Professional Documents
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Micronutrients
Micronutrients
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, micro-
nutrient-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 defi-
ciencies 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.
P
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-
man diet requires both macronutrients, Minerals
which are the main source of calories, Iron Women 14–50 years old 16
and micronutrients (⬇40 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 ⬎71 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, partic-
ularly 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
Author contributions: B.N.A. wrote the paper.
(7–10) but above the level that causes from young rats generate increased
Conflict of interest statement: B.N.A. is a founder of Ju-
acute symptoms. When one component amounts of oxidant by-products (13) and
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.
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in metabolism, including acceleration of consumption, and cardiolipin (a key Juvenon sells acetyl carnitine plus lipoic acid supplements
and does clinical trials on them. B.N.A.’s founder’s stock was
degenerative diseases. The optimum in- lipid found only in mitochondria). Oxi- 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: bames@chori.org.
some populations (7, 10). For example, dria, cells, tissues, and eventually organs © 2006 by The National Academy of Sciences of the USA
www.pnas.org兾cgi兾doi兾10.1073兾pnas.0608757103 PNAS 兩 November 21, 2006 兩 vol. 103 兩 no. 47 兩 17589 –17594
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 ⬇200 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 ⬇56% 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 ⱖ400 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
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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
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).
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.
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