common; it has been associated with chromosome breaks (56) and diabetes (48) in humans and colon cancer in mice (57). Selenium deficiency in mice induces genes linked to DNA damage and oxidative stress (58), and it has been suggested that selenium protects against cancer (59, 60). Potassium in table salt in elderly men was associated with a 40% decrease in cardiovascular disease compared with normal table salt in a randomized controlled trial (RCT) (61). Omega-3 fatty acid deficiency is associated with melanoma and other cancers (62) as well as cognitive dysfunction (63). The effect of B vitamin deficiency on mitochondria was reviewed recently (64). Vitamin B12 deficiency is common in the population (4); it is associated with cognitive dysfunction (65) and multiple sclerosis (66) and induces chromosome breaks (11). The cognitive dysfunction associated with B12 deficiency improved with supplementation within the first year of onset (67). Folate deficiency also causes chromosome breaks (11, 56, 68) and is associated with several human cancers (69, 70). Marginal thiamine deficiency in rats induces the formation of colonic aberrant crypt foci, a preneoplastic lesion in a model for detecting colon carcinogens (64). Thiamine deficiency is also associated with brain dysfunction and diabetes (64). Niacin deficiency in cellular and animal studies appears to be genotoxic (64, 71). Choline deficiency in humans increases DNA damage in lymphocytes (72). In rats, choline deficiency has been associated with brain dysfunction (73), oxidant release, and mitochondrial damage (72).
We and others discussed the need to set micronutrient requirements high enough to minimize DNA and mitochondrial damage (7, 8, 10, 11, 56, 64, 74). For each micronutrient we are investigating the level of deficiency that causes DNA and mitochondrial damage in humans because neither studies using human cells in culture nor studies using rodents can provide this information. End points such as DNA damage in humans might be useful indicators for refining EARs and upper limits (ULs) to more closely approximate the levels required for optimal health.
Some Micronutrient Deficiencies Impair Heme Synthesis, Which Can Result in Mitochondrial Decay, DNA Damage, and Cell Senescence.
Seven micronutrients (pyridoxine, pantothenate, zinc, riboflavin, iron, copper, and biotin) are required for heme synthesis in mitochondria (Table 2). It is likely that a deficiency in any of these seven will cause a deficit of heme and therefore of complex IV, of which heme-a is an essential component (7, 8, 75, 83, 85, 86). The results to date are in Table 2. The normal complement of complex IV keeps oxidants to a minimum; deficits of complex IV result in oxidant leakage, DNA damage, accelerated mitochondrial decay, and cellular aging (8, 83, 85). Table 2 is incomplete because the effects of some deficiencies on human cells in culture have not yet been determined. Deficiencies of iron, zinc, and biotin are discussed below.
Zinc.
Zinc inadequacy is common in adults, ≈12% of whom are below the EAR (4). In human cells in culture, zinc deficiency causes complex IV deficiency and the release of oxidants, resulting in significant oxidative damage to DNA (76–78). Zinc deficiency also causes chromosome breaks in rats (31) and is associated with cancer in both rodents and humans (104). As discussed above, these observations reinforce the need to determine what degree of deficiency in humans results in DNA damage. We think it is likely that the trigger for decreased heme synthesis is the inactivation of the second enzyme of the pathway, δ-aminolevulinate dehydratase, which contains eight atoms of zinc (85, 105). Zinc deficiency in human cells also inactivates other zinc-containing proteins such as the tumor suppressor protein p53 and the DNA base excision repair enzyme, apyrimidinic/apurinic endonuclease, with a resulting synergistic effect on genetic damage (76, 77).
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SHOULD PEOPLE TAKE AN MVM SUPPLEMENT FOR INSURANCE?
Despite the lack of definitive proof of efficacy, I and others believe that public health officials and physicians should recommend that people take a Multi Vitamins and Minerals supplement in addition to leading a healthy lifestyle (133): there are widespread low intakes (4); an impressive array of evidence for MVM supplementation exists, and there is an absence of realistic safety concerns. If this simple change could be implemented, and particularly if MVMs could be made available to the poor, a marked decrease in the prevalence of micronutrient intakes below the RDA would result.
CONCLUSION
Although many results are not definitive and much more research is needed, a large literature suggests that micronutrient inadequacy can lead to cancer and other long-term deleterious consequences. I present a triage theory that explains why these consequences might be expected. Short-term RCTs using end points associated with long-term disease, such as DNA damage and inflammatory markers, are likely to identify populations at risk and further refine levels of micronutrients required for optimum long-term health. Micronutrient inadequacies are widespread in the population, and a Multi Vitamins and Minerals supplement is inexpensive. A solution is to encourage supplementation, particularly in groups of people with widespread deficiencies, in addition to urging people to eat a more balanced diet.
