Main biomarkers associated with age-related plasma zinc decrease and copper/zinc ratio in healthy elderly from ZincAge study.

PURPOSE: Zinc (Zn) plays an essential role in many biological processes including immune response. Impaired Zn status promotes immune dysfunction, and it has been associated with enhanced chronic inflammation during aging. It has been suggested that the measurement of circulating Zn by itself could not reflect the real Zn status of an individual. It is therefore necessary to identify other determinants associated with plasma Zn to better understanding how physiopathological conditions during aging may affect the concentration of this metal. METHODS: We have investigated the association between Zn levels and some biomarkers in 1090 healthy elderly from five European countries to increase the accuracy in the assessment of the Zn status. Stepwise multivariate linear regression models were used to analyze the influence of factors such as age, dietary intake, inflammatory mediators, laboratory parameters and polymorphisms previously associated with Zn homeostasis. RESULTS: Plasma Zn decrement was most strongly predicted by age, while positive correlations were found with albumin, RANTES and Zn intake after adjustment for multiple confounders. HSP70 +1267 AA genotype was an independent factor associated with Zn plasma concentrations. Cu/Zn ratio was positively associated with markers of systemic inflammation and age and negatively associated with albumin serum levels. CONCLUSIONS: Our findings show the most important independent determinants of plasma Zn concentration and Cu/Zn ratio variability in elderly population and suggest that the decline with age of Zn circulating levels is more dependent on physiopathological changes occurring with aging rather than to its nutritional intake.

My Mind Project: the effects of cognitive training for elderly-the study protocol of a prospective randomized intervention study.

BACKGROUND: Cognitive decline and dementia represent a key problem for public health as they heavily impair social functioning and independent living. The development of new strategies to support recommendations for patients and their caregivers may represent an outstanding step forward. AIMS: To describe the study protocol and methods of "My Mind Project: the effect of cognitive training for elderly" (Grant No. 154/GR-2009-1584108), which investigates, by the use of a multidisciplinary approach, the effects of a comprehensive cognitive training programme on performances in aged subjects with mild-moderate Alzheimer's disease, mild cognitive impairment and normal cognitive functioning. METHODS: The study is a prospective randomized intervention for the assessment of cognitive training effects in three groups of elderly subjects with different cognitive status. A total of 321 elderly people were enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental group or to a control group. Cognitive performances and biochemical blood markers have also been analysed before cognitive training (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2) and after 2 years (follow-up 3). DISCUSSION: The results will be useful to identify some efficient programmes for the enhancement of cognitive performance in elderly with and without cognitive decline. CONCLUSION: The application of a non-pharmacological approach in the treatment of elderly with cognitive disorders could have a profound impact on National Health Service.

Association among 1267 A/G HSP70-2, -308 G/A TNF-α polymorphisms and pro-inflammatory plasma mediators in old ZincAge population.

Proinflammatory cytokines and heat shock proteins play relevant roles in the pathogenesis of inflammatory diseases. We investigated whether Hsp70 1267 A/G and TNF-α -308 G/A polymorphisms are associated with proinflammatory mediators, zinc status and laboratory parameters in 1,078 healthy elderly from ZincAge study. Hsp70 1267 A/G genotype and allele distribution were similar among various European countries, while a TNF-α genetic heterogeneity was observed between the Northern and the Southern European populations, with a major frequency of the -308 A variant in France, Germany and Poland. We used linear regression models to test additive, dominant or recessive associations of each SNP with proinflammatory mediators, laboratory parameters, metallothioneins and zinc status. Hsp70 1267 A/G SNP, but not TNF-α -308 G/A SNP, influences TNF-α and IL-6 plasma levels under additive, dominant and recessive models (for TNF-α only). An association between Hsp70 1267 A/G SNP and zinc plasma levels was observed in the dominant model. In particular, G allele carriers showed increased circulating pro-inflammatory cytokines and zinc. Moreover, both these SNPs affect creatinine levels suggesting a possible influence on renal function. In conclusion, Hsp70 1267 A/G SNP is associated with pro-inflammatory cytokine production in healthy elderly and might represent a possible determinant of individual susceptibility to inflammatory diseases.

[Biological risk and health care workers: analysis of the effects of work chronobiology on the immune system]. / Rischio biologico ed operatori sanitari: analisi dell'interferenza tra cronobiologia lavorativa e sistema immunitario.

BACKGROUND: Healthcare workers may be exposed to a variety of biological hazards. Although many studies have shown that some immunological alterations were related to work stress and sleep disorders, few studies investigated effects of shiftwork on the immunological system. OBJECTIVES: The aim of the study was to compare the immune status of a group of nurses on shiftwork with that of nurses working only day shifts. METHODS: A total of 138 nurses were evaluated at baseline and after a year of follow-up, via tests for perceived stress, daytime sleepiness, number of lymphocytes and subpopulation of CD3+, CD4+, CD8+-CD57+, CD19+ and CD56+, cytotoxic activity and lympho-prolferative response of NK cells, serum concentrations of IL-1beta, IL-6, INFgamma and TNFalpha. RESULTS AND CONCLUSION: No significant alterations of any of the studied parameters were found both at baseline and after a year of follow-up. The biological hazards for nurses do not seem to be increased by shiftwork.

+647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications.

Diabetes mellitus is a chronic disease characterized by an overproduction of reactive oxygen species, which perturbs zinc metabolism and promotes the onset of cardiovascular disease (CVD) in diabetic patients. Metallothioneins (MT) are cysteine-rich metal-binding proteins which, by means of their antioxidant and zinc-buffering properties, might prevent the development of diabetic cardiovascular complications. A recent investigation shows that a polymorphism (+647 A/C) in the human MT-1A gene, affects the intracellular zinc ion release (iZnR) from the proteins and is associated with longevity in Italian population. The aim of the present study is to assess the involvement of +647 A/C and +1245 A/G MT1A polymorphisms with the susceptibility to type 2 diabetes (DM2) and cardiovascular complications. The study included 694 old individuals: 242 old healthy controls, 217 DM2 patients without clinical evidence of CVD (DNC) and 235 diabetic patients with diagnosis of CVD (DCVD). +647 A/C MT1A polymorphism, but not the second SNP, was associated with DM2. C allele carriers were more prevalent in DNC and DCVD patients than in control group (OR=1.37, p=0.034; OR=1.54, p=0.002, respectively). C+ carriers was associated with higher glycemia and glycosylated hemoglobin in DCVD patients, but not in DNC or control subjects. No differences in plasma zinc, but a modulation of MT levels and iZnR in PBMCs were observed in DCVD cohort when related to +647 A/C MT1A polymorphism. In summary, this work provides novel evidence on the association of the +647 A/C MT1A polymorphism with DM2. Moreover, C+ carriers in DCVD patients presented a worse glycemic control, a reduced iZnR and a higher MT levels, suggesting a possible role of MT in diabetic cardiovascular complications.

Effects of interleukin-6 -174C/G and metallothionein 1A +647A/C single-nucleotide polymorphisms on zinc-regulated gene expression in ageing.

Decreased zinc ion availability in ageing is associated with altered immune response. One of the main regulators of zinc availability is metallothionein. Metallothionein induction is under the control of interleukin-6, a pro-inflammatory cytokine whose production is associated with poor ageing. The production of interleukin-6 is controlled, in part, by variability in the -174 nucleotide position. Under conditions of chronic inflammation, such as in ageing, zinc release by metallothionein is limited and may reduce zinc availability. Understanding the precise nature of the interactions between interleukin-6 and metallothioneins will aid in identifying individuals who are at risk of zinc deficiency. In the current study, we used gene arrays to investigate the effects of in vitro zinc supplementation on gene expression in elderly donors with described interleukin-6 and metallothionein 1a polymorphisms. Ingenuity Pathway Analysis identified several zinc-responsive genetic networks uniquely regulated only in elderly individuals with the pro-inflammatory interleukin-6 polymorphism. These include zinc-dependent decreased transcription of pro-inflammatory cytokines and alterations in metabolic regulatory pathways. The genomic effects of zinc increased in significance in the presence of the metallothionein 1a +647 C/A transition, suggesting that the interleukin-6 and metallothionein 1a genes act in a concerted manner to control zinc-regulated gene expression.

Effects of zinc supplementation on antioxidant enzyme activities in healthy old subjects.

A large body of experimental research indicates that oxidative stress contributes to the processes related to aging and age-related diseases. Trace elements, particularly zinc (Zn), are essential components of the endogenous enzymatic antioxidant defenses. The aim of this study was to determine the activity of three main antioxidant enzymes in plasma [i.e. superoxide dismutase (pSOD), catalase (CAT), glutathione peroxidase (GPx)] and of SOD in erythrocyte (eSOD) in a group of 1108 healthy elderly subjects from different European countries. The same enzymatic activities were evaluated in a subgroup of 108 subjects before and after Zn supplementation. We observed that eSOD activity increased with age, whereas plasma Zn decreased. Moreover, we found that women showed higher eSOD activity and lower plasma Zn compared to men. There were no age and gender-related differences in the activities of pSOD, CAT and GPx. After Zn supplementation, the activities of Zn-dependent enzymes (pSOD and eSOD), as well as plasma Zn concentration, were significantly higher than before supplementation. These results were not influenced by age, gender, plasma Zn variations (Delta Zn) and geographic area. These data suggest the potential beneficial effects of Zn supplementation on Zn-dependent antioxidant enzymes in healthy elderly subjects.

Differential effects of in vitro zinc treatment on gene expression in peripheral blood mononuclear cells derived from young and elderly individuals.

Mild zinc deficiency, which is prevalent in vegetarians, diseased individuals, and the general aging population, depresses immunity and increases risk of disease in later life. However, human zinc intervention trials have produced conflicting results, perhaps because many of these trials included young or zinc-sufficient subjects. Since heterogeneity of the adult population may impact on response to dietary zinc, nutrigenomic approaches aimed at understanding the impact of zinc on modulation of gene and protein activities may aid in identifying subsets of the population-in particular the aging population-with increased risk of zinc deficiency who might receive benefit from a dietary zinc intervention and in this way may influence the success of the intervention. In the current study we used nutrigenomic approaches to investigate the impact of age on zinc-regulated gene expression in peripheral blood mononuclear cells. Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, CA) identified several genetic networks and functional canonical pathways which appeared responsive to zinc that were differentially regulated in young and elderly individuals. These include tryptophan metabolism, eicosanoid signaling, p38 mitogen-activated protein kinase (MAPK) signaling, integrin signaling, purine metabolism, G-protein-coupled receptor signaling, and most significantly, peroxisome proliferator-activated receptor (PPAR) signaling. These data suggest that age impacts strongly on the transcriptional effects of zinc and provides evidence to support the hypothesis that young and elderly individuals may respond differentially to zinc intervention.

Psychosocial and biochemical interactions in aging: preliminary results from an Italian old sample of "Zincage" project.

The study of the interactions among biological factors and psychosocial conditions is a very innovative field, because data are lacking in the scientific literature. Among biological aspects, zinc is an essential element in the elderly, especially in relation to one of the proteins, such as albumin, involved in zinc transport into the cells. In this study, the aim is the assessment of the interrelationship between albumin value (used as an index of the body zinc status) and some psychosocial dimensions in elderly Italian sample recruited for ZINCAGE project, supported by the European Commission in the "Sixth Framework Programme". Some tests and questionnaires were administered to older people included in the trial: the "life-style questionnaire"; the mini mental state examination (MMSE); the geriatric depression scale (GDS-15 items). On the basis of the Senieur Protocol for gerontological studies, a sample of 291 Italian healthy old subjects has been recruited in Central Italy and divided into 3 age groups: (a) 125 subjects aged from 65 to 74 years, (b) 89 subjects aged from 75 to 84 years, (c) 77 subjects aged >or=85 years (classified like successful old people). No cognitive impairment assessed by MMSE was observed in 67.5% of the sample; 64.0% had GDS score less than 5, indicating no depression, whereas the prevalence of biological albumin deficiency (<3.5 g/dl) found in Italian old people was 21.0%. Sixty one percent of subjects with albumin deficiency displayed higher values of GDS (>or=5). These preliminary results showed an interrelationship among serum albumin value and psychosocial aspects in Italian old population, suggesting that low albumin values may be involved in impaired psychological dimensions.

[Mercury toxicity: trace element interactions and detoxification activity by L-arginine]. / Tossicità del mercurio: interazione con gli elementi essenziali in tracce e ruolo della L-arginina nel processo di detossificazione.

Mercury (Hg) exposure makes happen disease to humans and animals spreading in all body compartments, especially in liver and kidney. In these ones, copper, zinc, manganese and iron were investigated to assess perturbation of essential metals' homeostasis due to Hg chronic intoxication. Because L-arginine, is able to induce beneficial influence on immunologic functions on mice intoxicated with Hg, we also studied the efficiency of detoxification process before and after treatment with this aminoacid. Adding L-arginine to diet of the intoxicated mice we achieved a good restoration to normal homeostatic conditions.

Zinc and immunoresistance to infection in aging: new biological tools.

Infections can cause mortality when the immune system is damaged. The catalytic, structural (in zinc-finger proteins) and regulatory roles of zinc mean that this ion is involved in the maintenance of an effective immune response. Both zinc deficiency and impaired cell-mediated immunity combine during aging to result in increased susceptibility to infection. Dietary supplementation with the recommended daily allowance of zinc for between one and two months decreases the incidence of infection and increases the survival rate following infection in the elderly. This article reviews the biochemical pathways through which zinc might act to increase immunoresistance to infection in the elderly.

Zinc-dependent low thymic hormone level in type I diabetes.

Zinc is required for optimal functioning of the immune system. It was recently reported that one of the best-known thymic hormones responsible for the maturation and differentiation of the thymus-derived T-lymphocyte line, i.e., serum thymic factor (STF), is biologically active only when bound to zinc ions; in this form it has been called thymulin (Zn-STF). Because low serum and tissue zinc values have been reported to occur in diabetic conditions, and because defects of T-lymphocyte-dependent functions are also present in diabetic patients, even metabolically well-controlled diabetic patients, we investigated the serum level of zinc and the plasma level of both active Zn-STF and inactive STF thymic hormones in 15 young patients suffering from type I (insulin-dependent) diabetes. Serum zinc levels were significantly reduced in diabetic conditions and did not correlate with the degree of metabolic compensation measured by glycosylated hemoglobin. In diabetes, the active form of thymulin is strongly reduced, whereas the inactive form is abnormally elevated. In vitro zinc addition to diabetic plasma samples also induces zinc saturation of inactive thymic hormone molecules: the total thymic hormone measured in these experimental conditions shows values in diabetic patients comparable with those observed in healthy age-matched individuals, suggesting that low thymulin levels recorded in diabetic conditions are due not to a thymic failure in synthesizing and secreting thymic hormone but to a peripheral defect in zinc saturation of the hormone molecules. The zinc-dependent failure of thymic hormone, present even in fairly compensated diabetic conditions, might account for the apparent insulin-independent immunological abnormalities associated with type I diabetes.

[Influence of mercury on thymulin production: metallothioneins role]. / Influenza del mercurio sulla timulina. Ruolo delle metallotionine.

Occupational or environmental exposure to various metals affects human health. In particular, mercury is known to affect the immune system adversely. Metallothioneins (MTs) are low molecular weight, cysteine-rich, intracellular proteins, with high affinity for bivalent metals of which they regulate intracellular concentrations, thereby being playing a fundamental role in metal homeostasis. MTs protect cells from stress, inflammation and free radical damage and are involved in zinc homeostasis. Zinc has an important role in the immune system because it is indispensable for the activation andfunctioning of the thymic hormone, thymulin, which in turn is involved in T-lymphocyte differentiation and maturation. MTs participate in the detoxification process following acute poisoning, and are expressed in the various tissues, as well as in chronic intoxication, where continuous stress and the persistent inflammatory state induce their over-expression. The present study was undertaken to gain insights into the potential mechanisms acting on the immune system/altering the immune status in the presence of low mercury concentrations. To do this, the genic expression of MT-I and the amount of active thymulin produced by thymic endothelial cells were studied in mice exposed to different doses of mercury.

Thyroid function modulates thymic endocrine activity.

The thymus produces humoral factors that induce proliferation and differentiation of T-cells, which are responsible for cell-mediated immunity. Recent data in animals suggest that such thymic hormone activity is modulated by the neuroendocrine network and, in particular, by thyroid hormones, but no information is presently available in humans. To study this question, we measured the circulating thymic factor called thymulin (Zn-FTS) in hyperthyroid and hypothyroid patients. Thymulin levels were higher in hyperthyroid patients than in normal subjects, whereas hypothyroid patients had lower thymulin levels than normal subjects. A significant correlation was found between circulating thymulin and serum T4 and T3 levels. Thymulin changes could be reversed by appropriate treatment in both groups of patients. Recent data indicate that zinc is required to confer biological activity on thymic hormone molecules. This raised the question of whether the influence of thyroid status on thymulin activity could be mediated by changes in serum zinc concentrations. No support for such an explanation was obtained by thymulin measurements by a modified bioassay using an optimal zinc concentration in the assay system. In conclusion, thyroid status modulates thymic endocrine function in humans. Whether and to what extent such modulation is relevant to the function of the immune system remain to be established.

Thymulin deficiency and low 3,5,3'-triiodothyronine syndrome in infants with low birth weight syndromes.

Experimental and clinical evidence indicates that thymic endocrine function is under neuroendocrine control. Recently, a positive correlation was found between plasma thymulin (a major endocrine product of thymus) and serum thyroid hormone concentrations. Low serum thyroid hormone concentrations are frequently found in premature newborn infants. In this study we measured plasma thymulin by bioassay and serum T3 and T4 in a series of healthy fullterm newborns and in premature infants with various disorders. The study subjects were 26 healthy fullterm infants, 23 fullterm small for gestational age infants, 30 preterm appropriate for gestational age (AGA) infants, 22 preterm small for gestational age infants and 30 infants with respiratory distress syndrome, of whom 15 were fullterm and 15 were preterm AGA. Blood samples were obtained 3, 5, 10, 20, and 40 days after delivery. In the healthy fullterm infants plasma thymulin concentrations were low during the first days of life and subsequently increased, reaching normal values for children aged 1-12 months by the 10th day after birth. Persistently low plasma thymulin and serum T3 levels were found in the majority of infants with pathological conditions; the lowest values for both hormones were found in infants with respiratory distress syndrome. A highly significant positive correlation was present in all groups between mean plasma thymulin and serum T3, but not T4. Short term T3 administration in 6 additional preterm AGA infants caused a significant increase in plasma thymulin titers compared to those in 6 untreated infants. We conclude that plasma thymulin is decreased in premature newborns with the low T3 syndrome and that this abnormality may be reversed by administration of T3. These findings indicate that thymic endocrine activity is modulated by thyroid function in early postnatal life.

Effect of oral zinc administration on prolactin and thymulin circulating levels in patients with chronic renal failure.

High serum PRL and low zinc (Zn) levels are common findings in patients with chronic renal failure (CRF); in such patients serum Zn concentrations have been reported to be inversely correlated to serum PRL levels. Moreover, Zn regulates both thymus growth and the biological activity of the thymic hormone thymulin, and PRL-thymic interrelationships have been described. To determine whether hypozincemia alters serum PRL and plasma thymulin concentrations in CRF, 9 men with CRF treated by chronic hemodialysis were given 400 mg/day Zn sulfate, orally (4.96 meq/day Zn), for 6 months. Before treatment, serum PRL levels were significantly higher (P less than 0.001) in these patients than in normal men [mean, 28.7 +/- 20.7 (+/-SD) vs. 7.5 +/- 3.7 micrograms/L], and their serum PRL response to TRH (200 micrograms, iv) was impaired (mean maximal percent increase, 38.2 +/- 10.9 vs. 641 +/- 335; P less than 0.001). The plasma Zn-bound bioactive thymulin titer (1.3 +/- 0.7 1/log2), total thymulin titer (Zn-bound plus Zn-unbound forms, 2.1 +/- 0.8 1/log2), and serum Zn (13.1 +/- 2.4 mumol/L) were lower (P less than 0.001) in men with CRF than in normal men. Zn therapy did not induce any significant change in basal and TRH-stimulated serum PRL levels, while serum Zn levels significantly increased, reaching the normal range after the first week of treatment (17.8 +/- 6.3 mumol/L). Plasma total thymulin increased rapidly, reaching normal levels after 1 week, but Zn-bound thymulin increased modestly during the first month of treatment and more after 3 and 6 months of treatment. There was no age-related difference in plasma thymulin levels during therapy. We conclude that oral Zn administration in patients with CRF significantly increases both total and Zn-bound thymulin, but does not modify basal and TRH-stimulated serum PRL levels. The observation that Zn supplementation markedly increased plasma thymulin levels in uremic patients suggests that Zn is a potent stimulus for thymic hormone synthesis, and it can reverse the age-related diminution of thymic activity in CRF patients.

Age-dependent decline of T-cell cloning potential in mice.

Mice spleen cells capable of forming, under stimulation by phytohemagglutinin (PHA), single-cell derived colonies in an in vitro soft-agar system, show with advancing age a progressive reduction of their number, which occurs earlier than the decline of PHA response in fluid phase. In addition to their reduced number, old colony-forming T-cells show the same phenomena recorded in fibroblasts; for example, a decrease of their residual in vitro proliferation potential, as measured by the size of the colonies, reached during the culture period. The reduced number of responding units and the decreased colony size seem to be distinct phenomena, since in the immunodeficiency state of hypopituitary dwarf mice only the first defect is observable, whereas the size distribution is normal. Both the reduced number of T-cell colonies and their decreased proliferative potential in vitro observed in old age, can be restored by transplanting a neonatal FTS ("facteur thymique serique")-producing thymus, but not by injecting isolated thymocytes into old mice. A correlation seems to exist between the decline of T-cell colony potential with advancing age and the progressive deterioration of thymic endocrine activity.

Recovery of age-dependent immunological deterioration in Balb/c mice by short-term treatment with L-thyroxine.

The progressive decline of immune efficiency with advancing age has been investigated in Balb/c mice by measuring the spleen-cell responsiveness to both T- and B-mitogens and the capacity to form plaques after immunization with sheep erythrocytes. While the responsiveness to concanavalin A and lipopolysaccharide is not significantly decreased in old mice, the responsiveness to phytohaemagglutinin and the plaque-forming-cell capacity progressively diminish with advancing age. Such a functional decline has been correlated with the age-associated deterioration of the neurohormonal balance and particularly with the reduction of thyroxine blood levels. Reconstitution experiments carried out by treating animals of increasing ages with 15 daily injections of L-thyroxine have demonstrated that such a treatment is able to restore the age-related decline of immune efficiency, and that this recovery is associated with the reactivation of the thymic endocrine activity. These data are consistent with the idea that the neurohormonal balance may influence the immune efficiency and that its derangement with advancing age may represent one of the factors responsible for the aging of the immune system.

Zinc, infections and immunosenescence.

Infections may cause mortality in old age due to damaged immune responses. As zinc is required as a catalyst, structural (zinc fingers) and regulatory ion, it is involved in many biological functions, including immune responses. Low zinc ion bioavailability and impaired cell-mediated immunity are common in ageing and may be restored by physiological supplementation with zinc for 1-2 months, impacting upon morbidity and survival. This article reviews the role of zinc in immune efficacy during ageing, and also describes the main biochemical pathways involved in the role of zinc in resistance to infections in ageing in order to better understand the possible causes of immunosenescence.

Zinc, T-cell pathways, aging: role of metallothioneins.

Zinc is an essential trace element for many biological functions, including immune functions. Indeed zinc is required for the biological activity of a thymic hormone, called thymulin in its zinc-bound form, important for the maturation and differentiation of T-cells. With advancing age zinc, thymic functions and peripheral immune efficiency show a progressive decline. Supplementing zinc in old age restores them. Zinc is also relevant for liver extrathymic T-cell pathway, being preeminent in old age. Since zinc is also required for metallothioneins (MTs) biological functions, binding zinc with high affinity, aim of the present article is to summarize findings from our laboratory regarding the role of zinc on T-cell pathways, investigating also the possible cause of thymic involution and impaired liver extrathymic T-cell pathway in aging. Partial hepatectomy and liver regeneration are good models for this aim because of the likeness with aging for many immune functions, including thymic functions. MTs levels are increased, other than into the liver, also into the thymus during aging and in young hepatectomized (pHx) mice as compared to young sham controls. MTs may be one of the possible causes of reduced thymic efficiency and impaired liver extrathymic T-cell pathway in old age because of their higher zinc binding affinity rather than thymulin with consequent reduction of the free quota of zinc available for normal cell-mediated immunity. Following that, MTs may contribute to thymic involution and impaired peripheral immune efficiency in aging and in young pHx mice with different roles during the whole life of an organism: protective in young-adult age which may became, at least, dangerous for immune responses in aging. In order to limit or avoid this latter MTs possible role in aging, supplementing physiological zinc may be useful to improve immune responses in old age because of no interference of endogenous zinc on already high thymus MTs levels, but with caution for competition phenomena with copper, as documented in old mice and in syndrome of accelerate aging.