Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation.
ABSTRACT Aging is a complex process associated with physiological changes in numerous organ systems. In particular, aging of the immune system is characterized by progressive dysregulation of immune responses, resulting in increased susceptibility to infectious diseases, impaired vaccination efficacy and systemic low-grade chronic inflammation. Increasing evidence suggest that intracellular zinc homeostasis, regulated by zinc transporter expression, is critically involved in the signaling and activation of immune cells. We hypothesize that epigenetic alterations and nutritional deficits associated with aging may lead to zinc transporter dysregulation, resulting in decreases in cellular zinc levels and enhanced inflammation with age. The goal of this study was to examine the contribution of age-related zinc deficiency and zinc transporter dysregulation on the inflammatory response in immune cells. The effects of zinc deficiency and age on the induction of inflammatory responses were determined using an in vitro cell culture system and an aged mouse model. We showed that zinc deficiency, particularly the reduction in intracellular zinc in immune cells, was associated with increased inflammation with age. Furthermore, reduced Zip 6 expression enhanced proinflammatory response, and age-specific Zip 6 dysregulation correlated with an increase in Zip 6 promoter methylation. Furthermore, restoring zinc status via dietary supplementation reduced aged-associated inflammation. Our data suggested that age-related epigenetic dysregulation in zinc transporter expression may influence cellular zinc levels and contribute to increased susceptibility to inflammation with age.
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ABSTRACT: Zinc plays an essential role in many biochemical pathways and participates in several cell functions, including the immune response. This review describes the role of zinc in human health, aging, and immunosenescence. Zinc deficiency is frequent in the elderly and leads to changes similar to those that occur in oxidative inflammatory aging (oxi-inflamm-aging) and immunosenescence. The possible benefits of zinc supplementation to enhance immune function are discussed.Pathobiology of aging & age related diseases. 02/2015; 5:25592.
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ABSTRACT: A20 is an anti-inflammatory protein that suppresses ubiquitin dependent nuclear factor κB (NFκB) signaling, which can be regulated by the microelement, zinc. In mammals, zinc (Zn) deficiency contributes to a decrease in A20 abundance, which impairs the gut mucosa barrier. However, it is unclear whether the epigenetic reprogramming of the A20 promoter is involved in enhanced Zn-induced intestinal immunity, especially in avian species. Herein, we show that maternal organic Zn exposure resulted in significantly improved intestinal morphological characteristics, increased mucin 2 (MUC2) abundance, and secretory IgA (sIgA) production in progeny jejunums. Maternal and offspring Zn supplementation partially alleviated Zn-deficiency induced inflammatory response, accompanied by repression of NFκB signaling. Additionally, we observed DNA hypomethylation and histone H3 at lysine 9 (H3K9) hyperacetylation at the A20 promoter region and subsequent activated A20 expression in Zn-supplemented hens compared with control. Notably, maternal dietary organic Zn exposure exhibited greater attenuation of gut impairment, along with increased MUC2 expression and sIgA level, and decreased the abundance of TNF-α and A20 relative to the inorganic-Zn group. Furthermore, enhanced acetylated H3K9 and A20 transcription at day 14 was found in the offspring adequate dietary Zn group. Thus, A20 may be a novel inflammatory-suppressed factor of chick gut that is persistently promoted by dietary Zn supplementation via epigenetic modifications at A20 promoter.The Journal of Nutritional Biochemistry 11/2014; 26(2). · 4.59 Impact Factor
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ABSTRACT: Dysregulation of neuronal zinc homeostasis plays a major role in many processes related to brain aging and neurodegenerative diseases, including Alzheimer's disease (AD). Yet, despite the critical role of zinc in neuronal function, the cellular mechanisms underpinning its homeostatic control are far from clear. We reported that the cellular prion protein (PrP(C)) is involved in the uptake of zinc into neurons. This PrP(C)-mediated zinc influx required the metal-binding octapeptide repeats in PrP(C) and the presence of the zinc permeable AMPA channel with which PrP(C) directly interacted. Together with the observation that PrP(C) is evolutionarily related to the ZIP family of zinc transporters, these studies indicate that PrP(C) plays a key role in neuronal zinc homeostasis. Therefore, PrP(C) could contribute to cognitive health and protect against age-related zinc dyshomeostasis but PrP(C) has also been identified as a receptor for amyloid-β oligomers which accumulate in the brains of those with AD. We propose that the different roles that PrP(C) has are due to its interaction with different ligands and/or co-receptors in lipid raft-based signaling/transport complexes.Frontiers in Cell and Developmental Biology 08/2014; 2:41.