Low Micronutrient Intake May Accelerate the Degenerative Diseases of Aging Through Allocation of Scarce Micronutrients by Triage

PERSPECTIVE

Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage

Bruce N. Ames* Nutrition and Metabolism Center, Children’s Hospital of Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609

Contributed by Bruce N. Ames, October 6, 2006 (sent for review September 20, 2006)

Inadequate dietary intakes of vitamins and minerals are widespread, most likely due to excessive consumption of energy-rich, micronutrient-poor, refined food. Inadequate intakes may result in chronic metabolic disruption, including mitochondrial decay. Deficien- cies in many micronutrients cause DNA damage, such as chromosome breaks, in cultured human cells or in vivo. Some of these deficiencies also cause mitochondrial decay with oxidant leakage and cellular aging and are associated with late onset diseases such as cancer. I propose DNA damage and late onset disease are consequences of a triage allocation response to micronutrient scarcity. Epi- sodic shortages of micronutrients were common during evolution. Natural selection favors short-term survival at the expense of long-term health. I hypothesize that short-term survival was achieved by allocating scarce micronutrients by triage, in part through an adjustment of the binding affinity of proteins for required micronutrients. If this hypothesis is correct, micronutrient deficiencies that trigger the triage response would accelerate cancer, aging, and neural decay but would leave critical metabolic functions, such as ATP production, intact. Evidence that micronutrient malnutrition increases late onset diseases, such as cancer, is discussed. A mul- tivitamin-mineral supplement is one low-cost way to ensure intake of the Recommended Dietary Allowance of micronutrients throughout life.

oor nutrition has been linked to Table 1. Selected micronutrient inadequacy in the U.S. an increased risk of many dis- % ingesting less than eases, including cancer, heart Nutrient Population group the EAR from food disease, and diabetes. The hu- Pman diet requires both macronutrients, Minerals which are the main source of calories, Iron Women 14–50 years old 16 and micronutrients (Ϸ40 essential min- Magnesium All 56 erals, vitamins, and other biochemicals), Zinc All 12 which are required for virtually all met- Vitamins abolic and developmental processes. The B6 Women Ͼ71 years old 49 leading dietary sources of energy in the Folate Adult women 16 United States are abundant in carbohy- E All 93 drates and fats (1) but deficient in mi- C All 31 cronutrients (i.e., they are energy-dense Less than the EAR is used as a measure of inadequacy in populations (4, 5). The RDA is defined as 2 and nutrient-poor) (2). Such foods are standard deviations above the EAR. Data are from Moshfegh et al. (4). inexpensive and tasty and as a conse- quence are consumed excessively, particularly by the poor (3). Thus, even in the folic acid intakes above the RDA ap- such as the brain with an accompanying United States (4), inadequate intake of pear to be necessary to minimize chro- loss of ambulatory activity (9, 13–16). some vitamins and minerals is common mosome breaks (10, 11). The importance of optimizing meta- (Table 1). Suboptimal consumption of bolic function to prevent mitochondrial micronutrients (4) often accompanies Micronutrient Deficiencies May decay is illustrated by feeding the mito- caloric excess (6, 88) and may be the Accelerate Mitochondrial Decay and chondrial metabolites acetyl carnitine norm among the obese and contribute Degenerative Diseases of Aging, (ALC) and lipoic acid (LA) to old rats. to the pathologies associated with obe- Such as Cancer Carnitine is used for transporting fatty sity. Mitochondrial decay appears to be a acids into the mitochondria; the main Significant chronic metabolic disrup- major contributor to aging and its asso- form of carnitine in the plasma is ALC. tion may occur when consumption of a ciated degenerative diseases, including LA is a mitochondrial coenzyme and is micronutrient is below the current Rec- cancer and neural decay (12). Mitochon- ommended Dietary Allowance (RDA) dria from old rats compared with those (7–10) but above the level that causes from young rats generate increased Author contributions: B.N.A. wrote the paper. acute symptoms. When one component amounts of oxidant by-products (13) and Conflict of interest statement: B.N.A. is a founder of Ju- venon, a company that has licensed the University of Cali- of the metabolic network is inadequate, have decreased membrane potential, fornia patent (B.N.A. and T. Hagen, inventors) on acetyl there may be a variety of repercussions respiratory control ratio, cellular oxygen carnitine plus lipoic acid for rejuvenating old mitochondria. in metabolism, including acceleration of consumption, and cardiolipin (a key Juvenon sells acetyl carnitine plus lipoic acid supplements degenerative diseases. The optimum in- lipid found only in mitochondria). Oxi- and does clinical trials on them. B.N.A.’s founder’s stock was put in a nonprofit foundation at the founding in 1999. He take of each micronutrient necessary to dative damage to DNA, RNA, proteins, is director of Juvenon’s Scientific Advisory Board, but he has maximize a healthy lifespan remains to and lipids in mitochondrial membranes no stock in the company and does not receive any remu- be determined and could even be higher contributes to this decay (9, 13–16) and neration from them. than the current RDA, particularly for leads to functional decline of mitochon- *E-mail: [email protected]. some populations (7, 10). For example, dria, cells, tissues, and eventually organs © 2006 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0608757103 PNAS ͉ November 21, 2006 ͉ vol. 103 ͉ no. 47 ͉ 17589–17594 Downloaded by guest on October 2, 2021 reduced in the mitochondria to a potent resistance to oxidants compared with a and diabetes (48) in humans and colon antioxidant. LA is also an effective in- standard or magnesium-supplemented cancer in mice (57). Selenium deficiency ducer of Ϸ200 phase 2 antioxidant and diet (32). This evidence suggests that in mice induces genes linked to DNA thiol-protective enzymes, including those supplementation programs should be damage and oxidative stress (58), and it required for glutathione synthesis (17– considered, because there is little risk of has been suggested that selenium pro- 19). ALC and LA when added as a sup- magnesium toxicity (5). A standard mul- tects against cancer (59, 60). Potassium plement can act, in some cases synergis- tivitamin–mineral (MVM) supplement in table salt in elderly men was associ- tically, to restore much of the lost does not contain sufficient magnesium ated with a 40% decrease in cardiovas- mitochondrial function in old rats (13– (or calcium) because it would make the cular disease compared with normal 16), which appears to rejuvenate the supplement too bulky. table salt in a randomized controlled mitochondria and improve cognition and trial (RCT) (61). Omega-3 fatty acid other functions (9, 13–16). Vitamin D Deficiency. The dark skin of deficiency is associated with melanoma One possible mechanism of mitochon- people indigenous to southern India, and other cancers (62) as well as cogni- drial decay is that, with age, increased Africa, and other tropical regions pro- tive dysfunction (63). The effect of B oxidative damage to mitochondrial pro- tects against excessive UV light expo- vitamin deficiency on mitochondria was teins causes structural deformation of key sure from the sun. On the other hand, reviewed recently (64). Vitamin B12 de- enzymes that lowers their affinity for the dark skin interferes with the formation ficiency is common in the population enzyme substrate (16). Feeding old rats of vitamin D in the skin, which requires (4); it is associated with cognitive dys- the substrate ALC with LA for a few UV light. Thus, dark-skinned people in function (65) and multiple sclerosis (66) weeks decreases oxidative damage, allow- northern latitudes are often vitamin D- and induces chromosome breaks (11). ing the synthesis of new carnitine acyl deficient. For example, African Ameri- The cognitive dysfunction associated transferase with normal binding affinity cans as a group are particularly deficient with B12 deficiency improved with sup- (Km). This partially restores mitochondrial in vitamin D (33, 34). In The Nether- plementation within the first year of on- function; decreases oxidants, neuronal lands there is a very high level of vita- set (67). Folate deficiency also causes RNA oxidation, and mutagenic aldehydes; min D deficiency during pregnancy in chromosome breaks (11, 56, 68) and is and increases rat ambulatory activity and dark-skinned women (35, 36). Inade- associated with several human cancers cognition (13–16). ALC and LA are not quacy is prevalent in Caucasians as well (69, 70). Marginal thiamine deficiency in thought of as micronutrients, because they (37). Vitamin D deficiency has been es- rats induces the formation of colonic can be synthesized in the body, but they timated to account for 29% of cancer aberrant crypt foci, a preneoplastic le- are illustrative of many normal metabo- mortality in males (38) and has been sion in a model for detecting colon car- lites that may be beneficial in the elderly. strongly associated with colon, breast, cinogens (64). Thiamine deficiency is The association of several micronu- pancreatic, and prostate cancer (38–44). also associated with brain dysfunction trient deficiencies with degenerative It also has been associated with a vari- and diabetes (64). Niacin deficiency in disease, DNA damage, cancer, and mi- ety of diseases with long latency periods, cellular and animal studies appears to tochondrial decay is discussed below. including cardiovascular disease (45–51). be genotoxic (64, 71). Choline defi- A study of independent, community- ciency in humans increases DNA dam- Magnesium Deficiency. Magnesium intakes dwelling elderly people reported that age in lymphocytes (72). In rats, choline for Ϸ56% of adults in the United States nursing home admissions, and possibly deficiency has been associated with are below the Estimated Average Re- mortality, were strongly associated with brain dysfunction (73), oxidant release, quirement (EAR) (Table 1). Intakes vitamin D inadequacy (52). A large pro- and mitochondrial damage (72). below the EAR are especially prevalent spective study (50) in women reported We and others discussed the need to among the poor, teenagers (78% of 14- that intakes of Ն400 I.U. of vitamin D set micronutrient requirements high to 18-year-old males and 91% of 14- to per day from supplements was associ- enough to minimize DNA and mito- 18-year-old females), the obese, African ated with a 41% lower risk of multiple chondrial damage (7, 8, 10, 11, 56, 64, Americans, and the elderly (81%) (4, sclerosis compared with women that did 74). For each micronutrient we are in- 20–24). In humans, magnesium not consume vitamin D from supple- vestigating the level of deficiency that deficiency has been associated with ments. It was not possible to definitively causes DNA and mitochondrial damage colorectal and other cancers (25–28), attribute the effect to vitamin D, be- in humans because neither studies using hypertension, osteoporosis, diabetes, and cause it was mostly consumed in MVM human cells in culture nor studies using the metabolic syndrome (5, 29, 89). In a supplements, which were also associated rodents can provide this information. study of 4,035 men followed for 18 with lower risk; the authors concluded End points such as DNA damage in hu- years, the highest quartile with serum that vitamin D was the most likely ex- mans might be useful indicators for re- magnesium at baseline compared with planation. Some evidence in humans fining EARs and upper limits (ULs) to the lowest had a 40% decrease in all- and rodents suggests that vitamin D de- more closely approximate the levels re- cause mortality and cardiovascular dis- ficiency is associated with cognitive dys- quired for optimal health. ease and a 50% decrease in cancer function (90, 91). Numerous authors deaths (30). In primary human cells in have suggested that efforts to improve Some Micronutrient Deficiencies Impair culture, magnesium deficiency leads to vitamin D status by supplementation Heme Synthesis, Which Can Result in Mito- mitochondrial DNA damage, acceler- could reduce disease incidence and mor- chondrial Decay, DNA Damage, and Cell ated telomere shortening, activation of tality at low cost with few or no adverse Senescence. Seven micronutrients (pyri- cell-cycle arrest proteins, and premature effects (39, 41, 49, 53). Many experts doxine, pantothenate, zinc, riboflavin, senescence (D. W. Killilea, B.N.A., un- suggest the current RDA for vitamin D iron, copper, and biotin) are required published observations). Magnesium de- should be raised (54, 55). for heme synthesis in mitochondria (Ta- ficiency in rats leads to chromosome ble 2). It is likely that a deficiency in breaks (31) and cancer (25). In rats, a Other Micronutrient Deficiencies Associated any of these seven will cause a deficit of diet moderately deficient in magnesium with Chronic Degenerative Diseases. Cal- heme and therefore of complex IV, of increased mortality, blood pressure, in- cium deficiency is common; it has been which heme-a is an essential component flammation, and oxidants and decreased associated with chromosome breaks (56) (7, 8, 75, 83, 85, 86). The results to date

17590 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0608757103 Ames Downloaded by guest on October 2, 2021 Table 2. Micronutrient deficiency and heme: effects on human cells in culture tochondrial succinyl-CoA and glycine, and animals thus resulting in heme deficiency (83). Micronutrient Heme Complex IV Oxidative DNA Early Biotin deficiency in normal human lung deficiency deficit deficit stress damage senescence fibroblasts in culture caused a 40–50% decrease in heme content, oxidant re- Pyridoxine 75 AAlease, premature senescence, and DNA Zinc A 76–78 76–78 damage (83). The relationship of these Riboflavin 75 effects to human intake needs to be de- Iron 79 79 termined (108). Copper 80 81 82 Biotin 83 83 83 83 83 A New Hypothesis: Allocating a Scarce Pantothenate 75 84 Micronutrient by Triage Is there an explanation for the observa- Numbers represent references. A, H. Atamna, S. Askree, and B.N.A., unpublished data. tion that many micronutrient deficiencies are associated with chromosome are in Table 2. The normal complement (99, 100). Dietary iron deficiency in the breaks and cancer in humans, cause of complex IV keeps oxidants to a mini- absence of anemia decreases aerobic DNA damage in rodents or human cells mum; deficits of complex IV result in capacity and physical work performance, in culture, and, where assayed, cause oxidant leakage, DNA damage, acceler- which are improved by iron supplemen- early senescence? I propose DNA ated mitochondrial decay, and cellular tation (101). Iron deficiency has not damage and late onset disease are con- aging (8, 83, 85). Table 2 is incomplete been adequately studied as a possible sequences of a triage allocation mecha- because the effects of some deficiencies risk factor for cancer, and the results nism developed during evolution to on human cells in culture have not yet are discordant (102). However, many cope with episodic micronutrient shortages. For example, living creatures been determined. Deficiencies of iron, studies are looking for a monotonic re- Ϸ zinc, and biotin are discussed below. lationship and do not take into account always have required 15 metals/miner- Iron. Iron deficiency is the most common that one might expect cancer at levels of als for their metabolism, which are dis- micronutrient deficiency in the world, iron that are both too low and too high tributed very unevenly throughout the and anemia is widespread in underde- (79), as in hereditary hemochromatosis, Earth. Thus, episodic shortages probably veloped countries (87). Iron intake in a known risk factor for cancer (103). were common, as probably also was the case for vitamins and other essential U.S. menstruating women is low; Ϸ16% Zinc. Zinc inadequacy is common in micronutrients. Natural selection is are below the EAR (4). Hispanic adults, Ϸ12% of whom are below the known to favor short-term survival at women and the obese are at greater risk EAR (4). In human cells in culture, zinc the expense of long-term health when of being iron-deficient (6). In humans, deficiency causes complex IV deficiency they are in conflict. I hypothesize that iron deficiency anemia is associated with and the release of oxidants, resulting in as the scarcity of a micronutrient in- poor cognitive development in toddlers significant oxidative damage to DNA creases, and after homeostatic adjust- (92), suggesting that iron deficiency in (76–78). Zinc deficiency also causes ments, such as induction of transport humans during critical periods of devel- chromosome breaks in rats (31) and is proteins (109), a triage mechanism for opment harms the developing brain associated with cancer in both rodents allocating scarce micronutrients is acti- (92). Severe iron deficiency causes loss and humans (104). As discussed above, vated that favors short-term survival at of mitochondrial complex IV in selected these observations reinforce the need to the expense of long-term health, in part regions in the brain of neonatal rats determine what degree of deficiency in through an adjustment of the binding (93) and other changes in function, mor- humans results in DNA damage. We affinity of each protein for its required phology, and physiology of the brain think it is likely that the trigger for micronutrient. (88, 94). Iron deficiency in rats damages decreased heme synthesis is the inactiva- The consequences of such triage mitochondria and causes oxidant re- tion of the second enzyme of the path- would be evident at all levels. For exam- ␦ lease, oxidative DNA damage, and de- way, -aminolevulinate dehydratase, ple, in metabolic reactions, enzymes creased mitochondrial efficiency (79). which contains eight atoms of zinc (85, involved in ATP synthesis would be fa- Iron deficiency also is associated with 105). Zinc deficiency in human cells also vored over DNA-repair enzymes; in diminished immune function and neuro- inactivates other zinc-containing pro- cells, erythrocytes would be favored muscular abnormalities (95, 96). The teins such as the tumor suppressor pro- over leukocytes; and in organs, the primary measure used to identify iron tein p53 and the DNA base excision heart would be favored over the liver. deficiency in most human populations is repair enzyme, apyrimidinic͞apurinic Isozymes with different binding con- a reduction in hemoglobin to the point endonuclease, with a resulting synergis- stants for the coenzyme or metal in the of anemia (malaria, HIV, and other tic effect on genetic damage (76, 77). heart or liver could be one of several nutrient deficiencies may also lead to Biotin. Biotin deficiency is more common ways to accomplish this end. Physiologi- Ϸ anemia). The effects of iron deficiency than previously thought; 40% of preg- cal triage is well known: ‘‘when O2 de- occur along a continuum (88, 97), and nant women who do not take a multivi- livery to the tissues is inadequate . . . subclinical iron deficiency may have del- tamin show metabolic signs of deficiency vital organ function is maintained by eterious effects on heme biosynthesis. (106). Marginal biotin deficiency is tera- intrinsic neurohormonal compensatory Iron deficiency without anemia can also togenic in mice (106). Biotin is a pros- mechanisms resulting in distribution of occur in newborns exposed to intrauter- thetic group in four biotin-dependent organ blood flow primarily to the heart, ine hypoxia, such as infants of pre- carboxylases (three of which are solely brain, and adrenal glands and away eclamptic or diabetic mothers (98). In present in mitochondria) that replenish from other ‘nonvital’ organs’’ (110). such cases, iron is prioritized to ery- intermediates in the tricarboxylic acid Similarly, under conditions of deficiency, throid and hemoglobin synthesis, putting cycle (107). Biotin deficiency decreases organs such as the liver lose certain mi- the nonerythroid tissues at risk of iron the activity of these enzymes, leading to cronutrients first, before other more vi- deficiency and hence heme deficiency a decrease of two heme precursors, mi- tal organs (111–116, 150).

Ames PNAS ͉ November 21, 2006 ͉ vol. 103 ͉ no. 47 ͉ 17591 Downloaded by guest on October 2, 2021 The triage hypothesis suggests addi- This approach, focusing on micronutri- consumption of certain micronutrients. tional mechanisms that may be used by ent malnutrition, with additional atten- For example, consuming too high a dose the body to allocate scarce resources. tion to food fortification, in addition to of many of the minerals is toxic (e.g., This hypothesis is testable, and, if vali- continuing efforts to improve diet, might iron, zinc, copper, and selenium, and dated, suggests that it may be necessary be more successful in improving health. some of the vitamins, such as vitamin to optimize intakes of micronutrients It may be easier to convince people to A). Vitamin A was of particular concern according to the needs of the most dis- take an inexpensive MVM supplement until most MVM manufacturers pensable organ or cells in order to maxi- than to markedly change their eating switched recently to using more provita- mize longevity and retard cancer and habits. Evidence is accumulating that a min A. Excess iron is also not difficult other degenerative diseases of aging. MVM supplement, or smaller combina- to achieve in men and postmenopausal There is increasing evidence that nutri- tions of vitamins and minerals, also im- women, who should take readily avail- tional inadequacies during development prove long-term health, reducing heart able MVMs without iron and should can have consequences later in life disease, cancer, and cataracts and im- limit red meat consumption. In mice, (117). For example, fetal malnutrition proving immune function for those who both low (one-third of normal) intake of during the Dutch famine in 1944–1945 consume inadequate diets (122–137, a mixture of vitamins and a 5-fold ex- was associated with coronary artery dis- 155). The potential benefits of an cess caused an increase in intestinal neo- ease in adulthood (117, 118), although MVM in infection have been critically plasia (142). In rats, both too little and both micronutrient and macronutrient reviewed (138). too much iron resulted in mitochondrial malnutrition may have contributed to Should it be necessary to first demon- this late-onset disease. Broadly, such strate efficacy for preventing or delaying damage, release of oxidants, and DNA protein triage would represent an in- long-term chronic diseases such as can- damage (79). However, the percentage stance of ‘‘antagonistic pleiotropy,’’ as cer in RCTs before recommending of the population consuming more than proposed almost 50 years ago by Wil- MVM use (45, 156)? RCTs for micronu- the UL from food is very low compared liams (119) in which a single allele (e.g., trients and long-term effects are ex- with the percentage consuming less than an isozyme with a low affinity for a mi- tremely difficult to do correctly for the EAR (4). Thus, micronutrient defi- cronutrient) may encode both a benefi- many reasons (45): decades are some- ciencies are likely to be a far more im- cial (short-term survival of episodic times required in long latency diseases portant public health problem than deficiency) and a harmful (an increase (139, 140); there are different, and often excess consumption (4). This conclusion in degenerative disease) phenotype. The multiple, consequences of each micronu- is supported by the many epidemiologi- concept of enzyme triage is also broadly trient deficiency; large populations are cal and other human studies cited in this consistent with recent evolutionary the- required; this type of RCT is very ex- article. Thus, taking a daily standard ory about aging, which stresses that se- pensive, and, unlike for drugs, there is MVM supplement is unlikely to be of lection for reproductive success early in no commercial incentive to do trials; concern, because these amounts of mi- life may involve trade-offs that shorten and compliance is difficult to maintain cronutrients are not close to the UL (4). lifespan (120). Malnutrition has been for many years, particularly in controls, Despite the lack of definitive proof of discussed in relation to ‘‘investment pri- who can take readily available MVM efficacy, I and others believe that public orities’’ in birds (151), fetal program- supplements. For all of these reasons it health officials and physicians should ming in humans (152, 153), and type of is unlikely that it will be possible to ob- recommend that people take a MVM immunocompetence (154). tain definitive results from this type of supplement in addition to leading a Moderate reduction in dietary intake RCT, whether it be targeted at single healthy lifestyle (133): there are wide- of macronutrients (calorie restriction) micronutrients or MVMs. For example, spread low intakes (4); an impressive with adequate micronutrients extends two very large RCTs examined effects array of evidence for MVM supplemen- lifespan in various animals (121) but is of supplementation with a limited num- tation exists, and there is an absence of not inconsistent with the triage hypoth- ber of vitamins and minerals on cancer realistic safety concerns. If this simple esis because the normal level of calo- risk (134, 135). Although both of these change could be implemented, and par- ries fed controls could be in excess of RCTs reported a reduction in cancer ticularly if MVMs could be made avail- what is optimal for maximum lifespan. incidence or mortality with supplemen- able to the poor, a marked decrease in tation, methodological concerns have Should People Take an MVM Supplement the prevalence of micronutrient intakes been raised to argue that the results are below the RDA would result. for Insurance? not definitive (156). Fortification of food, such as folate The National Health and Nutrition Ex- Instead of relying only on long-term fortification, is another approach that amination Surveys (NHANES) (4) indi- RCTs (156), all scientific evidence has been shown to improve health and cate that the diets of many in the should be taken into account in making United States do not provide adequate supplementation recommendations (45, is valuable. Fortification, however, might intakes of all of the vitamins and miner- 141). RCTs on short-term end points not be sufficient for population sub- als recommended by official bodies (Ta- such as DNA damage (10) or markers groups that have special needs. For ex- ble 1). From NHANES and Table 1, it of inflammation (125) are feasible and ample, most African Americans are very seems likely that actual intakes of vari- are more likely to yield definitive re- low in vitamin D despite milk fortifica- ous micronutrients from food are not sults. Many other types of experiments tion (33); 75% are lactose-intolerant only inadequate for the poor, teenagers, in humans and animals, including bio- (53); and it seems prudent for African menstruating women, the obese, and the chemical, mechanistic, and epidemiolog- Americans to take a vitamin D or MVM elderly, but for much of the rest of the ical, are also relevant. supplement (54). Fortification is also population as well. However, decades of One does need to be concerned that problematic when some groups in the public health efforts to improve the cumulative effects of supplementation population would be benefited and some American diet have not been very suc- and fortification might exceed ULs. In- harmed. This is relevant for iron, be- cessful, particularly among the poor. creasing consumption of supplements cause menstruating women need more Why not recommend that a MVM sup- and increasing fortification emphasize than men or older women, some of plement be added to a healthy lifestyle? the need for vigilance to prevent over- whom may be getting too much.

17592 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0608757103 Ames Downloaded by guest on October 2, 2021 Other Possibly Useful Supplements times the RDA reversed the deficiency be expected. Short-term RCTs using Other useful supplements include fiber, (65, 148). Most smokers have an inade- end points associated with long-term and omega-3 fatty acids from fish oil, quate intake of vitamin C; 76% are be- disease, such as DNA damage and in- particularly eicosapentaenoic acid and low the EAR (4). The optimal intake of flammatory markers, are likely to iden- docosahexaenoic acid, which appear to micronutrients and metabolites can also tify populations at risk and further be important for brain function and vary with genetic constitution (146, 147, refine levels of micronutrients required have potent antiinflammatory activity 149) (e.g., iron requirements vary with for optimum long-term health. Micronu- (63, 141, 143). Inadequate fiber intakes, age and gender as discussed above). A trient inadequacies are widespread in both soluble and insoluble, are wide- study of a common polymorphism in the the population, and a MVM supplement spread and have adverse health conse- gene for mitochondrial manganese su- is inexpensive. A solution is to encour- quences (144); supplementation is peroxide dismutase demonstrated that age MVM supplementation, particularly inexpensive. Advice to take MVM sup- selenium, ␣-tocopherol, or lycopene in those groups with widespread defi- plements, fiber, and omega-3 fatty acid protected against prostate cancer, and ciencies such as the poor, teenagers, the supplements should always be coupled the combination of all three showed a obese, African Americans, and the el- with advice to eat a good diet, because 10-fold gradient of risk across quartiles derly, in addition to urging people to eat we also need other nutrients and proba- in one form of the polymorphism (149). a more balanced diet. bly phytochemicals that may not be A variety of MVM supplements have present in supplements (145). been developed that reflect different I am indebted to G. Ames, S. Askree, H. Atamna, K. Beckman, G. Block, B. German, needs depending on one’s age and gen- Variable Optimal Requirements L. Gold, H. Helbock, D. Killilea, J. King, T. der, and more are likely to be developed Klask, A. Lal, G. Li, M. Mietus-Snyder, J. The elderly may need more or less of with new knowledge. Nides, M. Stampfer, J. Suh, J. Vance, F. Vit- certain vitamins and metabolites com- eri, P. Wakimoto, W. Willett, and especially pared with younger people, but this is- Conclusion to J. McCann for their suggestions and con- sue has not been thoroughly examined Although many results are not definitive tributions. This work was supported by (146, 147). For example, Ϸ25% of and much more research is needed, a National Foundation for Cancer Research Dutch adults Ͼ70 years of age showed large literature suggests that micronutri- Grant M2661, National Center for Minority Health and Health Disparities Grant P60 mild-to-severe vitamin B12 deficiency ent inadequacy can lead to cancer and MD00222, National Center for Complemen- (148), most likely because of malabsorp- other long-term deleterious conse- tary and Alternative Medicine Grant R21 tion rather than low dietary intakes (4). quences. I present a triage theory that AT001918, and Research Scientist Award Vitamin B12 intakes at levels many explains why these consequences might K05 AT001323.

1. Block G (2004) J Food Composition Anal 17:439–447. 18. Suh JH, Wang H, Liu RM, Liu J, Hagen TM 38. Giovannucci E, Liu Y, Rimm EB, Hollis BW, 2. Kant AK (2000) Am J Clin Nutr 72:929–936. (2004) Arch Biochem Biophys 423:126–135. Fuchs CS, Stampfer MJ, Willett WC (2006) J Natl 3. Karp R (2006) in Modern Nutrition in Health and 19. Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen Cancer Inst 98:451–459. Disease, eds Olson JA, Shike M, Ross AC (Lippincott TM (2004) Curr Med Chem 11:1135–1146. 39. Garland CF, Garland FC, Gorham ED, Lipkin Williams & Wilkins, New York), pp 861–874. 20. Wakimoto P, Block G (2001) J Gerontol A Biol M, Newmark H, Mohr SB, Holick MF (2006) 4. Moshfegh A, Goldman J, Cleveland L (2005) Sci Med Sci 56:65–80. Am J Public Health 96:252–261. What We Eat in America, NHANES 2001–2002: 21. Fox CH, Mahoney MC, Ramsoomair D, Carter 40. Skinner H, Michaud D, Giovannucci E, Willett Usual Nutrient Intakes from Food Compared to CA (2003) J Natl Med Assoc 95:257–262. W, Colditz G, Fuchs C (2006) Cancer Epidemiol Dietary Reference Intakes (U.S. Department of 22. Vaquero MP (2002) J Nutr Health Aging 6:147–153. Biomarkers Prev 15:1688–1695. Agriculture Agricultural Research Service, 23. Ford ES (1998) Ethn Dis 8:10–20. 41. Gorham ED, Garland CF, Garland FC, Grant Washington, DC). 24. U.S. Department of Agriculture Agricultural Re- WB, Mohr SB, Lipkin M, Newmark HL, Gio- 5. Standing Committee on the Scientific Evaluation search Service. (1999) Data Tables: Food and Nutrient vannucci E, Wei M, Holick MF (2005) J Steroid of Dietary Reference Intakes, Food and Nutri- Intakes by Income, 1994–96. Available at www. Biochem Mol Biol 97:179–194. ͞ ͞ ͞ ͞ tion Board, Institute of Medicine (1997) Dietary barc.usda.gov bhnrc foodsurvey home htm. Ac- 42. Grant WB (2006) Prog Biophys Mol Biol 92: Reference Intakes for Calcium, Phosphorus, Mag- cessed September 20, 2006. 65–79. nesium, Vitamin D, and Fluoride (Natl Acad 25. Hartwig A (2001) Mutat Res 475:113–121. 43. Grant WB, Garland CF (2006) Anticancer Res Press, Washington, DC), pp 190–249. 26. Folsom AR, Hong CP (2006) Am J Epidemiol 26:2687–2699. 6. Nead KG, Halterman JS, Kaczorowski JM, Auinger 163:232–235. 44. van der Rhee HJ, de Vries E, Coebergh JW 27. Larsson S, Bergkvist L, Wolk A (2005) JAmMed P, Weitzman M (2004) Pediatrics 114:104–108. (2006) Eur J Cancer 42:2222–2232. Assoc 293:86–89. 7. Ames BN (2005) EMBO Rep 6:S20–S24. 45. Heaney RP (2006) Am J Clin Nutr 84:471–472. 28. Blondell JM (1980) Med Hypotheses 6:863–871. 8. Ames BN, Atamna H, Killilea DW (2005) Mol 46. Holick MF (2004) Am J Clin Nutr 80:1678S– 29. He K, Liu K, Daviglus ML, Morris SJ, Loria CM, Aspects Med 26:363–378. 1688S. Van Horn L, Jacobs DR, Jr, Savage PJ (2006) 9. Ames BN, Liu J, Atamna H, Hagen TM (2003) 47. Cantorna MT, Mahon BD (2004) Exp Biol Med Circulation 113:1675–1682. Clin Neurosci Res 2:331–338. (Maywood, NJ) 229:1136–1142. 30. Leone N, Courbon D, Ducimetiere P, Zureik M 10. Fenech M (2003) Nutr Res Rev 16:109–122. 48. Pittas AG, Dawson-Hughes B, Li T, Van Dam (2006) Epidemiology 17:308–314. 11. Fenech M (2005) Mutagenesis 20:255–269. 31. Bell LT, Branstrator M, Roux C, Hurley LS RM, Willett WC, Manson JE, Hu FB (2006) 12. Shigenaga MK, Hagen TM, Ames BN (1994) (1975) Teratology 12:221–226. Diabetes Care 29:650–656. Proc Natl Acad Sci USA 91:10771–10778. 32. Blache D, Devaux S, Joubert O, Loreau N, 49. Zittermann A (2006) Prog Biophys Mol Biol 13. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll Schneider M, Durand P, Prost M, Gaume V, 92:39–48. RT, Vinarsky V, Bartholomew JC, Ames BN (2002) Adrian M, Laurant P, Berthelot A (2006) Free 50. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Proc Natl Acad Sci USA 99:1870–1875. Radical Biol Med 41:277–284. Olek MJ, Willett WC, Ascherio A (2004) Neu- 14. Hagen TM, Moreau R, Suh JH, Visioli F (2002) 33. Harris SS (2006) J Nutr 136:1126–1129. rology 62:60–65. Ann NY Acad Sci 959:491–507. 34. Nesby-Odell S, Scanlon K, Cogswell M, Gillespie 51. Luong KV, Nguyen LT (2006) Curr Med Chem 15. Liu J, Head E, Gharib AM, Yuan W, Ingersoll C, Hollis BW, Looker AC, Allen C, Doughertly 13:2443–2447. RT, Hagen TM, Cotman CW, Ames BN (2002) C, Gunter EW, Bowman BA (2002) Am J Clin 52. Visser M, Deeg DJ, Puts MT, Seidell JC, Lips P Proc Natl Acad Sci USA 99:2356–2361. Nutr 76:187–192. (2006) Am J Clin Nutr 84:616–622. 16. Liu J, Killilea DW, Ames BN (2002) Proc Natl 35. Hollis BW, Wagner CL (2006) Am J Clin Nutr 84:273. 53. Byers KG, Savaiano DA (2005) J Am Coll Nutr Acad Sci USA 99:1876–1881. 36. van der Meer IM, Karamali NS, Boeke AJ, Lips 24:569S–573S. 17. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal P, Middelkoop BJ, Verhoeven I, Wuister JD 54. Bischoff-Ferrari H, Giovannucci E, Willett W, AK, Liu RM, Hagen TM (2004) Proc Natl Acad (2006) Am J Clin Nutr 84:350–353. Dietrich T, Dawson-Hughes B (2006) Am J Clin Sci USA 101:3381–3386. 37. Holick MF (2006) Mayo Clin Proc 81:353–373. Nutr 84:18–28.

Ames PNAS ͉ November 21, 2006 ͉ vol. 103 ͉ no. 47 ͉ 17593 Downloaded by guest on October 2, 2021 55. Johnson MA, Kimlin MG (2006) Nutr Rev 93. de Deungria M, Rao R, Wobken JD, Luciana M, 128. Holmquist C, Larsson S, Wolk A, de Faire U 64:410–421. Nelson CA, Georgieff MK (2000) Pediatr Res (2003) J Nutr 133:2650–2654. 56. Fenech M, Baghurst P, Luderer W, Turner J, 48:169–176. 129. Jacobs EJ, Connell CJ, Chao A, McCullough Record S, Ceppi M, Bonassi S (2005) Carcino- 94. Youdim MB, Yehuda S (2000) Cell Mol Biol ML, Rodriguez C, Thun MJ, Calle EE (2003) genesis 26:991–999. (Noisy-le-Grand) 46:491–500. Am J Epidemiol 158:621–628. 57. Lipkin M, Newmark H (1995) J Cell Biochem 95. Failla ML (2003) J Nutr 133:1443S–1447S. 130. Oakley GP, Jr (1998) N Engl J Med 338:1060–1061. 22(Suppl):65–73. 96. Viteri FE, Gonzalez H (2002) Nutr Rev 60:S77–S83. 131. Olshan AF, Smith JC, Bondy ML, Neglia JP, 58. Rao L, Puschner B, Prolla TA (2001) J Nutr 97. Dallman PR (1986) Annu Rev Nutr 6:13–40. Pollock BH (2002) Epidemiology 13:575–580. 98. Chockalingam UM, Murphy E, Ophoven JC, 131:3175–3181. 132. Scholl TO, Hediger ML, Bendich A, Schall JI, Weisdorf SA, Georgieff MK (1987) J Pediatr 59. Combs GF, Jr (2005) J Nutr 135:343–347. Smith WK, Krueger PM (1997) Am J Epidemiol 111:283–286. 60. Trumbo PR (2005) J Nutr 135:354–356. 146:134–141. 61. Chang HY, Hu YW, Yue CS, Wen YW, Yeh WT, 99. Rao R, Georgieff MK (2002) Acta Paediatr Suppl 91:124–129. 133. Willett WC, Stampfer MJ (2001) N Engl J Med Hsu LS, Tsai SY, Pan WH (2006) Am J Clin Nutr 345:1819–1824. 83:1289–1296. 100. Guiang SF, III, Georgieff MK, Lambert DJ, Schmidt RL, Widness JA (1997) Am J Physiol 134. Hercberg S, Galan P, Preziosi P, Bertrais S, 62. Denkins Y, Kempf D, Ferniz M, Nileshwar S, Mennen L, Malvy D, Roussel A, Favier A, Brian- Marchetti D (2005) J Lipid Res 46:1278–1284. 273:R2124–R2131. 101. Brutsaert TD, Hernandez-Cordero S, Rivera J, con S (2004) Arch Intern Med 164:2335–2342. 63. McCann JC, Ames BN (2005) Am J Clin Nutr Viola T, Hughes G, Haas JD (2003) Am J Clin 135. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, 82:281–295. Nutr 77:441–448. Wang GQ, Yang CS, Zheng SF, Gail M, Li GY, 64. Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien 102. Hercberg S, Estaquio C, Czernichow S, Mennen L, et al. (1993) J Natl Cancer Inst 85:1483–1492. PJ (2006) Chem Biol Interact 163:94–112. Noisette N, Bertrais S, Renversez JC, Briancon S, 136. Taylor PR, Wang GQ, Dawsey SM, Guo W, 65. Park S, Johnson MA (2006) Nutr Rev 64:373–378. Favier A, Galan P (2005) J Nutr 135:2664–2668. Mark SD, Li JY, Blot WJ, Li B (1995) Am J Clin 66. Miller A, Korem M, Almog R, Galboiz Y (2005) 103. Elmberg M, Hultcrantz R, Ekbom A, Brandt L, Nutr 62:1420S–1423S. J Neurol Sci 233:93–97. Olsson S, Olsson R, Lindgren S, Loof L, Stal P, 137. Li JY, Taylor PR, Li B, Dawsey S, Wang GQ, 67. Martin DC, Francis J, Protetch J, Huff FJ (1992) Wallerstedt S, et al. (2003) Gastroenterology Ershow AG, Guo W, Liu SF, Yang CS, Shen Q, J Am Geriatr Soc 40:168–172. 125:1733–1741. 68. Blount BC, Mack MM, Wehr C, MacGregor J, et al. (1993) J Natl Cancer Inst 85:1492–1498. 104. Fong LY, Zhang L, Jiang Y, Farber JL (2005) 138. Fawzi W, Stampfer MJ (2003) Ann Intern Med Hiatt R, Wang G, Wickramasinghe SN, Everson J Natl Cancer Inst 97:40–50. 138:430–431. RB, Ames BN (1997) Proc Natl Acad Sci USA 105. Jaffe EK (2004) Bioorg Chem 32:316–325. 139. Giovannucci E, Egan KM, Hunter DJ, Stampfer 94:3290–3295. 106. Mock DM (2005) J Nutr Biochem 16:435–437. MJ, Colditz GA, Willett WC, Speizer FE (1995) 69. Ames BN, Wakimoto P (2002) Nat Rev Cancer 107. Mock DM (1996) Biotin (Int Life Sci Inst Press, N Engl J Med 2:694–704. Washington, DC). 333:609–614. 70. Choi SW, Mason JB (2000) J Nutr 130:129–132. 108. Stratton SL, Bogusiewicz A, Mock MM, Mock 140. Giovannucci E, Stampfer MJ, Colditz GA, 71. Kirkland JB (2003) Nutr Cancer 46:110–118. NI, Wells AM, Mock DM (2006) Am J Clin Nutr Hunter DJ, Fuchs C, Rosner BA, Speizer FE, 72. da Costa KA, Niculescu MD, Craciunescu CN, Fi- 84:384–388. Willett WC (1998) Ann Intern Med 129:517–524. scher LM, Zeisel SH (2006) Am J Clin Nutr 84:88–94. 109. Moretti D, Zimmermann MB, Wegmuller R, 141. McCann JC, Ames BN (2006) Am J Clin Nutr 73. McCann JC, Hudes M, Ames BN (2006) Neurosci Walczyk T, Zeder C, Hurrell RF (2006) Am J Clin 83:920–921. Biobehav Rev 30:696–712. Nutr 83:632–638. 142. Bashir O, FitzGerald AJ, Goodlad RA (2004) 74. Ames BN (1998) Toxicol Lett 102–103:5–18. 110. Noori S, Friedlich P, Seri I (2004) in Fetal and Neonatal Carcinogenesis 25:1507–1515. 75. Richert DA, Schulman MP (1959) Am J Clin Nutr Physiology, eds Polin R, Fox W, Abman S (Saunders 143. Simopoulos AP (2002) Biomed Pharmacother 7:416–425. Elsevier, Philadelphia), Vol 1, pp 772–781. 56:365–379. 76. Ho E, Ames BN (2002) Proc Natl Acad Sci USA 111. Ben-Shachar D, Yehuda S, Finberg JP, Spanier I, 144. Standing Committee on the Scientific Evaluation 99:16770–16775. Youdim MB (1988) J Neurochem 50:1434–1437. of Dietary Reference Intakes, Food and Nutri- 77. Ho E, Courtemanche C, Ames BN (2003) J Nutr 112. Chen Q, Connor JR, Beard JL (1995) J Nutr tion Board, Institute of Medicine (2005) Dietary 133:2543–2548. 125:1529–1535. Reference Intakes for Energy, Carbonhydrate, 78. Oteiza PI, Clegg MS, Zago MP, Keen CL (2000) 113. Dallman PR, Siimes MA, Manies EC (1975) Br J Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Free Radical Biol Med 28:1091–1099. Haematol 31:209–215. Amino Acids (Macronutrients) (Natl Acad Press, 114. Erikson KM, Pinero DJ, Connor JR, Beard JL 79. Walter PW, Knutson MD, Paler-Martinez A, Lee Washington, DC), pp 339–421. (1997) J Nutr 127:2030–2038. S, Xu Y, Viteri FE, Ames BN (2002) Proc Natl 145. Willett WC (2001) Eat, Drink and Be Healthy 115. Kaladhar M, Narasinga Rao BS (1982) J Neuro- Acad Sci USA 99:2264–2269. (Simon & Schuster, New York). chem 38:1576–1581. 80. Reeves PG, DeMars LC (2006) J Nutr Biochem Nutrigenomics: 116. Kimura M, Itokawa Y (1989) in Magnesium in 146. Ames BN, Suh JH, Liu J (2006) in 17:635–642. Discovering the Path to Personalized Nutrition,edRo- 81. Rossi L, Lippe G, Marchese E, De Martino A, Health and Disease, eds Itokawa Y, Durlach J (Libbey, London), pp 95–102. driguez JKR (Wiley, Hoboken, NJ), pp 277–293. Mavelli I, Rotilio G, Ciriolo MR (1998) Biomet- 147. Ames BN, Elson-Schwab I, Silver EA (2002) als 11:207–212. 117. Huxley RR (2006) Am J Clin Nutr 84:271–272. 118. Painter RC, de Rooij SR, Bossuyt PM, Simmers TA, Am J Clin Nutr 75:616–658. 82. Johnson WT, DeMars LC (2004) J Nutr Osmond C, Barker DJ, Bleker OP, Roseboom TJ 148. Eussen SJ, de Groot LC, Clarke R, Schneede J, 134:1328–1333. (2006) Am J Clin Nutr 84:322–327; quiz 466–467. Ueland PM, Hoefnagels WH, van Staveren WA 83. Atamna H, Newberry J, Erlitzki E, Schultz CS, 119. Williams GC (1957) Evolution (Lawrence, Kans) (2005) Arch Intern Med 165:1167–1172. Ames BN (2006) J Nutr, in press. 11:398–411. 149. Li H, Kantoff PW, Giovannucci E, Leitzmann 84. Brambl R, Plesofsky-Vig N (1986) Proc Natl Acad 120. Kirkwood TB, Rose MR (1991) Philos Trans R MF, Gaziano JM, Stampfer MJ, Ma J (2005) Sci USA 83:3644–3648. Soc London Ser B 332:15–24. Cancer Res 65:2498–2504. 85. Atamna H (2004) Ageing Res Rev 3:303–318. 121. Barger JL, Walford RL, Weindruch R (2003) Exp 150. Pacheco-Alvarez D, Solorzano-Vargas RS, Gravel J Biol Chem 86. Atamna H, Liu J, Ames BN (2001) Gerontol 38:1343–1351. 276:48410–48416. RA, Cervantes-Roldan R, Velazquez A, Leon-Del- 122. Aisen PS, Egelko S, Andrews H, Diaz-Arrastia Rio A (2004) J Biol Chem 279:52312–52318. 87. World Health Organization (2001) Iron Defi- R, Weiner M, DeCarli C, Jagust W, Miller JW, ciency Anaemia: Assessment, Prevention, and 151. Nowicki S, Searcy WA (2005) Behav Neurosci Green R, Bell K, Sano M (2003) Am J Geriatr 119:1415–1418. Control. A Guide for Programme Managers Psychiatry 11:246–249. 152. Jones JH (2005) Am J Hum Biol 17:22–33. (WHO, Geneva). 123. Barringer TA, Kirk JK, Santaniello AC, Foley KL, 153. Sayer AA, Cooper C, Evans JR, Rauf A, 88. Parikh SJ, Edelman M, Uwaifo GI, Freedman Michielutte R (2003) Ann Intern Med 138:365–371. Wormald RP, Osmond C, Barker DJ (1998) Age RJ, Semega-Janneh M, Reynolds J, Yanovski JA 124. Bendich A, Mallick R, Leader S (1997) West Ageing 27:579–583. (2004) J Clin Endocrinol Metab 89:1196–1199. J Med 166:306–312. 89. vam Dam RM, Hu FB, Rosenberg L, Krishnan S, 125. Church TS, Earnest CP, Wood KA, Kampert JB 154. Long KZ, Nanthakumar N (2004) Am J Hum Biol Palmer JR (2006) Diabetes Care 29:2238–2243. (2003) Am J Med 115:702–707. 16:499–507. 90. Kalueff AV, Tuohimaa P (2006) Curr Opin Clin 126. Fairfield KM, Fletcher RH (2002) JAmMed 155. Bunin GR, Gallagher PR, Rorke-Adams LB, Nutr Metab Care, in press. Assoc 287:3116–3126. Robison LL, Cnaan A (2006) Cancer Epidemiol 91. Mackay-Sim A, Feron F, Eyles D, Burne T, 127. Giovannucci E, Stampfer MJ, Colditz GA, Hun- Biomarkers Prev 15:1660–1667. McGrath J (2004) Int Rev Neurobiol 59:351–380. ger DJ, Fuchs C, Rosner BA, Speizer FE, Willett 156. NIH State-of-the-Science Panel (2006) Ann In- 92. McCann JC, Ames BN (2006) Am J Clin Nutr, in press. WC (1998) Ann Intern Med 129:517–524. tern Med 145:364–371.

17594 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0608757103 Ames Downloaded by guest on October 2, 2021