Zinc deficiency and IL-6 -174G/C polymorphism in old people from different European countries: effect of zinc supplementation. ZINCAGE study.

IL-6 SNP at position -174 is associated with age-related diseases characterized by an impaired Zn status. This polymorphism seems also relevant in regulating the expression of proteins, such as Metallothioneins (MT), involved in the modulation of Zn homeostasis. Since high IL-6 levels in elderly induce hypozinchemia, the IL-6-174 SNP may be useful to identify old subjects who are at risk for Zn deficiency. The objectives of this study are: (1) to choose old subjects who effectively need Zn supplementation and (2) to study the effect of Zn supplementation on Zn, immune and psychological status in genetically selected subjects. For this purpose, a baseline study comprising 895 healthy old subjects recruited in Central-Northern and Southern European Countries was carried out by evaluating their dietary intake, psychological and immune parameters as well as their Zn status. A Zn supplementation trial was performed in 110 old subjects selected on the basis of their plasma Zn levels and IL-6 SNP. After correcting for age and Zn intake, C- carriers displayed higher MT and lower levels of several parameters related to zinc status (plasma Zn, erythrocyte Zn and NO-induced release of Zn in PBMC) than C+ carriers. Better NK cell cytotoxicity and psychological functions (PSS, MMSE) were also found in C+ than C- carriers strictly related to the zinc status. However, independently by the polymorphism, all subjects with plasma zinc < or = 10.5microM showed the worst immune response and psychological functions. Supplementation was carried out in C+ and C- carriers with stable low plasma zinc levels ( < or =10.5microM at baseline and at 1 year follow-up) and in C- carriers with unstable plasma zinc (< or =10.5microM at baseline and >10.5microM at 1 year follow-up). C+ carriers with plasma zinc >10.5microM were not supplemented because showing the best immune and psychological conditions. After 48+/-2 days of supplementation with 10mg/day of Zn-aspartate, the NO-induced release of Zn, erythrocyte Zn and NK cell cytotoxicity increased in all groups selected for supplementation, including C- with unstable plasma zinc. In conclusion, the sole assessment of plasma Zn level is not reliable to exclude C- carriers from Zn supplementation. A possible explanation for the conflicting data on the identification of IL-6-174G as a "risk allele" based on different dietary intake in the studied population is also suggested.

A novel Zip2 Gln/Arg/Leu codon 2 polymorphism is associated with carotid artery disease in aging.

Zinc deficiency represents a risk factor for carotid stenosis (CS) development. In mammals, members of the ZIP family regulate zinc uptake, and hZip2 is a human zinc importer upregulated by zinc depletion. The purpose of this study was to investigate the association of a novel Zip2 Gln/Arg/Leu codon 2 polymorphism with CS, analyzing 250 CS patients and 259 elderly controls. CS patients showed an increased GG genotype frequency (60% vs. 47.5%), and a reduced TT frequency (6% vs. 10%) (p < 0.05 by chi(2) test). In conclusion, Zip2 Gln/Arg/Leu polymorphism plays a role in the susceptibility to carotid artery disease.

Modulation of genes involved in zinc homeostasis in old low-grade atherosclerotic patients under effects of HMG-CoA reductase inhibitors.

Taking into account the antioxidant properties of zinc, it is difficult to explain the beneficial effects of HMG-CoA reductase inhibitors in the context of a well-known decreased zinc status. Therefore, intracellular zinc homeostasis was studied in patients with low-grade carotid atherosclerosis under treatment with HMG-CoA reductase inhibitors using a custom microarray-based approach developed by pooling information across microarray studies. Experimental data unravel an active zinc signaling in PBMC from low-grade atherosclerotic patients under lipid reduction therapy, suggesting that monitoring intracellular zinc status could be a key factor for an optimal strategy and targeting a level of intervention.

Metallothionein downregulation in very old age: a phenomenon associated with cellular senescence?

It is known that metallothionein (MT) mRNA expression first increases with age, but then decreases again in the very elderly. Here we report that MT protein levels also decrease in very old age, and that this is independent of dietary zinc intake. Age-related changes of MT, as well as alterations of zinc homeostasis (intracellular labile zinc and NO-induced zinc release), occur both in human PBMCs ex vivo and also in CD4+ T cell clones progressing through their finite life span in vitro. These results suggest that phenomena observed in very old people can be at least partially attributed to diminished cell proliferation.

Zinc, metallothioneins, and longevity--effect of zinc supplementation: zincage study.

Aging is an inevitable biological process that is associated with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. Because nutritional factors are involved in improving immune functions, metabolic harmony, and antioxidant defense, some nutritional factors, such as zinc, may modify susceptibility to disease and promote healthy aging. In vitro (human lymphocytes exposed to endotoxins) and in vivo (old or young mice fed with low zinc dietary intake) studies revealed that zinc is important for immune efficiency (innate and adaptive), antioxidant activity (supeoxide dismutase), and cell differentiation via clusterin/apolipoprotein J. Intracellular zinc homeostasis is regulated by metallothioneins (MT) via ion release through the reduction of thiol groups in the MT molecule. This process is crucial in aging because high MT levels are not able to release zinc, resulting in low intracellular free ion availability for biological functions. Improvement in these functions occurs in the elderly after physiological zinc supplementation. In this study, the selection of elderly subjects for zinc supplementation is discussed in relation to the genetic background of MT and pro-inflammatory cytokines, such as interleukin-6, because the latter is involved both in MT-gene expression and in intracellular zinc homeostasis.

Zinc-bound metallothioneins and immune plasticity: lessons from very old mice and humans.

The capacity of the remodelling immune responses during stress (named immune plasticity) is fundamental to reach successful ageing. We herein report two pivotal experimental models in order to demonstrate the relevance of the immune plasticity in ageing and successful ageing. These two experimental models will be compared with the capacity in remodelling the immune response in human centenarians. With regard to experimental models, one model is represented by the circadian rhythms of immune responses, the other one is the immune responses during partial hepatectomy/liver regeneration (pHx). The latter is suggestive because it mimics the immunosenescence and chronic inflammation 48 h after partial hepatectomy in the young through the continuous production of IL-6, which is the main cause of immune plasticity lack in ageing. The constant production of IL-6 leads to abnormal increments of zinc-bound Metallothionein (MT), which is in turn unable in zinc release in ageing. As a consequence, low zinc ion bioavailability appears for thymic and extrathymic immune efficiency, in particular of liver NKT cells bearing TCR gammadelta. The remodelling during the circadian cycle and during pHx of zinc-bound MT confers the immune plasticity of liver NKT gammadelta cells and NK cells in young and very old mice, not in old mice. With regard to human centenarians and their capacity in remodelling the immune response with respect to elderly, these exceptional individuals display low zinc-bound MT associated with: a) satisfactory intracellular zinc ion availability, b) more capacity in zinc release by MT, c) less inflammation due to low gene expression of IL-6 receptor (gp130), d) increased levels of IFN-gamma and number of NKT cell bearing TCR gammadelta. Moreover, some polymorphisms for MT tested in PBMCs from human donors are related to successful ageing. In conclusion, zinc-bound MT homeostasis is fundamental to confer the immune plasticity that is a condition "sine qua non" to achieve healthy ageing and longevity.

Plasticity of neuroendocrine-thymus interactions during ontogeny and ageing: role of zinc and arginine.

Thymic re-growth and reactivation of thymic functions may be achieved in old animals by different endocrinological or nutritional manipulations such as, (a) treatment with melatonin, (b) implantation of a growth hormone (GH) secreting tumour cell line (GH3 cells) or treatment with exogenous GH, (c) castration or treatment with exogenous luteinizing hormone-releasing hormone (LHRH), (d) treatment with exogenous thyroxin or triiodothyronine, and (e) nutritional interventions such as arginine or zinc supplementation. These data strongly suggest that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of these interactions in old age that is responsible for age-associated immune-neuroendocrine dysfunctions. The targets involved in hormones-induced thymic reconstitution may directly or indirectly involve hormone receptors, cytokines, arginine, and a trace element such as zinc, which is pivotal for the efficiency of neuroendocrine-immune network during the whole life of an organism. The effect of GH, thyroid hormones, and LHRH may be due to specific hormone receptors on thymocytes and on thymic epithelial cells (TECs), which synthesize thymic peptides. Melatonin may also act through specific receptors on T-cells. In this context, the role of zinc, which turnover is reduced in old age, is pivotal because of its involvement through zinc fingers in the gene expression of hormone receptors. In addition, the effects of zinc are multifaceted: from the reactivation of zinc-dependent enzymes, to cell proliferation and apoptosis, to cytokines expression and to the reactivation of thymulin, which is a zinc-dependent thymic hormone required for intrathymic T-cell differentiation and maturation as well as for the homing of stem cells into the thymus. Zinc is also required for arginine action, via NO pathway. The role of zinc is therefore crucial in neuroendocrine-thymus interactions. According to data in animals and humans, the above reported endocrinological manipulations (GH, thyroid hormones, and melatonin) or arginine treatment may also act via zinc pool in restoring thymic activity in ageing allowing improvements on peripheral immune efficiency.

Nutrient-gene interaction in ageing and successful ageing. A single nutrient (zinc) and some target genes related to inflammatory/immune response.

In this paper, we reviewed data regarding to the pivotal role played by the zinc-gene interaction in affecting some relevant cytokines (IL-6 and TNF-alpha) and heat shock proteins (Hsp70-2) in ageing, successful ageing (nonagenarians) and in some age-related diseases (atherosclerosis and infections). The polymorphisms of the genes codifying these proteins are predictive on one hand in longevity, such as IL-6 -174G/C locus, on the other hand 1267 Hsp70-2A/B or TNF-alpha -308G/A polymorphisms are associated to worsening atherosclerosis or severe infections, respectively, rather than longevity. Taking into account that longevity has a strong genetic component but, at the same time, is affected by life style and environmental factors, the analysis of these polymorphisms in association to some immune parameters (NK cell cytotoxicity) and nutritional factors (zinc) is a useful tool to unravel the role played by these genetic factors in longevity and in the appearance of age-related diseases. Indeed, these polymorphisms are associated with chronic inflammation, low zinc ion bioavailability, depressed innate immune response and high gene expression of metallothioneins, which have a limited zinc release for an optimal innate immune response in ageing. Therefore, the nutrient (zinc)-gene (IL-6, TNF-alpha and Hsp70-2) interaction is pivotal to keep under control the inflammatory/immune response with subsequent longevity, indicating these genes as "robust" for "healthy ageing".

Zinc-binding proteins (metallothionein and alpha-2 macroglobulin) and immunosenescence.

Zinc is a relevant trace element for the efficiency of the entire immune system. The binding of zinc with some proteins, such as metallothioneins (MT) and alpha-2 macroglobulin (alpha-2M) is crucial for the immune efficiency during ageing and in age-related diseases, because these proteins may be involved in antagonistic pleiotropic effects. Indeed, the presence of chronic inflammation during ageing, generally, induces overexpression of these proteins that, due to their original biological function in fighting stressor agents, continuously sequester intracellular zinc. As a consequence, a low zinc ion availability may appear in aged organisms leading to impairments of the immune response at thymic and extrathymic levels with the risk of the appearance of age-related diseases. Therefore, MT and alpha-2M turn from protective in "young-adult age" to harmful agents in "ageing" following the basic assumption of an evolutionary theory of ageing, named the "antagonistic pleiotropy", which suggests that a trade off between early beneficial effects and late negative outcomes can occur at a genetic and molecular level. On the other hand, some polymorphisms of MT (MT2A) and alpha-2M have been associated with atherosclerosis or Alzheimer disease, respectively. Physiological zinc supplementation in elderly restores the thymic endocrine activity and innate immune response (NK cell cytotoxicity) and increases the survival rate in old mice. Therefore, zinc supplementation is useful to achieve health longevity because these zinc-binding proteins may regain their original protective task against oxidative damage with, thus, a beneficial impact on immune response.

Zinc homeostasis in aging: two elusive faces of the same "metal".

Proteins involved in zinc homeostasis may be altered in aging. This phenomenon may lead to zinc deficiency in the peripheral blood and an accumulation of zinc bound to insoluble aggregates at the extracellular level in the brain. Therefore, it should be more correct to talk about aging as a condition associated with zinc dyshomeostasis rather than deficiency. Restoring functional zinc homeostasis in aging people is an attractive field for antiaging research, but requires further knowledge than the current state of the art.

1267 HSP70-2 polymorphism as a risk factor for carotid plaque rupture and cerebral ischaemia in old type 2 diabetes-atherosclerotic patients.

Patients with type 2 diabetes mellitus (NIDDM) are at risk for macrovascular disease complications, such as myocardial infarction (MI) or stroke from plaque rupture. Cytokines play a key role in plaque vulnerability. IFN-gamma inhibits collagen synthesis thereby affecting plaque stability. High IL-6, TNF-alpha, and dyslipidemia are risk factors for thrombosis. Abnormal increments of HSP70 in atherosclerotic plaques might lead to plaque instability and rupture caused by chronic inflammation, which up-regulates the expression of pro-inflammatory cytokines (IL-6 and TNF-alpha) in human monocytes. Studies of a polymorphic PstI site lying in the coding region at position 1267 of the HSP70-2 gene have shown that the BB genotype is associated with NIDDM. We screened 60 old NIDDM patients with carotid stenosis and 107 old healthy controls for 1267 HSP70-2 polymorphism in order to establish if an association with plaque frailty exists. Different genotypic distributions were observed between patients and healthy controls. An increased relative risk was associated with the B allele (p = 0.0107; odds ratio = 1.861). HSP70-2, IL-6, IFN-gamma, TNF-alpha gene expressions within the plaques and serum levels of triglyceride, total cholesterol and LDL cholesterol were tested from patients stratified according to their B+ (AB and BB) and B- (AA) genotypes. Plaque morphology (soft or fibrous-calcified) and the incidence of cerebral ischaemia were also assessed. B+ patients showed increased HSP70-2, IL-6, IFN-gamma, TNF-alpha and dyslipidemia as compared to B- carriers. The frequency of soft plaques increased in B+ in comparison to B- patients (67% versus 13%; odds ratio 13.0, p = 0.0006). A higher frequency of cerebral ischaemia (ictus or transient ischaemic attack (TIA)) was present in B+ than in B- genotype (53% versus 20%; odds ratio 4.57, p < 0.05) Hence, 1267 HSP70-2 polymorphism may be of use in identifying B+ NIDDM patients at risk for carotid plaque rupture and cerebral ischaemia.

Zinc, immune plasticity, aging, and successful aging: role of metallothionein.

The capacity of the remodeling immune responses during stress (immune plasticity) is fundamental to reach successful aging. We herein report two pivotal models to demonstrate the relevance of the immune plasticity in aging and successful aging. One model is represented by the circadian rhythms of immune responses; the other one is the immune responses during partial hepatectomy/liver regeneration (pHx). The latter is suggestive because it mimics the immunosenescence and chronic inflammation 48 hours after partial hepatectomy in the young through the continuous production of IL-6, which is the main cause of immune plasticity lack in aging. The constant production of IL-6 leads to abnormal increments of zinc-bound metallothionein (MT), which is, in turn, unable in zinc release in aging. As a consequence, low zinc ion bioavailability appears for thymic and extrathymic immune efficiency, in particular, of liver NKT cells bearing TCR gd. The remodeling during the circadian cycle and during pHx of zinc-bound MT confers the immune plasticity of liver NKT gamma delta cells and NK cells in young and very old age, not in old age. Therefore, zinc-bound MT homeostasis is crucial in conferring liver immune plasticity with subsequent successful aging.

Metallothionein isoforms (I+II and III) and interleukin-6 in the hippocampus of old rats: may their concomitant increments lead to neurodegeneration?

Metallothionein (MT)-III isoform is a brain metal-binding protein that, like the MT-I + II isoform, binds zinc with high affinity. In the young-adult age, MT-III isoform increases during transient stress while MT-I + II isoform decreases, suggesting compensatory phenomena between the two isoforms and a protective role of MT-III against oxidative damage. This role may be questioned during ageing, because the stress-like condition is chronic in ageing due to high persistent levels of interleukin-6. In the present study, high expression of MT-III and MT-I + II genes (examined by RT-PCR and in situ hybridisation) was found in the hippocampus of old rats. These results indicate that a large amount of free zinc ions can be sequestered by MT isoforms, leading to impaired zinc-dependent functions in the ageing brain. In addition, zinc (tested with the Timm's method) was found to be low in mossy fibres from the old hippocampus. As this method tests bound and unbound zinc, we also investigated free zinc ion bioavailability based on the ratio active thymulin/total thymulin. We found that zinc ion bioavailability was low in old rats, together with increased interleukin-6 mRNA, high expression of both MT isoforms and reduced number of synapses whose function is zinc-dependent, in the old hippocampus. The results indicate that concomitant increments of both MT isoforms may provoke detrimental synergistic effects leading to reduced free zinc ion bioavailability for synapses. As a consequence, compensatory phenomena between MT isoforms may not occur in the old hippocampus due to chronic stress-like condition elicited by high persistent levels of interleukin-6.

Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing?

BACKGROUND: With advancing age, thymic efficiency shows progressive decline due to thymic involution allowing impaired cell-mediated immunity and the appearance of age-related diseases. The intrinsic cause of thymic involution is still undefined. Chronic inflammation and high glucocorticoids (GCs) may be involved. However, transgenic mice, with increased GC sensitivity and over expression of GC receptors, display delayed age-associated thymic involution. This fact suggests that other substances may affect thymic involution. Among them, both isoforms of metallothioneins (MTs) I+II and III are the major candidates because their increments leads to organ atrophy in constant stress and are induced by IL-6, which increases in ageing. Enhanced MTs in ageing allows constant sequester of zinc ions and no subsequent zinc release leading to low zinc ion bioavailability for thymic efficiency. This sequester is very limited in very old age. Thus, we have investigated the MTmRNA (I+II and III) in the thymus from young, old and very old mice. METHODS: MTmRNA and IL-6mRNA (RT-PCR) in the thymus from different donors were tested. Concomitantly, TECs proliferation, zinc ion bioavailability (ratio total thymulin/active thymulin), thymulin activity and corticosterone were tested from different donors. RESULTS: Both isoforms of MTmRNA and IL-6mRNA increase in old thymus coupled with low zinc ion bioavailability, reduced TECs proliferation, impaired thymulin activity and enhanced plasma corticosterone in comparison with young. Conversely, although the thymus is involuted in very old mice because of no changes in thymus weight in comparison to old mice, reduced MTmRNA, especially MT-I+II isoforms, and low IL6mRNA occur. Concomitantly, good zinc ion bioavailability, maintained TECs proliferation, satisfactory thymulin activity and reduced corticosterone are observed in very old mice. CONCLUSIONS: The concomitant increments by high IL-6 of both MT isoforms in the thymus from old mice may be involved in thymic involution because provoking low zinc ion bioavailability, which is relevant for thymic efficiency. By contrast, the limited increments of MTs by low IL-6 induce good zinc ion bioavailability and satisfactory thymic efficiency in very old mice. Therefore, abnormal increased MTs may provoke complete thymic involution during ageing and the possible appearance of age-related diseases. If their increments are instead limited by low inflammation, healthy ageing and longevity may be reached.

Association of MT1A haplotype with cardiovascular disease and antioxidant enzyme defense in elderly Greek population: comparison with an Italian cohort.

Metallothioneins (MT), the antioxidant zinc-binding proteins, seem to mediate cardioprotection. It has been postulated that zinc homeostasis and MT function may be altered, as a consequence of oxidative stress, in cardiovascular disease (CVD), with a potential implication of MT genetic polymorphisms. The present study explores the role of +647A/C and +1245A/G MT1A polymorphisms on the susceptibility to CVD, zinc status and enzyme antioxidant activity, in the Greek and Italian populations. The country selection was based on the lower zinc status and the reduced zinc dietary intake in Greece than in Italy despite the similar Mediterranean dietary pattern. A total of 464 old, healthy control subjects and 369 old CVD patients more than 70 years of age were studied. Logistic regression model indicated that +1245 MT1A G+ genotype significantly increased the risk of CVD in Greece (34.4% vs. 23.2%; odds ratio=1.88, 95% confidence interval=1.14-3.08; P=.013) but not in Italy. Haplotype analysis showed an increment of CG haplotype frequency in CVD Greek patients (17.4% vs. 10.6%, P<.05). Differential country-related frequency distribution was also recorded. Applying a multivariate regression model, +647/+1245 MT1A haplotype was associated with a modulation of enzyme antioxidant activities in both countries. Decreased plasma zinc and reduced intracellular Zn release, as well as increased enzyme antioxidant activity, were more apparent in Greek healthy donors than in Italy. In conclusion, +1245 MT1A polymorphism and +647/+1245 MT1A haplotype are implicated in CVD in Greece but not in Italy, suggesting a role of gene-diet interaction in the disease predisposition.

Distinctive modulation of inflammatory and metabolic parameters in relation to zinc nutritional status in adult overweight/obese subjects.

Overweight and obesity are associated with low grade of inflammation and chronic inflammatory response characterized by abnormal production and activation of some pro-inflammatory signalling pathways. Taking into account that obesity is the direct result of an imbalance between energy intake and energy expenditure, the nutritional factors in the diet, with particular focus on zinc, may play a pivotal role in the development of obesity-associated comorbidities. Considering the potential interactions among zinc nutritional status, inflammation, overweight/obesity and insulin secretion, the aim of the present work was to clarify the influence of zinc dietary intake on some metabolic, inflammatory and zinc status parameters in adult overweight/obese subjects. We found a close interrelationship between nutritional zinc and obesity. In particular, subjects with a lower zinc dietary intake display a deeper inflammatory status, general impairment of the zinc status, an altered lipid profile and increased insulin production with respect to obese subjects with normal zinc dietary intake. Moreover, in the presence of low dietary zinc intake, the obese subjects are less capable to respond to oxidative stress and to inflammation leading to the development of obesity or to a worsening of already preexisting obesity status. In conclusion, a possible zinc supplementation in obese subjects with a deeper inflammatory status and more altered zinc profile may be suggested in order to limit or reduce the inflammation, taking also into account that zinc supplementation normalizes "inflammaging" as well as zinc profile leading to a correct intra- and extracellular zinc homeostasis.

Accumulation of cells with short telomeres is associated with impaired zinc homeostasis and inflammation in old hypertensive participants.

Critical shortening of telomeres, likely associated with a considerable increase of senescent cells, can be observed in PBMC of individuals aged 80 and older. We investigated the relationship between critical telomere shortening and zinc status in healthy or hypertensive participants with or without cardiovascular disease in old and very old participants. Telomere shortening and accumulation of cells with short telomeres (percent of cells with short telomeres) in advancing age was evident in patients and healthy controls, but exacerbated in those patients aged 80 and older. Moreover, in very old patients, the accumulation of % CST may impair intracellular zinc homeostasis and metallothioneins expression, which itself is linked to an increased number of inflammatory agents, thereby suggesting the existence of a possible causal relationship between % CST and zinc homeostasis. The determination of % CST could be a more reliable means than the simple measure of telomere length as fundamental parameter in ageing to determine whether individuals are still able to respond to stress.

l-Arginine normalizes NOS activity and zinc-MT homeostasis in the kidney of mice chronically exposed to inorganic mercury.

Inorganic mercury (HgCl2) exposure provokes damage in many organs, especially kidney. Inducible nitric oxide synthase (iNOS) expression, total NOS activity and the profiles of zinc (Zn), copper (Cu) and Hg as well as their distribution when bound to specific intracellular proteins, including metallothioneins (MT), were studied during HgCl2 exposure and after l-arginine treatment in C57BL/6 mouse kidney. HgCl2 exposure modulates differently iNOS expression and NOS activity, increasing iNOS expression but, conversely, decreasing total NOS activity in the mouse kidney. Moreover, during Hg exposure an increased MT production occurs. The kidney damage leads to a loss of urinary proteins, increased plasma creatinine and high Zn mobilization with consequent increased urinary Zn excretion. l-arginine treatment recovers NOS activity and induces a normalization of MT induction, plasma creatinine values and urinary proteins excretion, suggesting that l-arginine may limit kidney damages by Hg exposure.

Pro-inflammatory genetic background and zinc status in old atherosclerotic subjects.

Inflammation and genetics are prominent mechanisms in the pathogenesis of atherosclerosis (AT) and its complications. In this review we discuss the possible impact on AT development of several genetic determinants involved in inflammation, oxidative stress and cytoprotection (IL-6, TNF-alpha, IL-10, CD14, TLR4, MT, HSP70). Genetic polymorphisms of these genes may affect a differential inflammatory response predisposing to AT. However, allelic polymorphisms of genes which increase the risk of AT frequently occur in the general population but, only adequate gene-environment-polymorphism interactions promote the onset of the disease. Zinc deficiency has been suggested as an environmental risk factor for AT. With advancing age, the incidence of zinc deficiency increases for several reasons. Among them, dietary intake, malabsorption and genetic background of inflammatory markers may be involved. A crucial contribution may also be played by increased oxidative stress which may lead to the appearance of dysfunctional proteins, including metallothioneins (MT) that are in turn involved in zinc homeostasis. The detection of candidate genes related to inflammation and promoting AT and their reciprocal influence/interaction with zinc status might allow earlier appropriate dietary interventions in genetically susceptible subjects.