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Experimental Gerontology 43 (2008) 394–408

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Mini Review

Zinc supplementation for the treatment or prevention

of disease: Current status and future perspectives
Hajo Haase, Silke Overbeck, Lothar Rink *

Institute of Immunology, University Hospital, RWTH Aachen University, Germany

Received 11 September 2007; received in revised form 25 October 2007; accepted 4 December 2007
Available online 14 December 2007

Abstract

Zinc is a nutritionally essential trace element, and thus zinc deficiency may severely affect human health. Many studies were published
in which the effect of nutritional zinc supplementation on the incidence or severity of a certain disease was investigated. This review sum-
marizes the main observations and aims to evaluate the use of nutritional zinc supplementation for prevention and treatment of human
disease.
 2007 Elsevier Inc. All rights reserved.

Keywords: Zinc; Zinc supplementation; Infection; Immune system; Zinc deficiency; Essential trace element

1. Introduction Zinc deficiency leads to a retardation of growth and

development in children, retarded genital development
The importance of zinc was first documented for Asper- and hypogonadism, dermatitis and delayed wound healing,
gillus niger (Raulin, 1869). It took over 75 years to realize alopecia, poor pregnancy outcomes and teratology, and
that zinc is also an essential trace element for rats (Todd decreased immune function with a resulting increased sus-
et al., 1935), and an additional 30 years went by before it ceptibility to infections (Maret and Sandstead, 2006). The
was recognized that this was also true for humans (Prasad prevalence of zinc deficiency is estimated to be high, with
et al., 1963; Sandstead et al., 1967). billions of people at risk, in particular in the developing
Following the initial observation that zinc is required for world (Maret and Sandstead, 2006). In industrialized coun-
the catalytic activity of carbonic anhydrase (Keilin and tries, elderly people are a high risk group for zinc defi-
Mann, 1940), it became clear that zinc is a component of ciency. In the United States, the Third National Health
more than 300 enzymes from all six enzyme classes (Vallee and Nutrition Survey showed that zinc uptake decreases
and Falchuk, 1993). Bioinformatic estimates report that with age and only 42.5% of the participants who were 71
10% of the human proteome contain zinc binding motives years or older had an adequate zinc intake (Briefel et al.,
(Andreini et al., 2006). Based on its role in such a plethora 2000).
of cellular components, zinc has diverse biological func- Due to the wide prevalence of zinc deficiency and the
tions in enzymatic catalysis (Auld, 2001), redox regulation multitude of zinc’s essential biological functions, nutri-
(Maret, 2006), cellular signal transduction (Beyersmann tional correction of zinc deficiency may have a significant
and Haase, 2001), the immune system (Wellinghausen impact on different aspects of human health. Following this
et al., 1997), and neurons (Frederickson et al., 2005). rationale, over the years several hundred zinc supplementa-
tion studies have been conducted, investigating the effects
of nutritional zinc supplementation on different diseases,
* often with contradictory results.
Corresponding author. Tel.: +49 (0) 241 8080208; fax: +49 (0) 241
8082613. Zinc supplementation studies are difficult to compare
E-mail address: LRink@ukaachen.de (L. Rink). due to a number of reasons. First, the zinc status of the

0531-5565/$ - see front matter  2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.exger.2007.12.002
 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408 395

subjects has to be known, since zinc deficient subjects will of ‘‘anti-atherogenic’’ high-density lipoprotein (Black et al.,
likely react different to zinc supplementation than zinc suf- 1988; Hooper et al., 1980), revealing a possible health risk
ficient ones. Even when values are given, most studies mea- of high dose zinc supplementation. However, this is not a
sure total serum or plasma zinc. This is not an optimal general observation and in particular when lower doses
method for determining an individual’s zinc status, since are given this does not seem to pose a risk (Bonham
the bioavailability of the tightly protein bound zinc can dif- et al., 2003b; Boukaiba et al., 1993; Freeland-Graves
fer. Serum and plasma zinc are a suitable parameter for the et al., 1982; Samman and Roberts, 1988).
diagnosis of severe, clinical zinc deficiency, but not for Zinc has a profound impact on virtually all cells of the
identifying marginal zinc deficiency, which would be the immune system (Rink and Haase, 2007), and while low
main application for nutritional studies (Aggett, 1991; dose zinc supplementation to healthy persons does not
Haase et al., 2006). affect blood leukocyte or lymphocyte subsets (Bonham
Another major obstacle for the comparison of different et al., 2003a), it can increase the response of lymphocytes
studies is based on their design. While some studies are pla- to stimulation with mitogens (Duchateau et al., 1981a).
cebo controlled, others rely on untreated control groups, or The severity of immunosenescence, which is the age related
report single case studies only. In addition, the zinc supple- decline of immune function, corresponds to the age depen-
ment and the amount of zinc that is administered vary con- dent decline in zinc status, and is counteracted by zinc sup-
siderably. In some cases, the amount of elemental zinc can plementation (Haase et al., 2006). Zinc supplementation
not even be determined, since insufficient information has been shown to improve the cell-mediated immune
about the supplement is provided. For example, several response of healthy elderly (Fortes et al., 1998), the delayed
studies in which zinc sulfate was used do not specify its type hypersensitivity reaction (DTH) (Duchateau et al.,
chemical composition. Calculated according to their chem- 1981b; Cossack, 1989; Prasad et al., 1993), and plasma
ical formulas, the different forms of zinc sulfate contain dif- thymulin activity (Boukaiba et al., 1993; Prasad et al.,
ferent quantities of elemental zinc per total weight. ZnSO4 1993). However, when a group of elderly was investigated
contains 40.5% elemental zinc, while the zinc contents of who were not zinc deficient according to their plasma zinc
ZnSO4 · H2O (36.4%) and ZnSO4 · 7H2O (22.7%) are sig- levels, no effect of zinc supplementation was observed
nificantly lower. Accordingly, a dose of 220 mg zinc sulfate (Bogden et al., 1990), indicating that the efficiency depends
could correspond to approximately 90 mg (anhydrous on the individuals zinc status. In elderly, zinc-deficient per-
form), 80 mg (monohydrate), or 50 mg (heptahydrate) ele- sons, a shift in the T helper cell balance towards Th2 is
mental zinc, respectively, depending on the salt form that observed (Cakman et al., 1996). This corresponds well to
was administered. a study in which mild zinc deficiency was induced experi-
Further factors that should be taken into consideration mentally in healthy human volunteers. Here, the produc-
include the interaction of zinc with other nutrients. This tion of typical Th1 cytokines, the recruitment of naı̈ve T
may affect bioavailability, since substances like phytate cells, and levels of cytotoxic T cells were decreased (Beck
can bind zinc and reduce its uptake (Lonnerdal, 2000). et al., 1997). The impact of mild zinc deficiency on the
Also, higher zinc concentrations can interfere with the immune system shows that it can lead to an impairment
uptake of other trace elements, in particular copper, and of the immune defense. The reduction of the Th1 response
the beneficial effects of zinc supplementation may be abro- in healthy individuals indicates that zinc deficiency could
gated by induction of copper deficiency, which can lead to promote neoplasia and increase the susceptibility to viral
severe anemia and neutropenia (Prasad et al., 1978; Porter infections.
et al., 1977). High zinc concentrations obstruct immune
function (Wellinghausen et al., 1997), as demonstrated by 2.2. Vaccination
ex vivo mixed lymphocyte culture inhibition after one week
of supplementation with 80 mg elemental zinc per day Following an initial report that zinc supplementation
(aCampo et al., 2001; Faber et al., 2004), a dose that is can increase the number of positive responses and IgG
exceeded in many of the studies cited throughout this titers after tetanus vaccination (Duchateau et al., 1981b),
review. some studies tried to verify this effect for other vaccina-
This review aims to summarize current knowledge about tions, but with limited success (Table 1). Among those
zinc supplementation and to illustrate where zinc has been was the investigation of the influence of zinc on cholera
shown to have beneficial effects, where it has no effect, and vaccination in Bangladeshi children (Albert et al., 2003;
in which cases further studies are advisable. Qadri et al., 2004) and Norwegian medical students (Karl-
sen et al., 2003). Zinc treatment led to increased formation
2. Zinc supplementation for disease prevention of vibriocidal antibodies (Albert et al., 2003; Karlsen et al.,
2003), but suppressed the formation of antibodies against
2.1. Healthy persons Cholera toxin (Karlsen et al., 2003; Qadri et al., 2004).
The reason for this differential effect remains unclear.
Pharmacological doses of zinc given to healthy, zinc suf- Two other studies investigated the effect of zinc supple-
ficient human subjects were reported to reduce serum levels mentation on influenza vaccination in the elderly, both
396 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408

finding no effect of zinc (Provinciali et al., 1998; Remarque

Duchateau et al. (1981b)

Provinciali et al. (1998)

Remarque et al. (1993)
et al., 1993). Also, influenza vaccination in hemodialysis

Karlsen et al. (2003)

Albert et al. (2003)
Qadri et al. (2004)
patients, a population with a high incidence of zinc defi-

Turk et al. (1998)

ciency, was not altered by zinc supplementation (Turk
et al., 1998). However, a correlation between zinc status
Reference

and vaccination response is suggested by another report

stating that hemodialysis patients who did not respond
to diphtheria vaccination did have significantly lower
increased fecal antibody titers (IgA) increased vibriocidal AB

serum zinc levels than responders and age-matched con-

trols (Kreft et al., 2000).
At present the majority of the data contradicts the
Increased serum zinc and vibriocidal antibody titers

hypothesis that zinc supplementation can increase the

success rate or antibody titer after vaccination. How-
Increased plasma zinc; no effect on vaccination

Increased serum zinc; no effect on vaccination

Lower increase in cholera toxin IgA and IgG

Lower increase in serum IgA and IgG titers;

ever, cellular immunity does not recover very quickly

in zinc deficient individuals, and a sufficient duration
Anti-tetanus toxin IgG titer increased

of zinc administration prior to vaccination to suffi-

ciently restore T helper function may be necessary. In
the studies that did not find an effect, zinc was given
between 0 to 3 weeks prior to immunization, while
the positive outcome was observed after one month
of zinc administration (Duchateau et al., 1981b). Also,
all studies without an effect of zinc had continued the
Effect of zinc

supplementation regime after the immunization. Since

No effect

T cells are inhibited by relatively low doses of zinc

(Wellinghausen et al., 1997) and the formation of IgA
titers

and IgG requires T cell help, supplementation after

the vaccination may suppress T cells and make the
125 (Z), 124 (P)
125 (Z), 124 (P)

194 (Z), 190 (P)

13a (Z), 13a(P)

11 (Z), 11 (C)

immunization less effective.

15 (Z), 15 (P)

43 (Z), 41 (P)
Participants

Z, zinc; P, placebo; C, control; ZA, zinc acetate; ZS, zinc sulfate; d., days; w., weeks; mo., months.

3. Therapeutic zinc supplementation

11b(P)

3.1. Infectious diseases

60 d. total, starting 15 d. before
28 d., starting 7 d. before vacc.
w., starting 3 w. before vacc.
w., starting 3 w. before vacc.
d. starting 2 d. before vacc.

Zinc is essential for the immune system and zinc defi-

ciency has dramatic implications for immune function
(Fraker and King, 2004; Shankar and Prasad, 1998; Wel-
mo. prior to vacc.

linghausen et al., 1997). Hence, it is not surprising that zinc

deficiency increases the risk for several infectious diseases
like diarrhea, pneumonia, and malaria (Fischer Walker
and Black, 2004). Accordingly, zinc supplementation has
Period

1 mo.
vacc.

been suggested to be beneficial and has been investigated

1
6
6
9

in different experimental settings (Table 2).

ZS 120 mg (2–3 times per week after

One disease for which the use of zinc has been exten-
sively investigated is the common cold, and the results
Effect of zinc supplementation on vaccination

have already been summarized in detail elsewhere (Hulisz,

in 2 doses)

in 3 doses)

ZS 440 mg (daily in 2 doses)

ZS 400 mg (daily in 2 doses)
elemental)
elemental)

2004). These results are contradictory to some extent, and

Zinc species and dosage

design and sample size of several studies have been criti-

cized. Overall, it can be concluded that zinc is effective in
ZS 440 mg (daily

ZS 600 mg (daily
ZA 20 mg (daily,
ZA 20 mg (daily,

shortening the duration of the common cold, but only if

hemodialysis)

it is administered no later than 24 h within the onset of

Hemodialysis patients.

the symptoms (Hulisz, 2004). The mechanism by which

Healthy subjects.

zinc acts against the common cold is still not completely

understood. It has been found that zinc inhibits the rhino-
virus 3C protease, and hereby viral replication, but this
Vaccination

Influenza

effect was only observed in vitro and not in vivo (Turner,

Tetanus
Cholera
Table 1

2001). Also discussed is an interference of zinc with the

b
a

binding of the rhinovirus to its cellular receptor, the adhe-

Table 2
Zinc supplementation and Infectious diseases
Disease Zinc species and dosage Period Participants Effect of zinc supplementation Reference
Malaria ZA/ZG 70 mg (elemental, 15 mo. 55 (Z), 54 (P) No effect on plasma and hair zinc, trend towards fewer malaria episodes (not statistically Bates et al. (1993)
twice per week) significant), no effect on diarrhea or respiratory illness
ZG 10 mg (elemental, daily, 46 w. 136 (Z), 138 (P) Reduction in Plasmodium falciparum-mediated febrile episodes Shankar et al.
6 days per week) (2000)
ZS 12.5 mg (daily, 6 days 6 mo. 336 (Z), 344 (P) Increased serum zinc, no effect on malaria, but reduced prevalence of diarrhea Muller et al.
per week) (2001)
HIV/AIDS ZG 45 mg (three times daily) 15 d. 5 (Z), 5 (C) Increased zinc in red blood cells and number of HLA-DR+ cells, stimulation of Zazzo et al.
lymphocyte transformation and phagocytosis of opsonized zymosan by PMN (1989)
ZS 200 mg (daily) 1 mo. 29 (Z), 28 (P) Increase or stabilization in plasma zinc and body weight; increase in CD4+ T cells and Mocchegiani
plasma active zinc-bound thymulin; reduced or delayed frequency of opportunistic et al. (1995)

H. Haase et al. / Experimental Gerontology 43 (2008) 394–408

infections due to Pneumocystis carinii and Candida, not to Cytomegalovirus and
Toxoplasma
ZS 10 mg (daily, elemental) 6 mo. 44 (Z), 41(P) No effect of HIV-1 viral load, but reduction of morbidity from diarrhea Bobat et al.
(2005)
ZS 220 mg (daily) 1 mo. 31 (Z), 34 (P) No effects on immune response to tuberculosis, CD4/CD8 ratio, lymphocyte subsets and Green et al.
viral load (2005)
ZG 50 mg (daily) 6 d. 44 (Z), 45 (P) No improvement of antibody responses to a pneumococcal conjugate vaccine Deloria-Knoll
et al. (2006)
Recurrent aphthous ZS 660 mg (daily in 3 doses) 3 mo. 20 (P, Z) No therapeutic effect Wray (1982)
stomatitis ZS 220 mg (daily) 1 mo. 20 (Z), 20 (P) Increased serum zinc, serum albumin, and serum alkaline phosphatase activity; aphthae Orbak et al.
disappeared; reduced recurrence scores (2003)
Common cold >12 different studies variable results, zinc reduces duration of symptoms if administered within 24h of onset Hulisz (2004)
Acute lower ZG 10 mg (daily, elemental) 6 mo. 298 (Z), 311 (P) Increased plasma zinc, decreased episodes of infection Sazawal et al.
respiratory (1998)
infection ZA 20 mg (daily in 2 doses, 5 d. 76 (Z), 74 (P) Increase in serum zinc and recovery rates from illness and fever in boys Mahalanabis
elemental) et al. (2004)
Leprosy ZS 220 mg (daily) 18 mo. 8 (Z) Reduced dose of clofazimine; withdrawal of steroids; toleration of dapsone; reduced Mathur et al.
incidence and severity of erythema nodosum leprosum; gradual decrease in the size of (1983)
granuloma; gradual increase in the number of lymphocytes
ZS 220 mg (daily) 18 mo. 15 (Z), 10 (P) Increased serum zinc; decreased erythema, edema and infiltration; regrowth of eyebrows; Mathur et al.
reduced bacterial index of granuloma; increased neovascularization and endothelial cell (1984)
proliferation
ZA 400 mg (daily in 2 doses) 13 w. 17 (Z), 10 (P), Increased serum zinc and delayed hypersensitivity reactions; decreased size of skin el-Shafei et al.
10 (C) nodules; disappearance of erythema; regrowth of eyebrows (1988)
ZS 220 mg/d. 4 mo. 40 (Z) Improvements regarding frequency, duration and severity of erytheme nodosum Mahajan et al.
leprosum reactions; reduction in steroid requirement (1994)
Tuberculosis ZS 15 mg (daily) 6 mo. 40 (Z), 40 (P) Increased plasma retinol concentrations; earlier sputum conversion and resolution of X- Karyadi et al.
ray lesion area (2002)
Acute cutaneous ZS 2.5, 5 or 10 mg/kg (daily 45 d. 92 (Z), 12 (C) Increased serum zinc; decreased erythema and size of induration; increased cure rate Sharquie et al.
leishmaniasis in three doses) (2001)
Diarrheal diseases Multiple studies of different design Decreased duration, severity and occurrence of diarrhea Hoque and
Binder (2006)
Z, zinc; P, placebo; C, control; d., days; w., weeks; mo., months; ZA, zinc acetate; ZS, zinc sulfate; ZG, zinc gluconate.

397
398 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408

sion molecule ICAM-1, or an interaction of zinc with host of malnutrition and limited access to medication. Although
immune function (Hulisz, 2004). the zinc status of the children has not been determined, it
Another disease where zinc supplementation is success- can be assumed that many of them were zinc deficient
fully applied are the different forms of diarrhea. On the (Bobat et al., 2005; Green and Paton, 2006). Zinc supple-
one hand, diarrhea leads to increased intestinal loss of mentation with HIV positive patients should be performed
micronutrients, including zinc, which is corrected by zinc cautiously with constant monitoring of the patient’s zinc
supplementation. On the other hand, several studies, which status. While moderate supplementation to zinc-deficient
have already been summarized previously (Fischer Walker patients can help stabilize their immune system, supple-
and Black, 2004; Hoque and Binder, 2006), demonstrated mentation to zinc-sufficient ones may accelerate disease
that zinc can also reduce the duration, severity, and inci- progression and increase mortality.
dence of diarrhea. Especially in malnourished children in Leprosy patients with borderline tuberculoid leprosy,
the developing world, zinc administration, in addition to borderline lepromatous leprosy, and lepromateous leprosy
the standard oral rehydration, is a cost-effective and effi- were all found to have significantly reduced serum zinc lev-
cient way to reduce mortality from diarrhea. els compared to healthy controls (George et al., 1991).
Zinc is of particular importance for the development of Four different studies reported beneficial effects of zinc
T cells (Fraker and King, 2004; Wellinghausen et al., 1997). treatment on medication requirements and an improve-
Hence, it seems reasonable to use it as a supporting thera- ment of several immune parameters (el-Shafei et al.,
peutic intervention for patients with HIV/AIDS. Initial 1988; Mahajan et al., 1994; Mathur et al., 1983, 1984), indi-
studies seemed promising, reporting that short term supple- cating that zinc supplementation may support immune
mentation of a relatively small group of five patients led to function and also counteract symptoms secondary to zinc
an improvement of immune function, namely an increase in deficiency in leprosy. Another study reports that zinc has
the number of activated (HLA-DR positive) T cells, aug- similar effects on another form of mycobacterial infection,
mented lymphocyte transformation by phytohaemaggluti- tuberculosis (Karyadi et al., 2002).
nin and concanavalin A, and increased phagocytosis by Another pulmonary disease, acute lower respiratory
polymorphonuclear neutrophils (Zazzo et al., 1989). This infection, has also been reported to be beneficially affected
was supported by a paper that even described an increase by zinc supplementation. Two studies, during which rela-
in the number of T helper cells and a protective effect tively low doses of 10 mg elemental zinc per day were given
against infections with Pneumocystis carinii and Candida to children, reported generally decreased episodes of infec-
(Mocchegiani et al., 1995). However, recent papers did tion (Sazawal et al., 1998) and increased recovery rates
not find an effect on immune response, vaccination, CD4/ (Mahalanabis et al., 2004). Inexplicably, the latter study
CD8 ratio, or viral load (Bobat et al., 2005; Deloria-Knoll only found a significant effect in boys but not in girls
et al., 2006; Green et al., 2005). The only positive effect was (Mahalanabis et al., 2004).
a reduction of morbidity from diarrhea (Bobat et al., 2005). Zinc administration has also been tested during parasite
It has been shown that zinc deficiency is prevalent infection, namely malaria and cutaneous leishmaniasis.
among HIV infected persons, especially in malnourished Plasma zinc levels generally decline during the acute phase
patients or users of illicit drugs. In these cases, zinc defi- of an infection. This has been confirmed for acute malaria
ciency is a predictor of higher mortality, although it is infection and can be at least partially restored by nutri-
unclear if the zinc status has a direct influence on survival tional zinc supplementation (Duggan et al., 2005). The inci-
rates, or just correlates with the severity of the disease dence of Plasmodium falciparum-mediated febrile episodes
(Baum et al., 2000, 2003). However, it can not be general- was reported to be reduced by zinc supplementation com-
ized that patients with AIDS are zinc deficient, since anti- pared to the placebo group of preschool children located
retroviral therapy can normalize the zinc status (Rousseau in a malaria endemic region of Papua New Guinea (Shan-
et al., 2000). This is of particular importance because two kar et al., 2000), and a lower incidence of malaria in zinc-
nutritional studies showed that increased intake of zinc in supplemented children from Gambia was reported (Bates
HIV-1 infected patients led to an augmented risk for the et al., 1993). The latter was not statistically significant,
progression to AIDS (Tang et al., 1993) and lower survival and zinc did not have an effect on diarrhea or respiratory
(Tang et al., 1996). In the quartile of patients with the high- infection (Bates et al., 1993). An effect of zinc on the inci-
est total daily zinc intake (>20 mg/day) combined from dence of P. falciparum induced malaria was not confirmed
food and supplements, the risk for progression to AIDS by a larger study in Burkina Faso, however this time they
and poorer survival was doubled compared to the quartile found a reduction in the prevalence of diarrhea in zinc trea-
with the lowest intake of zinc (<11.6 mg/day) (Tang et al., ted malaria patients (Muller et al., 2001). Acute cutaneous
1993, 1996). A recent study has addressed the safety of zinc leishmaniasis was positively affected by application of zinc
supplementation, using a moderate dose of 10 mg elemen- sulfate (Sharquie et al., 2001), with a dose-dependent heal-
tal zinc per day and the authors came to the conclusion ing rate of >96% in patients treated with the highest dose of
that zinc supplementation has no adverse effects (Bobat 10 mg zinc sulfate per kg body weight, compared to 0% in
et al., 2005). However, it was performed in HIV-infected the control group. However, this study was not blind
South African children, a population with high prevalence or placebo controlled, and the control patients had
 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408 399

significantly different size, number, and localization of the cell disease have been shown to have increased urinary
lesions. excretion of zinc and, subsequently, reduced plasma, eryth-
There is in vitro evidence that zinc has a direct anti- rocyte, and hair zinc levels (Prasad et al., 1975). Sickle cell
leishmanial effect, inhibiting several enzymes from Leish- anemia patients seem to benefit from zinc supplementation,
mania (Al-Mulla Hummadi et al., 2005a,b). On the other since zinc positively influences serum hormone levels, phys-
hand, zinc may interact with the patient’s immune system. ical development, and affects immune function, e.g., reduc-
A successful response against the intracellular parasite ing the incidences of bacterial infections (Prasad et al.,
requires a Th1 immune response. Zinc deficiency leads to 1981, 1999; Prasad and Cossack, 1984; Zemel et al., 2002).
a reduction of Th1 cytokines (Beck et al., 1997), and
patients with cutaneous, mucosal, and visceral leishmania- 3.3. Diabetes
sis display significantly lower plasma zinc levels than con-
trol subjects (Van Weyenbergh et al., 2004). Thus, A general observation in diabetes, type 1 as well as type
correcting zinc deficiency could support the Th1-mediated 2, is a loss of zinc due to increased urinary excretion. The
defense against Leishmania. resulting decrease in total body zinc may contribute to dia-
Investigation of the use of zinc supplementation for the betic complications (Chausmer, 1998). Mechanistically,
treatment of recurrent aphtous stomatitis has led to con- zinc has been described as having an insulinomimetic effect
tradicting results. While it was reported that zinc sulfate (Coulston and Dandona, 1980; May and Contoreggi,
(660 mg per day) has no effect and therefore is not a recom- 1982). This may be based on its physiological role in insulin
mended treatment (Wray, 1982), a later report did find sig- receptor signal transduction, and in particular on its func-
nificant improvements (Orbak et al., 2003). Remarkably, tion as a regulator of protein tyrosine phosphatases (Haase
the latter study used only a third of the dose from the pre- and Maret, 2003, 2005a,b). Hence, zinc supplementation
vious one. Hence, a moderate zinc supplementation could may be deemed appropriate for diabetic patients. Further-
be more effective for the treatment of recurrent aphtous more, oxidative stress has been indicated as a significant
stomatitis than the application of a very high dose. contributor to the pathogenesis of diabetes. Many studies
cited in Table 4 report positive effects on oxidative stress
3.2. Genetic disorders measured by thiobarbituric acid reactive substances, an
indicator for lipid peroxidation (Anderson et al., 2001;
Zinc supplementation studies have been conducted in Faure et al., 1995; Roussel et al., 2003).
patients with different genetically based disorders (Table HbA1c, glycosylated hemoglobin, is frequently used as
3). The classical zinc deficiency syndrome Acrodermatitis a biomarker for glycaemic control in diabetes. Two stud-
enteropathica (AE) is based on a mutation of the intestinal ies with type 1 diabetic patients showed an increase
zinc transport protein hZIP-4 (Kury et al., 2002; Wang (Cunningham et al., 1994; de Sena et al., 2005), while
et al., 2002), which mediates zinc uptake from food in the another study, in type 2 patients, found a decrease
duodenum and jejunum. AE is characterized by skin HbA1c (Al-Maroof and Al-Sharbatti, 2006). Several oth-
lesions, developmental retardation, alopecia, and immune ers did not find effects on HbA1c or glucose metabolism
deficiency. All these symptoms are caused by zinc defi- (Anderson et al., 2001; Roussel et al., 2003; Niewoehner
ciency and are completely reversed by nutritional supple- et al., 1986). Promising results were found in a study
mentation with zinc. To date, continuous nutritional investigating the effect of zinc supplementation on sub-
supplementation with high doses of zinc is the standard jects with diabetic neuropathy. Reduced blood sugar lev-
treatment for AE (Maverakis et al., 2007). els were observed as well as improvement in motor nerve
Another disease where zinc is routinely used is Wilson’s conduction velocity (Gupta et al., 1998). Although zinc
disease, an autosomal recessive disorder with excessive accu- has in vitro effects on redox (Maret, 2006) and cellular
mulation of copper in the body. Here, the interference of glucose metabolism (Tang and Shay, 2001), only a redox
high zinc doses with copper uptake is utilized to reduce the effect is reproducible in vivo in different studies, whereby
copper uptake and the resulting symptoms (Brewer et al., the influence on glucose metabolism remains unclear.
1994; Hoogenraad et al., 1984, 1987; Rossaro et al., 1990). The effect of zinc on glucose metabolism may be species
Down syndrome, or trisomy of chromosome 21, is asso- specific. While the zinc status did affect glucose levels in
ciated with reduced plasma zinc levels (Fabris et al., 1984). experimental animals, intravenous injection of zinc
Several reports of a normalization of thymulin levels, thy- (25 mg) had no effect on plasma glucose in healthy or
roid hormones and functions of several different immune diabetic human subjects (Brandao-Neto et al., 1999).
cells indicate that zinc has several positive effects on the Furthermore, all in vitro experiments that indicated an
health of patients with Down syndrome (Bucci et al., effect of zinc on the cellular level were performed in a
1999; Chiricolo et al., 1993; Franceschi et al., 1988; Licas- murine cell line (Tang and Shay, 2001). Taken together,
tro et al., 1992, 1993, 1994a,b; Lockitch et al., 1989; Napo- there is a discernible indication that zinc is helpful
litano et al., 1990). against oxidative stress in diabetic patients, but the
There are clinical similarities between patients with effects of zinc supplementation on glucose metabolism
sickle cell anemia and zinc deficiency. Patients with sickle in humans require more detailed investigations.
 400
Table 3
Zinc supplementation and genetic disorders
Disease or Zinc species and Period Participants Effect of zinc supplementation Reference
disorder dosage
Sickle cell ZA 45 mg (daily in 3 6 to 18 4 (P, Z) Increase in plasma zinc and serum testosterone, decrease in plasma lactic dehydrogenase levels Prasad et al.
disease doses) mo. (1981)
ZA 45 mg (daily in 3 6 to 18 7 (Z), 7 (P) Increase in plasma zinc and serum testosterone, decrease in plasma lactic dehydrogenase levels
doses) mo.
ZA 30 mg (daily in 2 1 y. 5 (Z), 5 (P) Increase in plasma and erythrocyte zinc, greater increase in height, body weight and serum testosterone levels Prasad and
doses) 5 (P, Z) Cossack (1984)
ZA 50 to 75 mg (daily, 3 y. 11 (Z), 11 Increase in plasma, lymphocyte and granulocyte zinc and IL-2 production; decreased incidence of bacterial Prasad et al.

H. Haase et al. / Experimental Gerontology 43 (2008) 394–408

elemental) (P) infections, number of hospitalizations and vaso-occlusive pain crisis (1999)
10 mg (daily, 1 y. 20 (Z), 22 Increased plasma zinc levels, height, sitting height, knee height and arm circumference Zemel et al.
elemental) (P) (2002)
Acrodermatitis 3 mg/kd daily (elemental) as a starting dose Complete clearance of all symptoms Maverakis
enteropathica et al. (2007)
Down syndrome ZG 25 to 50 mg/day 6 mo. 64 (P, Z) Increase in serum zinc levels, no effect on several immune parameters Lockitch et al.
(1989)
ZS 1 mg/kg (daily) 4 mo. 25, 14 (C) Normalization of serum zinc, thymulin, thyroid stimulating hormone and 3,3 0 ,5 0 triiodothyonine; decreased Licastro et al.
incidence of infectious diseases (1992)
ZS 1 mg/kg (daily) 4 mo. 51 (Z), 15 Normalization of plasma zinc, thymulin, TSH and reversal T3 Licastro et al.
(C) (1993)
ZS 1 mg/kg (daily) 4 mo. 51 (Z), 23 Normalization of plasma zinc, thymulin, TSH and reversal T3; increased granulocyte activity Licastro et al.
(C) (1994b)
ZS 1 mg/kg (daily, 4 mo. 21 (Z), 18 Normalization of plasma zinc and thymulin levels; increased lymphocyte proliferation (PHA, Con A), Licastro et al.
elemental) (C) polymorphonuclear activity and CD3+ DR+ cells; reduced incidence of infections (1994a)
ZS 1 mg/kg (daily) 2 mo. 18 (Z) Increased plasma serum thymic factor level; reduced inactive serum thymic factor molecules; normalization of Franceschi
plasma zinc, thymulin activity and absolute number of CD2+ lymphocytes; reduced recurrent infections et al. (1988)
ZS 1 mg/kg (daily) 4 mo. 15 (Z), 10 Increased thymidine incorporation of PHA stimulated lymphocytes; decelerated DNA repair Chiricolo et al.
(C) (1993)
ZS 1 mg/kg (daily) 6 mo. 32 (Z), 52 Reduced thyroid-stimulating hormone levels in hypozincemic subjects Bucci et al.
(P) (1999)
ZS 1 mg/kg (daily) 9 mo. 22 (Z) Increased growth, growth hormone and somatomedin C levels Napolitano
et al. (1990)
Wilson‘s disease ZS 660 mg (daily in 3 1.5 to 5 (Z) Increased plasma zinc and decreased plasma copper; reduction in symptoms (necrosis and inflammation in the Rossaro et al.
doses) 7 y. liver, Kayser–Fleischer rings); normalization of serum albumin, prothrombin and urinary copper excretion (1990)
ZS 600 to 900 mg 2 y. 2 case Reduction in body stores of copper and in Kayser-Fleischer rings Hoogenraad
(daily in 3 doses) reports et al. (1984)
ZS 300 to 600 mg 1 to 27 (Z) Disappeared Kayser-Fleischer rings; normalization of free plasma copper concentration Hoogenraad
(daily in 3 doses) 323 m. et al. (1987)
ZA 150 mg (daily in 3 3 to 9 13 (Z) Decreased urinary and plasma copper levels Brewer et al.
doses, elemental) y. (1994)
Z, zinc; P, placebo; C, control; mo., months; y., years; ZA, zinc acetate; ZS, zinc sulfate; ZG, zinc gluconate.
 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408 401

3.4. Arthritis

Anderson et al. (2001)

de Sena et al. (2005)

Roussel et al. (2003)

Al-Maroof and Al-

Gupta et al. (1998)

Cunningham et al.
Faure et al. (1995)

Niewoehner et al.
Serum zinc levels are significantly reduced in patients

Sharbatti (2006)
with rheumatoid arthritis (RA) (Niedermeier and Griggs,
1971; Zoli et al., 1998), potentially due to malabsorption
Reference

of zinc by RA patients (Naveh et al., 1997). Moreover, a

(1994)

(1986)
negative correlation between the serum level of zinc and
the levels of the pro-inflammatory cytokines IL-1b and

Increased plasma zinc; decreased plasma lipid peroxidation as measured by thiobarbituric acid

Increased serum zinc levels; improvements regarding fasting blood sugar, post prandial blood
sugar as well as peripheral neuropathy as measured on median and common peroneal nerves
TNF-a was found (Zoli et al., 1998). An initial report from

Decreased plasma lipid peroxidation as measured by thiobarbituric acid reactive substances

Increased plasma zinc levels and selene glutathione peroxidase activtiy; decreased plasma

Simkin (1976) also described a beneficial effect of zinc sup-

plementation on RA with positive effects of zinc on morn-
ing stiffness and joint swelling. Two later studies of similar
design, administering the same dose of zinc sulfate, were
unable to confirm this finding (Mattingly and Mowat,
Increase in serum zinc and T lymphocyte response to phytohemagglutinin

1982; Rasker and Kardaun, 1982). Two further studies

found reduced in vitro release of reactive oxygen species
by monocytes (Herold et al., 1993) and activation of
polymorphonuclear cell phagocytosis (Peretz et al., 1994)
in patients with RA as a result of zinc supplementation,
but the clinical consequences of these observations
Increase in HbA1c and mononuclear leukocyte zinc

were not investigated and remain unclear. Taken together,

zinc treatment does not seem beneficial in cases of RA
(Table 5).
Decrease in HbA1c; increase in serum zinc

A similar activation of neutrophil chemotaxis, but with-

thiobarbituric acid reactive substances

out an effect on the disease, was found after zinc supple-

mentation in patients with psoriatic arthritis (Leibovici
Effect of zinc supplementation

et al., 1990). However, in this case another study exists that

reports a favorable development of psoriatic arthritis with
an improvement of several symptoms and a reduction in
the intake of analgesics (Clemmensen et al., 1980).
reactive substances
Increase in HbA1c

Z, zinc; P, placebo; C, control; w., weeks; mo., months; ZS, zinc sulfate; ZG, zinc gluconate.

3.5. Dermatological conditions

Delayed wound healing and skin lesions are among the

symptoms of zinc deficiency, and the effect of zinc supple-
mentation on several dermatological conditions has been
investigated (Table 6). In contrast to its reported effects on
(Z), 28 (P),

(Z), 15 (P),
20 (Z), 17 (C)

43 (Z), 43 (P)

(Z), 56 (P)
Participants

7 (Z), 6 (C)

9 (Z), 4 (P)

psoriatic arthritis (Leibovici et al., 1990), zinc treatment

18 (P, Z)

seems to be without effect on psoriasis (Burrows et al., 1994).

(C)

(C)

Acne is a condition for the treatment of which zinc is

54
28
60
15
20

frequently recommended either by topical or oral applica-

tion. While some reports do not find an effect after oral zinc
6 to 8 w.
Period

supplementation (Orris et al., 1978; Weismann et al., 1977),

3 mo.

1 mo.

4 mo.

3 mo.

6 mo.
6 mo.

6 w.

others report significant improvements (Goransson et al.,

1978; Hillstrom et al., 1977; Verma et al., 1980). There were
no obvious differences in study design or the amount or salt
ZS 660 mg (daily in 3

form of zinc so that no conclusive statement about the

Zinc glycine 7.5 to

ZS 660 mg (daily)
ZG 30 mg (daily)

ZG 30 mg (daily)
ZG 30 mg (daily)
ZG 50 mg (daily,
Zinc supplementation and diabetes

ZS 30 mg (daily,
Zinc species and

effectiveness of zinc for the treatment of acne can be made.

15 mg (daily)

In this respect it should be noted that overdosage has

elemental)

elemental)

repeatedly been reported when oral zinc supplementation

dosage

doses)

was applied for the treatment of acne. The resulting inter-

ference with copper uptake has led to severe anemia, leuko-
penia, and neutropenia at doses that exceeded 100 mg
neuropathy

elemental zinc per day (Porea et al., 2000; Salzman et al.,

diabetes

diabetes
Disease or

2002).
Diabetic
disorder
Table 4

Type II
Type I

Zinc administration has so far been found to be ineffec-

tive for the treatment of atopic eczema (Ewing et al., 1991),
 402 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408

but there are single reports that it was successfully used to

Herold et al. (1993)

Peretz et al. (1994)

Clemmensen et al.
treat rosacea (Sharquie et al., 2006) and recurring oral

Kardaun (1982)

Leibovici et al.
Mattingly and
Mowat (1982)
Simkin (1976)
ulcers (Merchant et al., 1977). Another form of ulcers,

Rasker and
chronic leg ulcers, were seemingly unaffected by zinc in
Reference

two studies (Floersheim and Lais, 1980; Greaves and Ive,

(1990)

(1980)
1972), but another report did find an effect, and especially
a correlation between serum zinc levels and healing (Hall-

Reduction in joint pains, morning stiffness and daily intake of analgesics; reduction in serum
immunoglobulins; increase in serum albumin and zinc levels; increase in mobility; decrease
Positive changes regarding joint swelling, morning stiffness, walking time; no improvements

book and Lanner, 1972). This indicates once again that

the patients zinc status may be a crucial indicator for the
effectiveness of any zinc supplementation.
Reduced release of reactive oxygen species by monocytes after in vitro stimulation

Increased plasma zinc, phagocytosis of blood polymorphonuclear cells, and mean

There exists a report about the high effectiveness of zinc

Reduction in joint pains and daily intake of analgesics; reduction in serum supplementation against viral warts (Al-Gurairi et al.,
2002). However, several methodological weaknesses in this
No anti-rheumatic activity, only increase in alkaline phosphatase level

paper were pointed out by Gibbs (2003), questioning the

in swelling of several joints; improvement of the overall condition validity of the results. Another striking effect is the com-
plete resolution of the yellow nail syndrome after zinc sup-
Activation of neutrophil chemotaxis, but no effect on disease

immunoglobulins; increase in serum albumin and zinc levels

plementation, but this is based on a single case report

without any controls (Arroyo and Cohen, 1993) and awaits
verification in a larger, placebo controlled study.

3.6. Miscellaneous diseases

In addition to the cases discussed above, zinc has also

been applied in an attempt to treat several other diseases,
with some examples being mentioned here (Table 7). Two
Effect of zinc supplementation

studies exist that investigate the effect of zinc supplementa-

tion in cancer patients during radiotherapy, showing that it
regarding grip strength

phagocytotic activity

can reduce side effects such as radiation induced oropha-

Z, zinc; P, placebo; C, control; d., days; w., weeks; mo., months; ZS, zinc sulfate; ZG, zinc gluconate.
No improvements

ryngeal mucositis and taste abnormalities (Ertekin et al.,

2004; Ripamonti et al., 1998). In this respect, it should be
noted that there is also a potential relationship between
zinc and the incidence of cancer, e.g., a correlation between
nutritional zinc supplementation and the incidence of pros-
tate cancer. While several reports state that a moderate
intake of zinc can decrease the risk for prostate cancer,
10 (Z), 10 (C)

13 (Z), 26 (C)
11 (Z), 11 (P)
9 (Z), 12 (P)

12 (Z), 9 (P)
Participants

data from the Health Professionals Follow-up study sug-

24 (Z, P)

gest that an intake of more than 100 mg per day could pro-
22 (Z)

11 (Z)

mote the incidence of aggressive prostate cancers (Jarrard,

2005). The effectiveness of zinc against prostate cancer is
still a matter of intense debate and subject of ongoing
8 w. to 24

research (Costello et al., 2005).

Period

6 mo.

2 mo.

6 mo.
12 w.

For age-related macular degeneration (AMD), a few

15 d.

6 w.

6 w.
mo.

smaller studies exist, some of which found significant effects

of zinc supplementation (Newsome et al., 1988), while oth-
Zinc species and dosage

ers did not (Stur et al., 1996). In the age-related eye disease
ZS 660 mg (daily in 3

ZS 660 mg (daily in 3

ZS 660 mg (daily in 3

ZS 660 mg (daily in 3

ZS 660 mg (daily in 3
Zn-Aspartate 260 mg

study, which monitored 3640 participants for over 5 years,

ZG 45 mg (daily,
(daily in 2 doses)

a significant effect of zinc alone, as well as in combination

Zinc supplementation and arthritis

with anti-oxidants (vitamins C and E, beta carotene), was

elemental)

found on the odds of developing advanced AMD. This

strongly suggests that nutritional zinc supplementation,
doses)

doses)

doses)

doses)

doses)

either alone or even more effective when taken with anti-

oxidants, is advantageous for elderly patients at risk for
macular degeneration (AREDS Research Group, 2001).
Zinc supplementation has also been examined in
Rheumatoid
arthritis

arthritis
Disease or

patients with several psychiatric illnesses. When zinc was

Psoriatic
disorder
Table 5

supplemented in addition to standard anti-depressant ther-

apy in 6 patients, reduced symptoms of unipolar depression
 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408 403

Table 6
Effect of zinc supplementation on dermatological conditions
Disease or disorder Zinc species and dosage Period Participants Effect of zinc supplementation Reference
Chronic leg ulcers ZS 660 mg (daily in 3 doses) 4 mo. 18 (Z), 18 (P) No effect Greaves and Ive
(1972)
ZS 660 mg (daily in 3 doses) 3 mo. 24 (Z), 23 (P) Increased serum zinc; no effect on healing Floersheim and
Lais (1980)
ZS 600 mg (daily in 3 doses) 4 mo. 13 (Z), 14 (P) Improved healing-rate, correlated to serum zinc Hallbook and
levels Lanner (1972)
Recurring oral ZS 220 to 660 mg (daily) 17 (Z), 15 (P) Reduction in frequency of episodes Merchant et al.
(aphthous) (1977)
ulcers
Psoriasis vulgaris ZS 660 mg (daily in 3 doses) 6 w. 13 (Z), 26 (C) Normalization of neutrophil random migration Leibovici et al.
and directed chemotaxis (1990)
Psoriasis ZS 220 mg (daily) 3 mo. 13 (Z), 11 (P) No effect Burrows et al.
(1994)
Yellow nail ZS 300 mg (daily) 2 y. 1(Z) Total resolution of yellow nails and Arroyo and
syndrome lymphoedema Cohen (1993)
Atopic eczema ZS 185 mg (daily in 3 2 mo. 22 (Z), 20 (P) No effect Ewing et al.
doses, = 67.5 mg elemental (1991)
Zn)
Rosacea ZS 300 mg (daily in 3 doses) 3 mo. 19 (P, Z) Decreased papules, pustules and erythema Sharquie et al.
(2006)
Acne vulgaris ZS 600 mg (daily in 3 doses) 1 to 3 20 (Z), 19 (P) Increase in serum zinc levels; no effect Weismann et al.
mo. (1977)
ZS 600 mg (daily in 3 doses) 3 mo. 29 (Z), 27 (P) Decrease in number of papules, infiltrates and Verma et al.
cysts; increase in serum vitamin A levels (1980)
ZS 600 mg (daily in 3 doses) 6 w. 27 (Z), 27 (P) Reduction in the numbers of lesions and scores Goransson et al.
(1978)
ZS 400 mg (daily in 2 doses) 3 mo. 48(Z), 43(P) Reduced papules and pustules Hillstrom et al.
(1977)
Moderate acne ZS 411 mg (daily in 3 doses) 2 mo. 12 (Z), 10 (P) Increase in serum zinc levels; no effects Orris et al. (1978)
Viral warts ZS 10 mg/kg (daily in 3 doses), 2 mo. 23 (Z), 20 Increased serum zinc; complete clearance of Al-Gurairi et al.
up to 600 mg per day (P), 20 (C) warts in most patients (2002)
Z, zinc; P, placebo; C, control; w., weeks; mo., months; y., years; ZS, zinc sulfate.

were observed (Nowak et al., 2003). It has also been for a limited number of diseases, while many others still
reported that zinc sulfate treatment reduced symptoms in require closer investigation. From the data it seems clear
children with attention deficit hyperactivity disorder (Bilici that zinc supplementation is recommendable for Acroder-
et al., 2004). In addition, there are case studies that describe matitis enteropathica, Wilson’s disease, diarrhea, and lep-
a beneficial effect of zinc treatment on patients with rosy. While zinc is effective for the causal treatment of
anorexia nervosa (Bryce-Smith and Simpson, 1984; Safai- some diseases, like AE, many other diseases lead to a
Kutti and Kutti, 1986). Due to similarities of the symptoms decrease in zinc status, like increased urinary excretion in
of patients with zinc deficiency and anorexia nervosa, it has diabetes and sickle cell disease. In addition to the primary
been suggested that zinc nutrition is involved in the effects of the disease, this can cause secondary complica-
etiology of this disorder (Bakan, 1979), but it should also tions due to zinc deficiency, which can also be treated with
be considered that the observed low serum zinc values zinc supplementation.
may simply be a result of dietary inadequacy (Sandstead, In many cases, contradicting results were described.
1986). Adequate and comparable supplementation protocols
Many of these reports seem promising, however they are required, since the daily doses of elemental zinc dif-
usually only represent single studies, sometimes with low fer, sometimes by one order of magnitude. Also, there is
numbers of participants. Confirmation by investigation of considerable variation between the bioavailability of the
the effects in larger study groups or identification of the different salt forms of zinc, making comparisons virtu-
underlying molecular mechanism would strengthen the ally impossible. Zinc bioavailability correlates with solu-
supposed usefulness for zinc supplementation in these bility in aqueous solution, with zinc sulfate and acetate
diseases. being highly soluble and easily absorbed, while zinc car-
bonate and oxide are practically insoluble and have sig-
4. Conclusion nificantly lower bioavailability (Allen, 1998). Also, zinc
absorption is negatively influenced by dietary factors
Despite the high number of studies, the effectiveness of like zinc-chelating phytates, and supported by high
nutritional zinc supplementation can only be concluded amounts of protein and single amino acids, in particular
404 H. Haase et al. / Experimental Gerontology 43 (2008) 394–408

Table 7
Effect of zinc supplementation on miscellaneous diseases
Disease Zinc species and Period Participants Effect of zinc supplementation Reference
dosage
Head and neck ZS 150 mg (daily in 3 10 to 13 15 (Z), 15 (P) Decrease in degree of mucositis, decelerated Ertekin et al.
cancer doses, elemental) w. development of confluent mucositis and faster (2004)
improvements
ZS 135 mg (daily in 3 11 w. 9 (Z), 9 (P) Reduced worsening and quicker recovery of taste Ripamonti
doses, elemental) acuity et al. (1998)
Unipolar ZA 25 mg (daily, 3 mo. 6 (Z), 8(P) Reduction of symptoms Nowak et al.
depression elemental) (2003)
Attention deficit ZS 150 mg (daily) 3 mo. 95 (Z), 98 (P) Increased serum zinc and free fatty acid levels; Bilici et al.
hyperactivity reduced hyperactive, impulsive and impaired (2004)
disorder socialization symptoms
Anorexia nervosa ZS 45 to 90 mg 4 to 16 5 (Z) Increased weight gain Safai-Kutti and
(daily, elemental) mo. Kutti (1986)
ZS 45 to 150 mg 4 mo. 1 case report Increased weight gain; improved taste; no depression Bryce-Smith
(daily in 3 doses, and Simpson
elemental) (1984)
Macular ZS 200 mg (daily in 2 1 to 2 y. 80 (Z), 71 (P) Less visual loss; lesser decrease in mean visual acuity; Newsome et al.
degeneration doses) eyes remained stable or showed less accumulation of (1988)
visible drusen
ZS 200 mg (daily) 24 mo. 56 (Z), 56 (P) Increased serum zinc levels Stur et al.
(1996)
zinc oxide 80 mg average 903 (P), 904 (Z), Significantly decreased odds for developing AMD in AREDS
elemental zinc per of 6.3 y. 945 (A), 888 groups treated with zinc alone and zinc + anti- Research
day (Z + A) oxidants Group (2001)
Z, zinc; P, placebo; A, antioxidants; w., weeks; mo., months; y., years; ZA, zinc acetate; ZS, zinc sulfate.

histidine and methionine (Lonnerdal, 2000). Another Acknowledgement

aspect is the gastric pH, especially for the insoluble zinc
salts, which can be partially converted into more soluble We thank Romney S. Haylett for critical reading of the
zinc chloride in the presence of gastric acid (Allen, manuscript.
1998).
In certain cases, like Wilson’s disease and AE, high
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