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

Abstract

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.

Zinc–gene interaction related to inflammatory/immune response in ageing

“…Interestingly, in this last study C-old and nonagenarian subjects display also impaired innate immune response (NK cell cytotoxicity) coupled with increased MTs, zinc deficiency and low zinc ion bioavailability in comparison with C+ carriers [56]. A functional implication of the IL-6 -174G/C locus on MT expression and zincregulated genes has been also recently confirmed by targeted studies with in vitro zinc supplementation [98] as well as in vivo [95,108].…”

“…The main results of the project confirmed a strong contribution of MT genetic variants in regulating zinc homeostasis and perhaps its dietary requirements as well as their relevance in longevity and in some age-related pathologies [34,57,95,98]. Moreover, it has been confirmed that IL-6 -174 polymorphisms can be used to identify old subjects with higher risk to develop zinc deficiency [98,108]. The study revealed also that contradictory data existing on the association between IL-6 -174 polymorphisms and chronic disease can find a rationale in the different dietary intake of zinc existing in the different population studied [108].…”

“…Moreover, it has been confirmed that IL-6 -174 polymorphisms can be used to identify old subjects with higher risk to develop zinc deficiency [98,108]. The study revealed also that contradictory data existing on the association between IL-6 -174 polymorphisms and chronic disease can find a rationale in the different dietary intake of zinc existing in the different population studied [108]. Finally it is important to conclude considering an important aspect of zinc homeostasis which, in our opinion, will have profound implications for the individual zinc dietary requirements and propensities to develop particular agerelated disease.…”

“…In other words, the studies performed in northern European populations report that C-allele might not be any more the ''risk allele''. This fact can be at least partially explained by the higher zinc intake in these populations [108]. Moreover, the determination of the genetic variations of the IL-6 -174G/C locus associated to a dietary assessment or to a comprehensive evaluation of the zinc status has been reported as an useful strategy to identify old subjects who can benefit of zinc supplementation without health risks.…”

Zinc, metallothioneins and immunosenescence

“…110 (Z) 10 mg Zn as aspartate for 7 weeks Increased NK cell cytotoxicity (48,68) Old mice Male Balb/c 10 (C) 18 mg Zn as sulphate (22 mg/l in drinking water)…”