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University of California, Berkeley and Children's Hospital and Research Center at Oakland, Oakland, CA 94609
3 To whom correspondence should be addressed. E-mail: bames{at}chori.org.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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10% in the U.S.) causes oxidation and DNA damage in human cells. 2) The Km concept. Approximately 50 different human genetic diseases that are due to a poorer binding affinity (Km) of the mutant enzyme for its coenzyme can be remedied by feeding high-dose B vitamins, which raise levels of the corresponding coenzyme. Many polymorphisms also result in a lowered affinity of enzyme for coenzyme. 3) Mitochondrial oxidative decay with age. This decay, which is a major contributor to aging, can be ameliorated by feeding old rats the normal mitochondrial metabolites acetyl carnitine and lipoic acid at high levels. They restore the Km for acetyl carnitine transferase and the velocity of the reaction as well as mitochondrial function; reduce levels of oxidants, neuron RNA oxidation and mutagenic aldehydes; and increase old-rat ambulatory activity and cognition.
KEY WORDS: • essential vitamins and minerals • DNA damage • aging • cancer
Metabolic harmony
Maximum health and life span require metabolic harmony. It is commonly thought that American's intake of the >40 essential micronutrients (vitamins, minerals and other biochemicals that humans require) is adequate. Classic deficiency diseases such as scurvy, beriberi, pernicious anemia and rickets are rare. We think the evidence suggests that much metabolic damage occurs at levels between the level that causes acute micronutrient deficiency disease and the recommended dietary allowances (RDA). 4 However, the prevention of more subtle metabolic damage is not addressed by current RDA. When one input in the metabolic network is inadequate, repercussions are felt on a large number of systems and can lead to degenerative disease. This may, for example, result in an increase in DNA damage (and possibly cancer), or neuron decay (and possibly cognitive dysfunction) or mitochondrial decay (and possibly accelerated aging and degenerative diseases). The optimum amount of folic acid or zinc that is truly "required" is the amount that minimizes DNA damage and maximizes a healthy life span, which is higher than the amount needed to prevent acute disease. The requirements of the old for vitamins and metabolites are likely to be different from those of the young, but this issue has not been seriously examined. An optimal intake of micronutrients and metabolites also varies with genetic constitution. A tune-up of micronutrient metabolism should give a marked increase in health at little cost. It is inexcusable that anyone in the world should have an inadequate intake of a vitamin or mineral, at great cost to that person's health, when a year's supply of a daily multivitamin/mineral pill as insurance against deficiencies costs less than a few packs of cigarettes. The poor, in general, eat the worst diets and have the most to gain from multivitamin/mineral supplementation and improvement in diet. As Hippocrates said, "Leave your drugs in the chemist's pot if you can heal the patient with food."
Why micronutrients?
Although many degenerative diseases benefit from optimal nutrition, and although optimal nutrition clearly involves more than adequate micronutrients, there are important reasons for focusing on micronutrients and health, particularly DNA damage (1). 1) More than 20 years of effort to improve the American diet have not been notably successful, particularly with less-educated people, although this work must continue. A parallel approach that focuses on micronutrient intake is overdue and might be more successful, because it should be easier to convince people to take a multivitamin/mineral pill as insurance against ill health than to change their diet significantly. 2) A multivitamin/mineral pill is inexpensive, recognized as safe and supplies the range of vitamins and minerals that a person requires although not the essential fatty acids. It is likely that these essential fatty acids will be available as supplements soon, because evidence is mounting on their utility. Fortification of food is another approach that is useful, but it has been implemented very slowly as with the folate fortification. Moreover, fortification of food does not allow for differences between individuals. For example, menstruating women need more iron than men or older women, who may be getting too much. That is why two types of vitamin pills are marketed: one with iron and one without. With more knowledge, it seems likely that a variety of multivitamin pills will be developed that reflects knowledge about different needs depending on age, sex, genetics, etc.
DNA damage from vitamin and mineral deficiencies
DNA damage, which is a cause of cancer (although not the only one), is recognized as deleterious and can be assayed easily and relatively inexpensively in human white cells during intervention studies, in contrast to cancer. Our strategy in the laboratory has been to use a variety of human cell lines in culture, to cause growth limitation by deficiency of a particular micronutrient and then to measure DNA damage by a variety of assays followed by collaborations on human intervention studies. We are also developing improved assays for measuring DNA damage in humans.
Deficiency of vitamins B-12, folic acid, B-6, niacin, C or E, or iron or zinc appears to mimic radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions or both. Half of the population may be deficient in at least one of these micronutrients (2). We have shown (3) that folate deficiency breaks chromosomes due to massive incorporation of uracil in human DNA (millions per cell) with subsequent single-strand breaks in DNA formed during base-excision repair: two nearby single-strand breaks on opposite strands cause the chromosome to break. The level of folate where we see high uracil and breaks was present, before the recent flour supplementation, in 25% of the U.S. population and close to half of poor urban minorities due to poor diets. Deficiencies (<50% of the RDA) of vitamins B-12 (10% women; 5% men) or B-6 (10% of U.S.) also cause high levels of uracil incorporation in human DNA and chromosome breaks as indicated by our new evidence and as expected from mechanistic considerations (4,
5). We are currently attempting to determine the level of these three vitamins that minimizes both nuclear and mitochondrial DNA damage in humans (3–
5). Micronutrient deficiency may explain, in good part, why the quarter of the population that eats the fewest fruits and vegetables (five portions a day is advised) has about double the cancer rate for most types of cancer when compared to the quarter with the highest intake: 80% of American children and adolescents and 68% of adults do not eat five portions a day (2). A number of other degenerative diseases of aging are also associated with low fruit and vegetable intake.
Inadequate iron (25% of women of menstruating age in the U.S. ingest <50% of the RDA) causes oxidative damage to mitochondria and mitochondrial DNA in rats (6,
7). The poor tend to have the lowest levels and intake (8,
9). Inadequate zinc intake (10% of the U.S. ingest <50% of the RDA) in human cells in culture causes oxidative DNA damage, inactivation of copper, zinc–superoxide dismutase, inactivation of tumor suppressor protein p53 (a zinc protein) and inactivation of oxidative DNA repair; these effects can multiply to cause severe genetic damage (9a). It would be useful if one of these markers were a suitable marker of zinc deficiency in humans, because there is currently no good marker. Selenium deficiency in human cells in culture causes DNA damage under oxidative stress conditions.
Common micronutrient deficiencies, which are likely to damage DNA by the same mechanism as radiation and many chemicals, appear to be orders of magnitude more important (2, 10). We are currently working on comparing radiation with micronutrient deficiencies and trying to put risks in perspective. The poor are not served if huge resources are put into minor hypothetical risks and major risks are not addressed.
Sperm DNA damage and vitamins/minerals
We are investigating the effects of inadequate micronutrient intake on genetic damage to sperm (2). We have shown that folic acid deficiency decreases sperm count in rats by 90%, and that uracil is found in sperm DNA of men on low-fruit and -vegetable diets. Our recent work on folate inadequacy in humans in collaboration with the U.S. Department of Agriculture Human Nutrition laboratory (11) shows an inverse association between the level of the nonmethyl-tetrahydrofolate pool but not the methyl-tetrahydrofolate pool with both sperm count and quality, which is consistent with a uracil-misincorporation mechanism. We had previously shown (2) that men with low–vitamin C intake had more oxidative damage to their sperm DNA, and that male smokers (smoking depletes the vitamin C level markedly) had more oxidative damage to their sperm. Recent epidemiological data support the notion that smoking males have more offspring with childhood cancer.
Zinc deficiency may also contribute to sperm damage; zinc is known to be essential for normal male reproductive function. In the Middle East where low-zinc, high-phytate diets are common (phytate binds zinc so that it is nutritionally unavailable), zinc-deficient males exhibit delayed sexual maturation and hypogonadism. Zinc is present at very high concentrations in seminal fluid (100 µg/mL) relative to blood plasma (<1 µg/mL) and is mainly of prostatic origin. In a collaborative study between our laboratory and that of Janet King, a survey of 69 healthy men revealed suggestive correlations between seminal plasma zinc and both total sperm count and semen volume. In a recent intervention study (12), 24 subfertile men who took a daily supplement that contained both 66 mg of zinc sulfate and 5 mg of folic acid for 26 wk experienced a 74% increase (from baseline) in total normal sperm count. The study did not examine an independent effect of zinc and folate. Although vegetarian males are generally more healthy than nonvegetarians, those who consume whole grains (which contain phytate) could be at risk for low zinc intakes and possible reproductive problems in addition to the known possibility of vitamin B-12 deficiency.
Micronutrient inadequacy and cognitive dysfunction
Many micronutrient deficiencies appear to contribute to cognitive dysfunction in addition to iodine deficiency, which has long been known to increase cretinism in the offspring of iodine-deficient mothers. There is a large literature that shows that inadequate iron or zinc intake causes cognitive dysfunction in rats and humans (13, 14). An analysis of data from the Women, Infants and Children program, which is geared to promote good nutrition in the low-income population, indicates that 18.5% of the children in the program were anemic in 1999; this is not much progress from the 21% in 1995 (F. Viteri, personal communication). Our studies on mechanism in the case of iron suggest that cognitive dysfunction may be due to mitochondrial damage in the brain (6). A large number of studies (15) have found beneficial effects of micronutrient supplementation on cognitive function in children. Another large literature supports the case that low intake of the vitamins folate, B-12 and B-6 with accompanying homocysteine accumulation contributes to Alzheimer's disease (16, 17). Essential long-chain fatty acids such as docosahexaenoic acid, usually derived from fish oil in the diet, make up 30% of the fatty acids of the neurons and appear to be the factors in breast milk that account for the increased intelligence of children fed breast milk compared to formula (18). Studies implicate docosahexaenoic acid deficiency in Alzheimer's disease, attention-deficit hyperactivity disorder and dementia (19, 20).
Dark skin, vitamin D and calcium deficiency
The hormone vitamin D is formed in the skin with the aid of ultraviolet (UV) light from sunshine; however, too much exposure to UV light is dangerous. Humans who originate from northern areas with little UV radiation have light skin to maximize their exposure to UV rays, whereas people from southern areas have dark skin to minimize their UV light exposure. Northern populations in the U.S. are exposed to insufficient sunshine and individuals are often chronically vitamin-D deficient unless they drink vitamin D–fortified milk. Dark-skinned people who live in northern areas such as the northern cities of Boston, Detroit, Cleveland, Chicago and Seattle who don't drink fortified milk are the people who are primarily at risk unless they take a supplement. "Although both dark- and light-skinned individuals can produce vitamin D in response to UV light, this response is much more limited in dark-skinned individuals. The 25-hydroxyvitamin D [25(OH)D] levels in African-Americans and Hispanics are, therefore, lower than Caucasians in the U.S." (21). In a study in Boston, 80% of African-Americans and 60% of Hispanics were vitamin D deficient (22 and M. F. Holick, personal communication). Vitamin D is necessary for calcium mobilization for bone formation, and brittle bones are a consequence of vitamin D deficiency. In addition, there is an inverse relationship between vitamin D intake or levels and several types of cancer, primarily colorectal cancer and colorectal adenomas; there is also evidence for a connection with prostate cancer (23– 26). A higher intake of calcium has been shown to lower risk for colorectal adenoma recurrence (27). A plausible mechanism by which vitamin D deficiency could increase cancer is the known inhibitory effect of vitamin D metabolites on cell proliferation, which is an essential component of carcinogenesis (25). African-Americans have almost double the prostate cancer rate of whites and also have lower levels of the vitamin D metabolite 25(OH)D in their blood (26). Europeans and other northern people domesticated cows thousands of years ago and developed the ability as adults to metabolize lactose, which is a major sugar in cow's milk. Most of the rest of the world cannot use lactose as adults and therefore show lactose intolerance when they drink cow's milk and tend to avoid it; 70% of African-Americans, 53% of Mexican-Americans and 90% of Asians are lactose intolerant compared to 15% of northern Europeans and their descendents. Thus, dark-skinned people such as African-Americans and some Hispanics tend not to drink milk as adults, and as they also tend not to take vitamin supplements, these individuals are all the more likely to be calcium and vitamin D deficient (9). Most nutrient deficiencies correlate as well with poverty or low education as with ethnicity. However, in some cases, such as vitamin D or calcium, it is clear that genetics is an important contributor. African-Americans have lower calcium, magnesium, potassium and folate intakes than whites (9). The vitamin D/calcium story illustrates why understanding genetics is important in some cases to develop appropriate interventions for the populations at risk.
Obesity: Do micronutrient deficiencies counteract satiety?
There is an epidemic in the U.S. of obesity with associated insulin resistance and type II diabetes. Although this epidemic is widespread in all groups, it is most prevalent in the poor and particularly in African-Americans and Hispanics. It has been estimated (28) that the toll on health will exceed that of smoking. We hypothesize that micronutrient deficiency counteracts the normal feeling of satiety after sufficient calories are eaten. This may be a biological strategy for obtaining missing nutrients, which is important in fertility. Thus, part of the reason for the obesity epidemic may be that energy-dense, micronutrient-poor diets leave the consumer deficient in key micronutrients (29), e.g., calcium, and constantly hungry. A recent paper provides convincing evidence that dairy-product consumption, the main source of calcium, is inversely related to obesity, diabetes and insulin resistance in the large CARDIA (Coronary Artery Disease Risk Development in Young Adults) study (30).
Delaying the mitochondrial decay of aging
Oxidative mitochondrial decay is a major contributor to aging (31– 35). We are making progress in reversing some of this decay in old rats by feeding them normal mitochondrial metabolites acetyl carnitine (ALCAR) and lipoic acid (LA) at high levels. The principle behind this effect appears to be that with age, increased oxidative damage to protein causes a deformation of structure of key enzymes with a consequent lessening of affinity (Km) for the enzyme substrate (36). The effect of age on the enzyme-binding affinity can be mimicked by reacting it with malondialdehyde (a lipid-peroxidation product that increases with age). Feeding the substrate ALCAR with LA, a mitochondrial antioxidant, restores the velocity of the reaction (Km) for ALCAR transferase and mitochondrial function (36). In old rats (versus young rats), mitochondrial membrane potential, cardiolipin level, respiratory control ratio and cellular O2 uptake are lower; oxidants/O2, neuron RNA oxidation and mutagenic aldehydes from lipid peroxidation are higher (33, 36– 43). Ambulatory activity and cognition declines with age (37, 38). Feeding old rats ALCAR with LA for a few weeks restores mitochondrial function; lowers oxidants, neuron RNA oxidation and mutagenic aldehydes and increases rat ambulatory activity and cognition (as assayed with the Skinner box and Morris water maze) (36– 38).
Common micronutrient deficiencies accelerate mitochondrial decay
Heme biosynthesis is predominantly in the mitochondria. Interfering with heme synthesis causes specific loss of complex IV with consequent release of oxidants (44, 45). Iron deficiency (25% of menstruating women in the U.S. ingest <50% of the RDA) also causes release of oxidants and mitochondrial decay (46) presumably through lack of heme (44). Vitamin B-6 deficiency (10% of Americans ingest <50% of the RDA) would also cause a heme deficiency (44). The consequences are likely to be accelerated aging and neural decay (46a).
The Km concept and metabolism
As many as one-third of all mutations in a gene result in the corresponding enzyme having an increased Michaelis constant/Km (a decreased binding affinity) for a coenzyme, and therefore result in a lower rate of reaction. Thus, many of the carriers of 50 human genetic diseases that are due to defective enzymes can be remedied or ameliorated by the administration of high doses of the B-vitamin component of the corresponding coenzyme, which raise levels of the coenzyme and at least partially restore enzymatic activity (47). Several single-nucleotide polymorphisms, in which the variant amino acid reduces coenzyme binding and thus enzymatic activity, are likely to be remediable by increasing cellular concentrations of the cofactor through high-dose vitamin therapy. Some examples include C 677 T/Ala222Val methylenetetrahydrofolate reductase (NADPH) and the cofactor FAD (in relation to cardiovascular disease, migraines and rages), the C609T/Pro187Ser mutation in NAD(P):quinone oxidoreductase1 and FAD (in relation to cancer), the C131G/Ala44Gly mutation in glucose-6-phosphate 1-dehydrogenase and NADP (in relation to favism and hemolytic anemia) and the Glu487Lys mutation (present in one-half of Asians) in aldehyde dehydrogenase and NAD (in relation to alcohol intolerance, Alzheimer's disease and cancer). The Km concept is relevant for mitochondrial aging as well as for human nutrition. To encourage further discussion and new information on this topic, we have set up a Web site at www.KmMutants.org.
Public health
A metabolic tune-up is likely to have enormous health benefits, particularly for those with inadequate diets such as many of the poor and the elderly who need improvement the most, although it is currently not being addressed adequately by the medical community. The issues discussed here highlight the need to educate the public about the crucial importance of optimal nutrition and the potential health benefits of something as simple and affordable as a daily multivitamin/multimineral supplement. Tuning up metabolism to maximize the human health span will require scientists, clinicians and educators to abandon outdated paradigms of micronutrients merely preventing deficiency disease and explore more meaningful ways to prevent chronic disease and achieve optimal health through optimal nutrition.
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FOOTNOTES |
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2 This study was supported by National Foundation for Cancer Research Grant 00-CHORI, Ellison Medical Foundation Grant SS-0422-99, The Wheeler Foundation Fund of the University of California, National Institute on Aging Grant AG17140 and National Institute of Environmental Health Sciences Center Grant P30-ES01896.
4 Abbreviations used: ALCAR, acetyl carnitine; LA, lipoic acid; RDA, recommended dietary allowance.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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