The paper shows the results on the relationship between zinc status, psychological dimensions (cognitive functions, mood, perceived stress) and nutritional aspects in European healthy old subjects recruited for ZINCAGE Project (supported by the European Commission in the Sixth Framework Programme). The old healthy subjects were recruited in Italy, Greece, Germany, France, Poland taking into account the different dietary habits between Northern and Southern European Countries and the pivotal role played by zinc for psychological functions. Measures of the cognitive status, mood and perceived stress level were obtained at baseline, using the "Mini Mental State Examination (MMSE)"; the "Geriatric Depression Scale (GDS - 15 items)" and the "Perceived Stress Scale (PSS)", respectively. Nutritional status was assessed using "Frequency Food Questionnaire". The sample included 853 old subjects, classified in 4 groups of age: 60-69-years-old (n = 359); 70-74-years-old (n = 225); 75-79-years-old (n = 153); 80-84-years-old (n = 116). Subjects were studied on the basis of plasma zinc, in which zinc

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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.

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Pro-inflammatory cytokine response and NK activity are controlled by the availability of zinc ion, whose intra-cellular transport is regulated by metallothioneins. In order to closely examine the importance of circulating zinc in the modulation of immune response during ageing, in the balance of Th2/Th1 equilibrium and finally in the reversibility of systemic low grade inflammation, we evaluated the changes occurring in plasma IL-6 and MCP-1 concentrations and NK lytic activity in a healthy low grade inflamed elderly population, following zinc-aspartate supplementation. In addition, we aimed to highlight the potential interaction among circulating zinc increments, changes in immunological parameters and +647 MT1a and -174 IL-6 polymorphic alleles. Thirty-nine healthy individuals (60-83 years) from the ZINCAGE cohort (previously typed for +647 MT1a and -174 IL-6 polymorphisms) were supplied with zinc-aspartate. Blood samples collected before and after supplementation underwent basal laboratory determinations (circulating zinc, albumin and C-reactive protein) and immunological studies (plasma IL-6 and MCP-1 and NK lytic activity). Zinc supplementation in subjects with low or borderline-normal circulating zinc increased the concentration of this ion and modulated plasmatic IL-6 and MCP-1 as well as NK lytic activity. An interactive effect of polymorphic alleles of MT1a and IL-6 genes on zinc, IL-6, MCP-1 and NK activity was evidenced following supplementation, indicating the genetic background as one of the determinants for identifying groups of subjects that can take advantage of therapeutic intervention.