Discovery of Zinc for Human Health and Biomarkers of Zinc Deficiency

Abstract Zinc deficiency in humans was recognized for the first time in 1963, and a recommended dietary allowance (RDA) for zinc was established by the US National Academy of Sciences in 1974. The present World Health Organization (WHO) estimate is that nearly 2 billion subjects living in the developing world may have zinc deficiency. This is mainly because they subsist on cereal proteins which contain high quantities of organic phosphate compounds, which combine with zinc making it unavailable for absorption. The major adverse clinical effects of zinc deficiency are growth retardation, decreased cell-mediated immunity, impairment of cognitive functions, increased oxidative stress, and upregulation of inflammatory cytokines. Our studies have shown that nearly 30% of healthy, well-to-do elderly subjects living in developed countries may also be zinc deficient due to an increased phytate to zinc molar ratio in their diet. Over 300 enzymes and 2000 transcription factors are now known to require zinc for their functions and stability of their structures, and several studies have now shown that zinc may be a molecular signal for neuronal and immune cells. Fourteen ZIP and 10 ZNT zinc transporters are known to maintain intracellular zinc homeostasis. Therapeutic impacts of zinc on human health are also being investigated. Zinc is being used for the treatment of acute diarrhea in infants and children in developing countries globally, and this has resulted in saving millions of lives. Zinc is now an approved drug for the treatment and maintenance therapy of Wilson's disease, a serious fatal genetic disorder. According to a recent Cochrane Review, zinc is the only treatment which is effective in decreasing the incidence of infections and pain crises in patients with sickle cell disease. Zinc acetate lozenges have been shown to decrease the duration of the common cold by 50%, provided the treatment is started within 24 h of the onset of symptoms, the solution chemistry of the zinc preparation is proper, and the zinc dosages are adequate. Age-related macular degeneration (AMD) accounts for a large proportion of legal blindness in elderly subjects throughout the world. The Age-Related Eye Disease Study Group (AREDS) was supported by National Eye Institute. The National Institutes of Health (NIH) has now reported the results of their 10-year zinc supplementation study in patients with AMD. Zinc was effective in decreasing the incidences of blindness and progression of AMD in elderly subjects. Most importantly, zinc-supplemented subjects showed increased longevity and this was due to a decrease in cardiovascular events. No other micronutrient has shown this dramatic effect on decreasing mortality in the elderly. Our placebo-controlled, zinc supplementation trial in the elderly has shown that zinc supplementation decreased the incidence of infections by 66% and improved cell-mediated immunity. Also, we showed that oxidative stress markers and gene expression of inflammatory cytokines were decreased in elderly subjects who received zinc supplementation. These studies suggest that zinc supplementation in the elderly may have a preventive role in atherosclerosis. Plasma zinc is widely used as a biomarker of zinc deficiency in humans. This test is, however, neither specific nor sensitive. Assays of immunological markers such as plasma active thymulin and gene expression of IL-2 in PHA-stimulated lymphocytes are very sensitive and specific for the diagnosis of human zinc deficiency. The assay of zinc in cells such as lymphocytes and granulocytes are better than plasma zinc; however, even these assays are less sensitive than immunological biomarkers.