Trace metals and the elderly

Clin Geriatr Med 18 (2002) 801 – 818

Trace metals and the elderly Craig J. McClain, MDa,b,*, Marion McClain, MSa, Shirish Barve, PhDa, Maria G. Boosalis, PhDc a

Department of Internal Medicine, University of Louisville Medical Center, 550 S. Jackson Street, ACB 3rd Floor, Louisville, KY 40292, USA b Veterans Administration Hospital, 800 Zorn Avenue Louisville, KY 40206, USA c College of Allied Health Professions, University of Kentucky, 121 Washington Ave., Lexington, KY 40256, USA

The elderly are at nutritional risk as a result of multiple physiological, social, psychological, and economic factors [1 – 3]. Elderly persons have a higher incidence of chronic diseases and associated intake of medications that may affect nutrient utilization. An example is diuretic use, which can cause increased urinary loss of trace metals such as zinc. Social and economic conditions can adversely affect dietary choices and eating patterns. Physiological functions naturally decline with age, which may influence absorption and metabolism. Loneliness and reluctance to eat may complicate an already marginal situation. This article reviews specific trace metals (zinc, copper, selenium, and chromium) in relation to the elderly. Our objectives are to provide Dietary Reference Intakes for older adults, to provide information on presenting features and functional consequences of trace metal deficiency, and to discuss potential effects and/or benefits of trace metal supplementation in the elderly.

Dietary reference intakes for older adults The Dietary Reference Intakes (DRIs) are comprised of four categories of reference intakes designed to reflect the latest understanding of nutrient requirements based on optimizing health in individuals and groups (eg, gender, age)

* Corresponding author. Department of Internal Medicine, University of Louisville Medical Center, 550 S. Jackson Street, ACB 3rd Floor, Louisville, KY 40292. E-mail address: [email protected] (C.J. McClain). 0749-0690/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 6 9 0 ( 0 2 ) 0 0 0 4 0 - X

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rather than merely preventing nutritional deficiencies [4 –6]. These four DRIs categories are: 1. Estimated average requirement (EAR), the intake that meets the estimated nutrient need of 50% of the individuals in that group and serves as the basis for developing the recommended dietary allowance. 2. Recommended Dietary Allowance (RDA), the intake that meets the nutrient need of 97% to 98% of individuals in that group. 3. Adequate intakes (AIs), the average observed or experimentally derived intake by a defined population or subgroup that appears to sustain a defined nutritional state, such as normal circulating nutrient values, growth, or other functional indicators of health. If no EAR can be determined, no RDA can be set; consequently, the AI serves as a goal for intake. 4. Tolerable upper intake level (UL), the maximum intake by an individual that is unlikely to pose risks of adverse health effects in 97% to 98% of individuals. It is important to note that the UL is not intended to be a recommended level of intake. For most nutrients, these levels refer to total intake from food, fortified food, and nutrient supplements. Because these revisions are rather recent, vitamin/ mineral formulations may not have been altered as yet to reflect these new recommendations. Table 1 shows the DRIs for trace minerals.

Table 1 The dietary reference intakes of the four trace minerals discussed Zinc Males Females Adults
19 years of age

51 – 70 years and >70 years; RDA is 11 mg/day 51 – 70 years and >70 years; RDA is 8 mg/day Tolerable upper intake level (UL) is 40 mg/day

Copper Males Females 5 Adults
19 years of age

51 – 70 years and >70 years; RDA is 900 ug/day 1 – 70 years and >70 years; RDA is 900 mg/day UL is 10,000 mg/day

Selenium Males Females Adults
19 years of age

51 – 70 years and >70 years; RDA is 55 mg/day 51 – 70 years and >70 years; RDA is 55 mg/day UL is 400 mg/day

Chromium Males

51 – 70 years and >70 years; adequate intake (AI) is 30 mg/day Females 51 – 70 years and >70 years; adequate intake (AI) is 20 mg/day A tolerable upper intake level (UL) was not determined for Cr

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Zinc Zinc is an essential trace element required for protein synthesis and the function of several hundred zinc metalloenzymes and zinc finger proteins. Zinc may also have antioxidant and antiatherogenic properties [7,8]. Approximately one quarter to one third of ingested zinc is absorbed, with modulating factors including competing influences such as phytic acid, zinc status of the subject, and underlying intestinal diseases that may impair zinc absorption or increase intestinal zinc loss. Zinc is absorbed mainly from the small intestine, with colonic absorption being negligible. Zinc is excreted mainly in the feces, with urinary zinc excretion normally being negligible (< 600 mg/24 hr). Zinc is normally bound in the plasma; approximately 70% is bound loosely to albumin, 25% is more tightly bound to alpha-2 macroglobulin, and the remaining is bound to peptides and amino acids. The serum zinc concentration is the most frequently used method of assessing zinc status, but, as discussed later, depressed serum zinc concentrations can also be induced by stress or inflammation. Major food sources for zinc are proteins, such as red meat, and there is a direct correlation between dietary protein and dietary zinc intake. Much of our knowledge concerning the metabolic roles of zinc in humans is derived from manifestations of zinc deficiency either in zinc-deficient animals or in patients with acrodermatitis enteropathica (a hereditary disease of impaired zinc absorption) or acquired zinc deficiency due to an underlying disease process [9]. Eight major functional consequences of zinc deficiency are relevant to the elderly; health care providers should be aware of these diverse presenting features:        

skin lesions diarrhea impaired wound healing and impaired protein metabolism hypogonadism altered visual function anorexia, impaired taste altered mental function altered immune function

Mechanisms for zinc deficiency and hypozincemia can be divided into two main categories: (1) redistribution and (2) true deficiency due to traditional mechanisms such as poor dietary intake, increased excretion, and so forth. Redistribution is an increasingly recognized area whose importance needs to be clarified further. The hypozincemia and altered zinc metabolism in a variety of stress, trauma, and/or gastrointestinal states is due to inflammation with a redistribution of zinc. This redistribution is mediated by cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-6), and probably to a lesser extent by stress hormones. Cytokines injected into experimental animals or humans cause a marked decrease in the serum zinc

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concentration and the internal redistribution of zinc, with zinc going into certain tissues such as the liver [10]. The elderly often exhibit biochemical evidence of mild inflammation secondary to arthritis, urinary tract infection, and so forth. The other form of zinc deficiency is the more classically accepted form, that of zinc deficiency and hypozincemia caused by decreased dietary intake, poor absorption, increased excretion, and so forth. The elderly frequently have inadequate zinc intake, as well as clinical or biochemical zinc deficiency [2,11]. Skin lesions/acrodermatitis Acrodermatitis enteropathica (AE) is a rare hereditary disease occurring in infancy that is characterized by skin lesions, alopecia, failure to thrive, diarrhea, and impaired immune function with frequent infections [12]. Skin lesions in this disease usually tend to occur around the eyes, nose, and mouth and over the buttocks and perianal region. The skin lesions of zinc deficiency are very similar from one animal species to another and are an easily recognizable functional consequence of zinc deficiency. Skin lesions of zinc deficiency have been reported in a variety of other disease processes such as Crohn’s disease, short bowel syndrome, and chronic alcoholism (with or without liver disease) [13 –16]. The mechanisms for these skin lesions and their regional distribution are still unclear. Elderly persons often develop nonspecific skin lesions around body orifices and about the feet and ankles. To determine whether nonspecific skin lesions in the elderly might be caused by zinc deficiency, Weismann et al [17] performed a trial of zinc supplementation in geriatric patients with hypozincemia and skin lesions. They evaluated 585 institutionalized elderly subjects of whom 26 had skin lesions. Ten of these 26 patients had depressed serum zinc concentrations, and this subset of 10 patients was treated with 600 mg/day of zinc sulfate for 4 weeks. Serum zinc levels increased in these ten, but no clear-cut improvement in skin abnormalities was noted. This study is probably the best examination to date of the efficacy of zinc supplementation on nonspecific skin lesions in elderly persons, with results being generally negative. Our personal experience is that we occasionally see patients with mild skin lesions in a classic distribution that do respond to zinc replacement. The critical factor probably relates to how classic the skin lesions are for zinc deficiency, with nonspecific lesions having a low likelihood of response. Diarrhea Diarrhea is a regular complication of AE [12]. Diarrhea has been reported in patients who develop severe zinc deficiency during total parenteral nutrition therapy, and in some instances this diarrhea persisted while the patients were taking nothing by mouth [14,15]. Certain patients who have zinc deficiencyassociated diarrhea have very high zinc losses in their stool, and this loss likely

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exacerbates both a worsening of zinc status and diarrhea in these patients [14]. Zinc deficiency could contribute to diarrhea for many reasons, including decreased intestinal disaccharidase activity, Paneth cell abnormalities, and other immune dysfunctions, increased intestinal permeability, and poor intestinal epithelial repair to name a few [9,18]. No randomized studies have been performed on zinc supplementation in elderly persons having diarrhea; however, controlled studies in infants and/or children with diarrhea in underdeveloped countries have shown significant beneficial effects of zinc supplementation. Pooled analyses of seven trials of zinc supplementation in children with diarrhea (three trials evaluated acute diarrhea; four trials evaluated chronic diarrhea) showed reduced duration and severity of diarrhea and reduced mortality in some instances [18]. Impaired wound healing and protein metabolism Zinc is required for normal nucleic acid metabolism, in the synthesis of structural proteins such as collagen, in various enzymatic pathways, in polyamine metabolism, and for normal insulin-like growth factor (IGF-1) production. Thus, it seems logical that a positive zinc balance would be important for wound healing. The importance of zinc in wound healing was first studied by Pories et al [19], who observed improved healing of pilonidal sinuses with zinc administration. Subsequent controlled studies by Hallbook and Lanner [20] demonstrated that zinc supplementation improved wound healing of venous leg ulcers in patients who had decreased serum zinc concentrations. Moreover, 17 patients in Boston with chronic leg ulcers had significantly decreased serum zinc concentrations [21]. Studies in rats confirmed that zinc deficiency slowed healing of excised and thermal injuries, but excess zinc in the diet did not enhance wound healing [22]. Studies from our laboratory showed that patients receiving TPN who developed clinical and biochemical zinc deficiency had low levels of visceral proteins such as prealbumin and transferrin. These levels normalized with zinc supplementation alone [23]. This early research stimulated more recent studies of nutrition and zinc supplementation on wound healing in the elderly. This has been a topic of great interest because of the problems with pressure sores and the difficulty in healing of some surgical wounds in the elderly. Finucane [24] reviewed seven studies and found that there was no clear relationship between global malnutrition and pressure sores, and that the data were often contradictory. A subsequent nutritional intervention study from France using a commercially available dietary supplement (including zinc) demonstrated a decrease in the incidence of pressure ulcers in critically ill older patients [25]. This was a randomized controlled study involving 672 subjects over age 65. However, the difference in the incidences in ulcers, while statistically significant, was relatively small (41% versus 47%), and issues have been raised concerning study design and data interpretation [25,26]. Moreover, Houston et al [27] reported adverse effects of large-dose zinc supplementation in an institutionalized older population with pressure ulcers. This study showed that supplementation with zinc sulfate at 100 mg/d was associated with increased infection

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and nausea and/or vomiting without obvious beneficial effects on ulcer healing. Thus, it is clear that ‘‘adequate’’ zinc is necessary for normal protein metabolism and wound healing, but ‘‘extra’’ zinc appears to provide no additional benefit and may be harmful.

Hypogonadism and sexual dysfunction Hypogonadism is a major manifestation of zinc deficiency in animals, and zinc deficiency has been suggested to cause hypogonadism in humans [28,29]. Research from Prasad’s group demonstrated primary testicular failure in adult male subjects with sickle cell anemia [30]. These investigators assessed the effect of zinc supplementation on a variety of indicators of sexual function in young males with sickle cell disease [31]. Oral zinc supplementation produced a significant increase in basal and stimulated testosterone levels as well as plasma and neutrophil zinc. When zinc supplementation was discontinued for 6 months in three zinc-replete men, their serum testosterone and neutrophil zinc levels decreased significantly [31]. These early studies provided strong evidence that zinc supplementation improves hypogonadism in selected zinc-deficient men. It has been proposed that zinc deficiency plays a pathogenic role in the human hypogonadism observed in some underdeveloped countries and in disease processes such as regional enteritis, uremia, and chronic alcoholism [9]. The hypogonadism of zinc deficiency appears to be primarily a gonadal defect [32]. Compared with zinc-sufficient controls, zinc-deficient animals have reduced basal testosterone levels, markedly depressed testosterone responses to human chorionic gonadotrophin stimulation, and lower weights of testes and other androgen-sensitive organs. Similarly, human volunteers placed on a zinc-deficient diet developed decreased libido, depressed serum testosterone levels, and marked reduction in sperm counts [33]. In a study of 50 infertile males, serum and semen zinc concentrations were significantly decreased and correlated [34]. Prasad et al showed that zinc supplementation of marginally zinc-deficient ‘‘normal’’ elderly men for 6 months significantly increased serum testosterone levels [35]. Lastly, men taking the diuretic hydrochlorothiazide had significantly decreased serum zinc concentrations, and complaints of sexual dysfunction improved in some (but not all) after zinc supplementation [36].

Visual function Some of the highest concentrations of zinc in both humans and animals are found in the retina and other ocular tissues [37]. Vitamin A is necessary for normal vision, and there is increasing evidence to suggest that zinc plays a role in vitamin A metabolism, especially as it relates to the eye. Vitamin A deficiency is a well-recognized cause of night blindness, with the active or aldehyde form of vitamin A (retinal) being necessary for rhodopsin synthesis. Zinc deficiency may interfere with vitamin A metabolism at multiple levels, including decreased

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generation of retinal, and by decreasing retinol binding protein (RBP) production and/or release from the liver [38]. In 1939, Patek and Haig [39] stimulated interest in nutritional factors other than vitamin A as being necessary for normal night vision. They reported that most alcoholic cirrhotics evaluated had defects in night vision; the majority improved or corrected with vitamin A therapy. However, a subgroup did not improve, suggesting another variable might be exerting a deleterious effect on the retina. Subsequent research confirmed depressed night vision in alcoholic cirrhotics, and identified subsets of cirrhotics who improved with zinc supplementation [40,41]. Similarly, patients with primary biliary cirrhosis have been shown to have impaired night vision and hypozincemia [42]. Important studies by Keeling and coworkers demonstrated that cirrhotics with low neutrophil zinc concentrations had depressed night vision as assessed by electroretinography (ERG), and the abnormalities in night vision correlated with the depression of the neutrophil zinc concentration [43]. We reported impaired dark adaptation in a zinc deficient patient with Crohn’s disease that improved with zinc therapy and then worsened with withdrawal of zinc therapy [44]. To investigate the possibility of a zinc deficiency –induced anatomic defect in the retina, Leure-duPree [45,46] treated rats with the zinc chelating agents dithizone and 1,10-phenanthroline or with a zinc-deficient diet. Degenerative changes of the retinal pigment epithelium (RPE) and unusual osmiophilic inclusion bodies in RPE were observed with both forms of zinc deficiency. Newsome et al [47] showed that zinc supplementation was helpful in preventing macular degeneration. Macular degeneration is the major cause of vision loss in the elderly in the United States, and thus is of great clinical consequence to the elderly. This study was a prospective, randomized, doubleblind, placebo-controlled study of the effects of zinc supplementation in 151 patients with drusen or macular degeneration. This initial report prompted the Age-Related Eye Disease Study [48], which was designed to determine whether or not antioxidant or zinc supplements delay age-related macular degeneration and vision loss. Based on the last recommendations from this group (report #8), the combination of antioxidant + zinc should be considered in patients over the age of 55 who demonstrate risk for age-related macular degeneration. Zinc may be protective of the retina through multiple mechanisms, including antioxidant and membrane-stabilizing roles [37]. Zinc deficiency may also play a role in cataract formation. Patients with AE often develop cataracts [49]. Oxidative stress is thought to be a major mechanism for cataract formation, and zinc has antioxidant activity. Mice lacking copper –zinc superoxide dismutase are highly prone to develop phytochemical cataracts [50]. Anorexia Another major manifestation of zinc deficiency is anorexia, which alters taste and smell. The mechanisms by which zinc deficiency produces anorexia are

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currently unclear [51]. While it is clear that zinc deficiency in animals produces a profound and specific anorexia, the exact association between zinc and anorexia in humans is less clear. Alterations in taste acuity, alterations in circulating amino acid concentrations and catecholamine levels in total brain and specific regions of the hypothalamus, and altered membrane fluidity and receptor function have all been hypothesized to be related to anorexia [52]. In addition, several neurotransmitters known to regulate appetite are also influenced or affected by a deficiency of zinc in both animals and humans [51]. In humans, a deficiency of zinc has been shown to reduce circulating levels of leptin [53]. This reduction in circulating leptin levels seems to be related to a decrease in the amount of leptin produced per gram of adipose tissue as well as the decrease in body fat that accompanies a zinc deficiency [54]. Further research in this area of appetite regulation and zinc may shed light on the ‘‘anorexia of aging’’ that is often seen in elders. Geriatric subjects often complain of anorexia and impaired taste sensation and have decreased food consumption. Greger [55] showed that approximately 20% of elderly institutionalized patients had impaired taste acuity; however, this did not correlate with dietary zinc intake or zinc levels. A subsequent study by this same group [56] evaluated the effects of zinc supplementation on altered taste acuity in the elderly. Forty-nine institutionalized elderly subjects were randomized to 15 mg/d of zinc as zinc sulfate or placebo for 95 days. Hair zinc significantly increased in the zinc-supplemented patients, but there was no significant improvement in taste acuity. Thus, it appears that altered taste acuity in the elderly is generally not related to zinc status. To our knowledge, no major studies have been performed on zinc and anorexia in the elderly. Altered mental status Zinc deficiency may cause alterations in mental status. Experimentally induced zinc deficiency in humans may be associated with irritability or apathy, which is reversed with zinc supplementation [9]. Children with AE often experience apathy or confusion, both of which respond to zinc supplementation. Moreover, zinc supplementation has been reported to produce a modest improvement in mental function in hypozincemia patients following head injury [57]. The possible role of zinc deficiency on mental function in the elderly has received limited attention. Stafford et al [58] evaluated zinc status using serum and leukocyte zinc and found no significant correlation between mental impairment and zinc status; however, significant relationships were observed between mental status and plasma albumin levels, plasma total protein concentrations, and protein intake. Significantly decreased levels of circulating zinc were reported in subjects diagnosed with major depression compared with normal controls, and intermediate zinc values were noted in those subjects classified as having minor depression [59]. In animals (during periods of rapid brain growth or juvenile and adolescent periods) zinc deficiency may affect cognitive development [60]. In general, activity is decreased, emotional behavior is increased, and memory along

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with the capacity to learn is impaired in zinc-deficient animals. Unfortunately, studies in humans to date are limited in this area. A possible role for zinc in dementia, including Alzheimer’s disease (AD), has received some investigative attention. In one study, a significant correlation between the intake of thiamin, vitamin B-12, selenium and zinc, and blood levels of total antioxidant capacity was observed in a group of patients with vascular dementia but not in those with AD or dementia with Lewy bodies [61]. In another study, the concentrations of zinc in postmortem serum and four brain regions were measured in nine AD subjects and eight control subjects [62]. A significant elevation of zinc was found in the serum of the AD subjects compared with agematched controls, even though there was no significant difference in the concentration of zinc in the amygdala, hippocampus, cerebellum, and superior and middle temporal gryi between the two groups. Recent in vitro and animal studies have evaluated the potential role of zinc in AD etiopathogenesis involving amyloid beta-peptide, a major constituent of senile plaques found in the brains of AD patients, as well as the zinc-binding protein S100beta, an interacting partner with the microtubule-associated protein tau [63 – 67]. Conflicting reports exist regarding the role of zinc, because zinc deficiency leads to memory impairment in young rats [68] as well as an acceleration in the brain aging in another rat model [69]. More research in this area—human in vivo studies, in particular—needs to be performed before a consensus on the role of zinc in AD can be reached. The authors know of no study concerning the effects of zinc supplementation on mental status in the elderly. Altered immune function Zinc plays a vital role in normal immune function. Initial in vitro studies have identified zinc as a potent T-lymphocyte mitogen for both man and animals over a narrow range of concentrations [70]. Zinc deficiency in animals causes thymic and lymph node atrophy and impaired cell-mediated cutaneous hypersensitivity [71]. Lymphocytes isolated from zinc-deficient animals show impaired response to phytohemagglutinin and depression of T cell – dependent antibody production [71 –73]. The effect of zinc deficiency on immune function in humans was studied initially in children with AE, a congenital disorder characterized by both impaired zinc absorption and immunodeficiency. Leukocyte function and cell-mediated immunity are impaired in these children and reversed with zinc supplementation [74]. Golden and associates described thymic atrophy in children with protein energy malnutrition and zinc deficiency [75,76]. After zinc supplementation, the thymic atrophy reversed, as assessed by sequential chest roentgenograms. Several groups then documented immune dysfunction in small groups of patients with various disease processes (eg, short-bowel syndrome, renal failure, sickle cell anemia, and so forth) that was associated with zinc deficiency and improved with zinc supplementation [9,77,78]. Recent studies have explored mechanisms of zinc deficiency – induced immune dysfunction. Elegant research from Fraker et al [77] has documented

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the association between glucocorticoid activity, lymphocyte apoptosis, and zinc deficiency. They postulated that large amounts of zinc are required to produce billions of lymphocytes daily. Many of these lymphocytes die without being gainfully used in an immune response and are nutritionally expensive. Thus, from an adaptive stress response, it may make sense to have increased glucocorticoid-mediated lymphocyte apoptosis during zinc deficiency. With aging, there is a distinct decline in T cell responses accompanied by major changes in T cell function, including decreased proliferation and secretion of IL-2 upon stimulation of the T cell receptor (mimicking changes in zinc deficiency). This knowledge has stimulated a number of studies evaluating zinc supplementation on immune function and infections in the elderly [79]. Initial studies such as those by Duchateau showed beneficial effects when zinc sulfate (220 mg bid  1 month) was administered to 15 subjects over the age of 70 [80]. Prasad et al [81] demonstrated a high frequency of mild zinc deficiency in ambulatory elderly as assessed by blood cell zinc concentrations. Zinc supplementation in a selected zinc-deficient population improved serum thymulin levels, cutaneous/skin testing, taste acuity, monocyte interleukin-1 (IL-1) production, and lymphocyte ecto 50- nucleotidase activity. Girodon et al [82] evaluated trace element and vitamin supplementation on infectious complications over a 2-year period. Patients receiving trace metals (zinc 20 mg/day + selenium 100 mg/day) or trace metals + antioxidants had less infections [83]. A subsequent study by this group in a large population of institutionalized elderly found that trace metal supplementation improved antibody response to influenza vaccine and a decrease in respiratory infections was nearly significant ( P = 0.06). If zinc supplementation is undertaken, very high doses of zinc should be avoided, because they may actually cause immunosuppression [84]. Potential complications of zinc supplementation Zinc supplementation may also cause toxicity, especially high-dose zinc supplementation. Regular high-dose oral zinc therapy can induce copper deficiency with subsequent anemia and neutropenia [85]. Immune suppression may also occur with high-dose zinc supplementation [84]. Thus, if zinc supplementation is to be administered, it should generally be done in ‘‘low levels’’ ( < 40– 50 mg/day) unless the patient is on a protocol and is being regularly monitored for adverse effects such as copper deficiency. Some of the unimpressive outcomes observed in previously referenced zinc supplementation studies may have been due in part to the excessive doses used.

Copper Copper, like zinc, is important in a variety of enzyme pathways, including superoxide dismutase, lysyl oxidase, dopamine beta hydroxylase, and cyto-

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chrome C-oxidase [86,87]. Copper is abundant in a variety of food sources, including organ meats (especially liver), nuts, and legumes; however, the elderly have been documented to be at high risk for inadequate copper intake [11]. Copper status is classically assessed by the serum copper concentration. As with zinc, serum copper is also influenced by factors other than total body stores, with hormonal status and inflammation being especially important. Ceruloplasmin, the main copper binding protein, is an acute phase reactant, and its synthesis is stimulated by inflammatory mediators such as IL-1 and TNF. Thus, during stress or inflammation, serum copper levels may increase while serum zinc decreases [88]. Copper is absorbed mainly in the upper GI tract where approximately 30% to 80% is absorbed depending on a variety of factors, including ingestion of other minerals such as zinc, dietary fiber content, and dietary protein content. Copper is excreted mainly through the bile and lost in the gastrointestinal tract, with urinary losses being minimal. Because of the importance of bile in copper excretion, patients with liver disease may have diminished copper excretion, and copper intake in these subjects may need to be reduced accordingly. Initial studies in animals showed that copper deficiency resulted in anemia because of impaired recycling of iron from the reticuloendothelial endothelial (RE) system to the bone marrow. The discovery of the autosomal recessive disorder aceruloplasminemia has demonstrated the critical role of ceruloplasmin in allowing movement of iron from tissue stores [89]. Individuals with aceruloplasminemia have low plasma copper because of the absence of ceruloplasmin, and they have increased iron deposits in the liver, pancreas, and brain. They often develop dementia and other neurologic problems, as well as type I diabetes. Copper deficiency in humans usually presents as anemia that doesn’t respond to iron supplementation, leukopenia, neutropenia, and much less often hypopigmentation, immune dysfunction, and skeletal abnormalities [90,91]. Although anemia is the classic manifestation of copper deficiency, increased cholesterol with atherosclerosis, and neurologic problems such as AD are also being recognized [92,93]. Copper has been shown to be important in angiogenesis, and mild copper deficiency is being used as an experimental form of cancer therapy [94]. There are many factors that can affect copper availability, with a highly clinically relevant factor being zinc supplementation. Zinc induces the metalbinding protein metallothionein in the intestine and impairs copper absorption. This is the rationale for zinc treatment in patients with Wilson’s disease; however, subjects who take over-the-counter zinc from health food stores in excess doses (>50 mg elemental zinc) can run the risk of inducing copper deficiency with subsequent anemia and neutropenia. A variety of disease states or conditions also place patients at risk for copper deficiency, including cystic fibrosis, Crohn’s disease, malabsorptive disorders, and patients taking excess zinc supplementation. Moreover, patients on chronic tube feeding such as the institutionalized elderly are at risk for clinical copper deficiency, including hematologic complications of anemia [90,91].

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Selenium Selenium is incorporated as selenocysteine at the active sites of multiple selenoproteins [95,96]. The best recognized of these are the glutathione peroxidase enzymes, which are critical in antioxidant defense systems. Thioredoxin reductase is also a seleno-cysteine –containing enzyme. Selenoproteins are also important for thyroid function, muscle metabolism, and sperm function, as well as immune function. Selenium status is usually determined by the serum selenium concentration or determining a marker of selenium status, such as erythrocyte glutathione peroxidase activity. Low serum selenium levels are welldocumented in elders and in disease processes such as type II diabetes, which increases with aging [97,98]. Severe clinical selenium deficiency typically presents as cardiomyopathy and myopathy [99]. Keshan disease is a form of dilated cardiomyopathy which occurs in China in areas where the soil is poor in selenium. This cardiomyopathy can be improved or reversed with selenium supplementation. In developed countries, selenium deficiency associated cardiomyopathy has been reported in patients receiving TPN [100]. In several of the cases, there was improvement in cardiac function with selenium supplementation. Cardiomyopathy that improved with selenium supplementation has also been reported in malnourished patients such as those with Crohn’s disease and cystic fibrosis. Low cardiac selenium levels have also been reported in patients with AIDS, thus raising the question of whether AIDS cardiomyopathy may be related to selenium status. Epidemiologic studies have associated a decreased serum selenium concentration with coronary artery disease and cardiovascular death [101]. Unfortunately, the role of selenium in cardiovascular disease and cardiomyopathy in the elderly has received little investigative attention [102]. Micronutrient deficiencies are traditionally thought to cause increased in susceptibility to infection due to impairment in host defense systems. Selenium deficiency appears to act in a highly novel fashion in relation to viral infections. Beck and coworkers [103,104] initially showed that selenium-deficient mice develop an inflammatory cardiomyopathy when infected with normally avirulent or benign strains of Coxsackie virus. Control mice fed a selenium-sufficient diet do not develop cardiac pathology when infected with this same virus. It is important to note that these investigators demonstrated that this new viral virulence was due to mutations in the viral genome itself. Thus, the avirulent virus mutated to a virulent strain. These virulent strains continued to cause pathology even when administered to mice fed a normal diet. This same group has made similar observations with the influenza virus [105]. These observations have great implications for how host nutritional status may influence mutational changes in a viral genome. The implications are also great for the elderly—the institutionalized elderly, in particular—because viral infections are easily transmitted from one subject to another. Lastly, there is a great interest in the potential role of selenium in carcinogenesis [106,107]. For many types of cancer, there is an inverse

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relation between cancer incidence and the selenium content of the soil. Selenium is being used as a therapeutic agent in certain types of cancer, the best publicized being prostate cancer [107]. Epidemiologic data suggest that men with high selenium and vitamin E intakes have a lower risk for prostate cancer. A large randomized trial (the Selenium and Vitamin E Chemoprevention Trial, or the SELECT study) will enroll over 30,000 men in a prostate cancer prevention trial, with two of the arms being selenium alone or selenium with vitamin E.

Chromium Of the trace metals discussed, chromium is the least characterized with regard to requirements and biochemical functions [108,109]. It has been known for almost half a century that chromium appears to be necessary for normal glucose metabolism. The main signs and symptoms of deficiency in mammals include glucose intolerance with peripheral insulin resistance, altered lipid metabolism, neuropathy, and encephalopathy. Dietary intake of chromium in the United States is frequently inadequate (including in the elderly). Processed meats, whole grains, and certain vegetables have high chromium concentrations. Well-documented individual cases of chromium deficiency have been reported, with patients usually presenting with glucose intolerance and neuropathy. A recent study suggested that this may occur even in the face of normal or increased chromium levels [110]. There is considerable controversy in the literature concerning the role of chromium in improving glucose tolerance. In various patient populations including the elderly, some studies have reported improved glucose tolerance, while other researchers have reported negative studies. This has prompted some investigators to speculate that there may be a subset of glucose intolerance in patients who respond to chromium (possibly those who are deficient). Unfortunately, simple accurate methods for determining chromium status are not easily available. Chromium also has been touted as a performance-enhancing nutrient; however, there are limited data to support this claim [111].

Conclusions Most studies show that the elderly have depressed intakes of the trace materials zinc, copper, selenium, and chromium. Multiple potential manifestations of trace metal deficiencies may occur in the elderly. If mineral supplementation is to be initiated, it is important to administer doses that would be below the tolerable upper intake level. Many of the negative studies of zinc supplementation used doses well above this level, and the negative results of these studies may be due to this inappropriate dosing.

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