Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation

School of Biological and Population Health Sciences, Oregon State University, OR 97331, USA.
The Journal of nutritional biochemistry (Impact Factor: 3.79). 09/2012; 24(1). DOI: 10.1016/j.jnutbio.2012.07.005
Source: PubMed


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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    • "Dietary zinc deficiency is common among the elderly, and has been attributed to dysfunction in the body’s immune response, including changes in the antioxidant defense system, which manifest in part as an increase in the incidence of infection and inflammatory processes (Kelly et al., 1996; Mocchegiani et al., 2000, 2008; Haase and Rink, 2009; Wong et al., 2013). Unfortunately, although zinc deficiency is frequently observed in the aged population, results regarding the effect of zinc supplementation on healthy aging have been somewhat inconsistent, and a consensus has yet to be reached on the benefits of such treatment (Mocchegiani et al., 2008). "
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    ABSTRACT: Brain aging is marked by structural, chemical, and genetic changes leading to cognitive decline and impaired neural functioning. Further, aging itself is also a risk factor for a number of neurodegenerative disorders, most notably Alzheimer's disease (AD). Many of the pathological changes associated with aging and aging-related disorders have been attributed in part to increased and unregulated production of reactive oxygen species (ROS) in the brain. ROS are produced as a physiological byproduct of various cellular processes, and are normally detoxified by enzymes and antioxidants to help maintain neuronal homeostasis. However, cellular injury can cause excessive ROS production, triggering a state of oxidative stress that can lead to neuronal cell death. ROS and intracellular zinc are intimately related, as ROS production can lead to oxidation of proteins that normally bind the metal, thereby causing the liberation of zinc in cytoplasmic compartments. Similarly, not only can zinc impair mitochondrial function, leading to excess ROS production, but it can also activate a variety of extra-mitochondrial ROS-generating signaling cascades. As such, numerous accounts of oxidative neuronal injury by ROS-producing sources appear to also require zinc. We suggest that zinc deregulation is a common, perhaps ubiquitous component of injurious oxidative processes in neurons. This review summarizes current findings on zinc dyshomeostasis-driven signaling cascades in oxidative stress and age-related neurodegeneration, with a focus on AD, in order to highlight the critical role of the intracellular liberation of the metal during oxidative neuronal injury.
    Frontiers in Aging Neuroscience 04/2014; 6:77. DOI:10.3389/fnagi.2014.00077 · 4.00 Impact Factor
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    • "Inadequate zinc intake certainly contributes to deficiency in many elderly patients (Singh et al. 1998; Pepersack et al. 2001) but effects of chronic inflammation and age-related decline in zinc transport mechanisms may also contribute to a functional zinc deficiency (Turnlund et al. 1986; Wong et al. 2012). For example, senescence of rat vascular smooth muscle cells involves decreased ZnT expression (Patrushev et al. 2012) and an age-related decline in plasma zinc was associated with increased methylation of the ZIP6 promoter and an exaggerated inflammatory response in mice (Wong et al. 2012). Furthermore , zinc supplementation restored plasma zinc levels leading to a reduction in markers of inflammation and oxidative stress in elderly subjects (Bao et al. 2010). "
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    ABSTRACT: Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.
    Genes & Nutrition 01/2014; 9(1):379. DOI:10.1007/s12263-013-0379-x · 2.79 Impact Factor
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    • "The low-grade of systemic inflammation, generally accomplished by zinc deficiency and altered zincbound Metallothioneins (MT) production (Mocchegiani et al. 2012), is a common condition during ageing. Such abnormalities contribute to a dysfunction of the inflammatory/immune response (Wong et al. 2013), to a decline in physical function and to the development of some age-related diseases, such as atherosclerosis, "
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    ABSTRACT: 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.
    Biogerontology 11/2013; 15(1). DOI:10.1007/s10522-013-9480-1 · 3.29 Impact Factor
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