Written by: Khushboo Verma

Reviewed by: Kritika Pathak and Madelyn Robinson

In the 1960s, dry and wrinkled skin, growth retardation, delayed puberty, iron deficiency anemia, and immune dysfunction with life-threatening opportunistic infections were seen in Iranian and Egyptian population that mainly relied on a diet of cereal proteins rich in phytates. Phytates were found to interfere with the absorption of metal ions like iron and zinc (Lönnerdal, 2000; Ma et al., 2007; Masum Akond et al., 2011; Ananda S. Prasad, 2008). These learnings gave rise to the suspicion that zinc deficiency was the underlying factor in these presentations (Cabrera, 2015; Ananda S. Prasad, 2013). Similar clinical features were noted in patients maintained on intravenous nutrition lacking adequate trace elements, which led to the recognition of zinc as the common link (Kay & Tasman-Jones, 1975; Shankar & Prasad, 1998). It is now known that zinc is an essential element. It is a cofactor that facilitates the function of many enzymes and proteins. Zinc modulates cell proliferation and inflammation via interaction with transcription factors such as nuclear factor kappa B (NF-κB). Hence, the body's immune function and hormonal signaling depend on its availability as well (Cabrera, 2015; Haase & Rink, 2009). 

Zinc is primarily derived from dietary sources, and suboptimal nutrition is usually the most common cause of its deficiency. Older adults with severe immobility, multiple comorbidities, malabsorption, unfavorable drug interactions, and inability to consume solid foods are increasingly vulnerable to zinc deficiency (Cabrera, 2015; Younoszai, 1983). Acrodermatitis enteropathica, which is characterized by an inability to absorb dietary zinc, and sickle cell anemia are common inherited conditions associated with severe zinc deficiency (Cabrera, 2015; Nistor et al., 2016; Ochocinski et al., 2020; Shankar & Prasad, 1998). The human body maintains 2-3 grams of zinc in the stored form. While most of it is bound to proteins, the availability of free intracellular zinc is crucial for its function as a regulator (Cabrera, 2015; Haase & Rink, 2009; Shankar & Prasad, 1998). The availability of free intracellular zinc depends on carrier proteins (from ZnT and ZIP families) and the amount of zinc bound to the antioxidant buffering protein, metallothionein (MT) (Bin et al., 2018; Haase & Rink, 2009; Kambe et al., 2014; Murakami & Hirano, 2008). 

At any age, zinc deficiency triggers events that mirror the immunologic decline seen with aging (immunosenescence) (Haase et al., 2006). Neutrophils are cells that form the first line of defense against pathogens (disease-causing agents). While there is no change in the absolute neutrophil count, as zinc stores dwindle, neutrophils cannot carry out their pathogen-killing processes (Haase & Rink, 2009). This could partly be due to the role of zinc in superoxide dismutase (SOD) enzyme activity that clears reactive oxygen species (ROS), a crucial endpoint to the free radical-dependent destruction of intracellular organisms (Moroni et al., 2005). Monocytes, precursors of macrophages, also exhibit a similar impairment (Wirth et al., 1989). The functional incompetence of macrophages develops early in the course of zinc deficiency. Zinc protects macrophages from toxin-induced apoptosis (programmed cell death) (Shankar & Prasad, 1998). In the presence of virus-infected or cancer cells, natural killer (NK) cells induce differentiation of naïve T cells to Th1 helper cells via interferon-gamma (IFN-γ) signaling, which implies an increased risk of viral infections and cancer in the absence of adequate zinc stores (Haase & Rink, 2009).

Figure 1: Effects of zinc deficiency on immune mediators (Maares & Haase, 2016)

The thymus, a small organ located in the chest cavity, is the site for T cell maturation and differentiation (Gameiro et al., 2010; Grossi et al., 1991). The decrease in thymus size (atrophy) and loss of function seen with advancing age are accelerated in zinc deficiency (Giugliano & Millward, 1987; Golden et al., 1977). The effect of zinc insufficiency on thymic atrophy and decreased T cell proliferation has been attributed to apoptotic cell death of thymocytes (cells of the thymus) (Fraker & King, 2004; McLeod, 2001). The scarcity of zinc causes an imbalance between pro- and anti-apoptotic factors, dysregulation of DNA fragmentation enzymes, and accumulation of toxic metabolites that together compromise cellular resistance to apoptosis (Giannakis et al., 1991; McLeod, 2001). As CD4+ helper T cells decrease in number, there is a relative increase in dysfunctional CD8+ cytotoxic T cells lacking in antigen recognition, proliferation, and cytotoxic action (Beck et al., 1997). Thymulin, a peptide hormone secreted by thymic epithelial cells (TECs), which is essential for T-cell maturation and cytotoxicity, relies on zinc for its activation (Dardenne et al., 1990; Haase & Rink, 2009; A S Prasad et al., 1988). B lymphocyte proliferation and antibody production are significantly reduced in mice fed a zinc-limited diet for 30 days (Shankar & Prasad, 1998). 

In mice who underwent allogeneic hematopoietic stem cell transplantation, an increase in the number of endothelial cells (ECs) capable of regenerating the thymic cells was demonstrated. It was seen that zinc administration stimulated the GPR39 receptors on the ECs to activate the BMP4 pathway and increased the proliferation of TECs, offering a possible path to thymic regeneration (Iovino et al., 2019; Wertheimer et al., 2018).

Moreover, zinc is vital for maintaining the skin's barrier function and the linings of gastrointestinal and pulmonary tracts (Ohashi & Fukada, 2019; Roscioli et al., 2017; Shankar & Prasad, 1998). A lack of zinc is related to cerebral aging and neurodegeneration from apoptotic neuronal cell death (Cabrera, 2015; Szewczyk, 2013). Zinc regulates the transcription factor, NF-kB, which induces transcription of genes to increase cytokine (chemical mediators of inflammation) production, resulting in a persistent low-level inflammation triggered by the higher oxidative stress in zinc deficiency that facilitates cellular aging (oxi-inflamm-aging) (Bryan et al., 2013; Jarosz et al., 2017; Marreiro et al., 2017). The unregulated inflammatory cascade in zinc-restricted states leads to a heightened response to infections resulting in septic shock and multi-organ effects (Cabrera, 2015; Maywald & Rink, 2015).   

 Figure 2: Zinc activates protein A-20, which inhibits (broken arrow) the IkB kinase (IKK), causing inhibition of the inflammatory cascade. In zinc deficiency, the protein A-20 is ‘free,’ and the activation of NF-κB and subsequent generation of inflammatory cytokines are left unregulated (Cabrera, 2015)

The zinc status of the body is most often measured using serum or plasma zinc levels, and a concentration below 70 μg/dL is considered low (Cabrera, 2015; Haase & Rink, 2009). The values vary based on the fasting status of an individual and may not represent intracellular zinc levels (Cabrera, 2015; Haase & Rink, 2009; Wieringa et al., 2015). Labile intracellular zinc measurement may be a more accurate measure of an individual's zinc status (Cabrera, 2015; Carpenter et al., 2016). While the recommended daily intake of zinc is 8 - 11 mg in adults, the frequency, duration, and chemical form for supplementation remain ambiguous. Over-administration of zinc has been associated with impaired absorption of copper, which can lead to severe anemia and neutropenia (Maret & Sandstead, 2006; Samman & Roberts, 1988). It may also be counterproductive and result in a diminished immune response (Shankar & Prasad, 1998). 

With the administration of zinc improving cell division in the thymus and reversing immunologic deficits seen in the elderly, its role in countering aging is worth exploring. Zinc can potentially be used with other hormonal and pharmacologic compounds to oppose aging processes synergistically.

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