Does promoter methylation of the SLC30A5 (ZnT5) zinc transporter gene contribute to the ageing-related decline in zinc status?

Abstract

A decline in Zn status with ageing may contribute to the development of frailty, including impaired immune function, and increased incidence of age-related degenerative diseases. This decline may be a result of reduced dietary Zn intake and/or impaired Zn absorption in the gut. The Zn transporter ZnT5 may play a key role in the absorption of dietary Zn. The corresponding gene (SLC30A5) has a CpG island in its promoter region, so could be regulated by epigenetic mechanisms. It is hypothesised that methylation of the SLC30A5 promoter region is increased with age and that a resulting reduction in ZnT5 expression contributes to the decline in Zn status observed with ageing. This hypothesis has been addressed through (1) studies of effects of SLC30A5 promoter methylation on gene expression in vitro and (2) in vivo measurements of the DNA methylation status of this gene domain. It has been established in vitro that methylation of the human SLC30A5 promoter region results in reduced expression of an associated reporter gene. Second, this gene region shows variable levels of methylation in vivo. Correlation between the level of methylation at this locus and age would support the hypothesis that age-related hypermethylation of this region has the potential to modulate dietary Zn absorption. This premise is being investigated by analysis of additional samples from a human adult cohort to test the hypothesis that methylation of the SLC30A5 promoter region contributes to the age-related decline in Zn status.

The relative validity and repeatability of an FFQ for estimating intake of zinc and its absorption modifiers in young and older Saudi adults

“…The mean daily Zn intake assessed by the FFQ (10·6 mg) is very similar to the mean values (10·50 mg) obtained by Samman et al (29) in Australia and Alissa (25) (10·23 mg) in Table 6 Mean daily intakes of zinc, phytic acid and protein estimated by the first administration of the FFQ (FFQ1), the 3 d food record (FR) and the second administration of the FFQ (FFQ2), according to age and gender groups, among males and females aged [20][21][22][23][24][25][26][27][28][29][30] Saudi Arabia but substantially lower than that reported by Barrett and Gibson (38) (15·3 mg) for Australian participants using an FFQ method. The mean phytic acid intake of Saudi adults (521·33 mg) was lower than intake of British (917 mg) (46) and New Zealand adults (1498 mg) (41) when using a 4-7 d weighed intake method and FFQ, respectively.…”

Global DNA methylation in old subjects is correlated with frailty

“…Some of these genes might be needed to maintain the reserve capacity and the efficiency in the response to adverse stressors at levels ensuring the survival (Coneyworth et al 2009). Likely, the hypomethylation observed in frail subjects can be associated to an accentuated deficiency to achieve the remethylation after DNA replication that, as reported in Gravina and Vijg (2010), occurs during aging.…”

Zinc: dietary intake and impact of supplementation on immune function in elderly

“…Since there is a CpG island in the ZnT5 gene promoter region, the expression of ZnT5 may potentially be regulated by its promoter methylation status. Preliminary studies in three adult cohorts from northern England show correlations between methylation of specific CpG sites in the ZnT5 promoter and age, supporting the hypothesis that the age-related reduction in ZnT5 expression in the intestine may contribute to the decline in Zn status observed with ageing (Coneyworth et al 2009). The expression of other Zn transporters involved in dietary Zn absorption may also be potentially regulated by DNA methylation.…”

“…Old subjects display also a reduction in zinc cellular uptake in comparison to young-adults perhaps due to the cellular senescence, which is less responsive to zinc because altered gene expressions of some zinc transporters (Zip1, Zip2 and Zip3) on cellular membrane occur (Giacconi et al 2011). Alternatively, epigenetic mechanisms might occur in the promoter region of the zinc transporters leading to an hypermetylation of the gene with subsequent decreased zinc absorption in the intestinal lumen, as supposed for the zinc transporter ZnT5 (Coneyworth et al 2009). Anyway, regardless of the mechanism involved, the zinc dietary intake and intestinal zinc absorption are deficient in aging leading to an increased risk for the appearance of degenerative age-related diseases.…”