Opti-Biologics

“Presenting Scientific Research for Optimization of Everyday Life"

Supplement Review #3: Zinc

August 30, 2022
 
Background
Zinc is a common mineral found throughout the world, including in humans. It is an essential mineral and plays a crucial role in various biological and chemical pathways. Zinc can be consumed through the dietary intake of foods such as beef, chicken, eggs, and dairy products. Despite the wide availability of these foods, zinc deficiency still impacts a large number of individuals across the world. According to various sources, zinc deficiency affects around 12% of the population or approximately 39.5 million people in the United States. Senior citizens of the United States seem to be most affected, with 40% of zinc-deficient individuals being over the age of 60 years. Many professionals have found that with increasing age comes a decline in metabolism, not only due to the oxidative stress of many cells but also the failure to absorb nutrients from the small intestine. The remaining 60% of zinc-deficient cases are primarily caused by a diet low in zinc-rich foods, possibly due to poor nutritional education or other socioeconomic factors. Although 12% of the US population is reported to be zinc-deficient, nutrition and optimization of these nutrients are never so binary. An example of why this number may be false is the testing parameters. Serum zinc levels are tested for in blood tests, and mass spectrometry is performed to show zinc concentration in blood plasma. While mass spectrometry is the industry's gold standard, a time-dependent and non-longitudinal concentration dependent on recent food intake is extremely misleading. Briefly, an individual with SNPs allowing for lower serum zinc concentration but adequate functionality will test deficient on a blood panel. This misrepresentation may lead to the prescription of zinc supplements, which puts the patient at risk for other metabolic problems associated with high zinc concentrations. For this reason, any physician analyzing micronutrient concentrations must obtain longitudinal data (i.e., multiple blood tests every couple of months) to diagnose a patient with a micronutrient deficiency. Another factor that may impact zinc utility is exercise. Since intense exercise impacts metabolism, it may impact the amount of zinc an individual requires. 
Findings from Literature
While testing for zinc deficiency is quite problematic, it can be generally said that with accurate micronutrient monitoring and food tracking, an individual can decide whether or not zinc supplementation is beneficial. Besides being an essential micronutrient for basic physiological functions, zinc can also help improve the immune system, metabolism, and endocrine system. Zinc supplementation has been demonstrated in many randomized controlled trials to be highly beneficial to type 2 diabetes mellitus patients. In a randomized, double-blind clinical trial, 40 obese subjects were assigned to receive oral zinc supplementation (30mg/day) or a placebo. Both groups were also put on a calorie-restricted diet, and each group was subjected to treatment for 15 weeks. After weeks, all subjects had improved anthropometric and insulin parameters. However, the zinc-supplemented group had significantly improved measurements when compared to the placebo group. Measurements include body weight, hip and waist circumference, BMI, C-reactive protein (CRP), and homeostatic model assessment of insulin resistance (HOMA-IR). 
A systematic review, which compiles multiple trials and analyzes the data accordingly, investigated whether zinc supplementation could improve symptoms of depression. The review found that zinc supplementation could be used as an adjunct to prescription medications or individually to improve symptoms of depression. While there are many limitations, including the number of studies available on zinc and depression, considering the safety profile of zinc supplementation at a reasonable dose, it is safe to say that zinc supplementation can be used to improve symptoms of depression. In a more recent randomized clinical trial, conducted in 2013, the group that was supplemented with zinc showed a significantly decreased Beck's depression score. The research concluded that zinc supplementation in conjunction with antidepressants significantly improved symptoms of depression when compared to patients receiving placebo and antidepressants. 
Interestingly, zinc supplementation has been investigated concerning obesity and type 2 diabetes mellitus. While these studies were conducted using a rodent model, their findings highlight important features of zinc supplementation and its effects on metabolism. Future studies should investigate the effects of zinc supplementation on a variety of metabolic and endocrine parameters. The first study investigated the effects of zinc supplementation on obesity-induced rats. These rats were fed a high-fat diet and either supplemented with zinc or branched-chain amino acids for 19 weeks. After 19 weeks, rats fed a high-fat diet had significantly increased weight gain, abdominal fat pad, plasma insulin, leptin, and triglyceride levels when compared to rats fed a standard diet. However, the rats fed a high-fat diet and supplemented with zinc had significantly lower body weight, insulin, leptin, abdominal fat, and triglyceride levels than rats fed a high-fat diet and supplemented with branched-chain amino acids. This study suggests that zinc supplementation may alleviate some of the parameters associated with a high-fat diet. A similar study investigated the effects of zinc supplementation on glucose metabolism, which is extremely impaired in both obesity and diabetes. To investigate the role of zinc in glucose metabolism, rats were fed a high-fat diet, mimicking an obesity model, and supplemented with zinc. It was demonstrated that zinc supplementation improved glucose metabolism via many pathways, some of which included increasing glucose absorption and improving hepatic glycolysis. 
Another systematic review, conducted in 2022, investigated zinc supplementation and inflammatory markers. This meta-analysis included 35 randomized controlled trials with a total of 1995 participants. The study also found that high sensitivity C-reactive protein (hs-CRP) is significantly decreased in patients receiving an oral zinc supplement. While hs-CRP was significantly decreased, CD3 and CD4 levels were significantly increased. This marked increase in CD3 and CD4 levels demonstrates a higher proportion of T cells that respond to a specific antigen. Due to this property, zinc supplementation may be associated with improved immune function. 
Zinc & the Immune System
Zinc plays a vital role in many physiological processes, including but not limited to DNA synthesis, immune regulation, and cardiovascular homeostasis. The initial wave of the COVID-19 pandemic increased public awareness surrounding zinc. This is mostly because drinks and “immune-boosting” packets available in stores were increasing in sales, which usually contain some form of zinc. A 2020 systematic review investigated whether zinc supplementation impacts the occurrence and severity of respiratory tract infections. This study found that in a population where zinc deficiency is unlikely, additional zinc supplementation may decrease the occurrence and severity of respiratory tract infections. Likewise, a 2021 systematic review investigated the effects of zinc supplementation on COVID-19 severity and found that zinc significantly reduced mortality in COVID-19 patients. 
The Mechanism of Zinc in the Immune System
Zinc is considered a trace mineral, meaning that the body requires very little of this mineral. A brief background to understand the immune system is required before getting into the mechanistic details involving zinc and its effect on cell differentiation. The immune system is important for preventing foreign pathogens from invading the body’s host tissue. A common misconception is that the immune system is “smarter” than it is. In the end, the immune system is composed of different cell types that have different roles in preventing and killing foreign pathogens. These cells do have a conscious mind, and that can oftentimes be overlooked. These cells are programmed to recognize a set of amino acids in a particular order, such that even if a host cell has this peptide on its surface, it is prone to be killed by immune cells. There are many more complications, including cell subtypes, but, for the sake of zinc, T cells are most affected. T cells are immune cells that are produced by the thymus. These cells contain lots of important surface proteins and carbohydrates that allow them to recognize and kill cells. Of much importance, the T-cell receptor (TCR) is a protein found on the surface of T-cells. In the TCR, an antigen-binding site contains the complementary sequence of amino acids to a particular sequence. When a TCR that contains the complement to antigen “X” binds to the “X” antigen, the TCR undergoes a conformational change that sends a cascade of signals into the T-cell. These signals ultimately promote the T-cell to release granzymes or some other killing enzyme into the cell that contains the “X” antigen. Fortunately, our T-cells have a special feature, which is that they can recognize “self” cells. To do this, the T-cells can express a cluster of differentiation (CD) proteins that bind to a molecule exclusively expressed on the host (“self”). Of course, viruses and other pathogens can program host cells to express these “self” proteins even when they are infected. For simplicity, T cells are split into different types, such as helper T cells and cytotoxic T cells. Each of these types can be split into subtypes such as T helper 9 or Th9. These different subtypes recognize different antigens and have different proteins on their cell surfaces. Our bodies can use minerals, vitamins, and other molecules to promote differentiation into a specific subtype. Another way to approach this is that adequate nutrition fuels an adequate immune response. 
One such mineral is zinc, which affects the differentiation of Th0 cells into Th9 cells. Th9 cells are a relatively new subset of Th cells and they are considered pro-inflammatory. Zinc supplementation dampens the production of Th9 cells, which provides tolerability against allogeneic immune responses. Another critical role of zinc is suppressing Th17 cells, which are commonly associated with autoimmune diseases. Lastly, zinc supplementation alters T-cell population ratios, for example, the Th2/Th1 ratio. The Th2/Th1 ratio is significantly reduced in an older population when compared to a younger population, and zinc supplementation may ameliorate this reduction by influencing T cell populations. One mechanism by which zinc influences Th1 differentiation is by increasing IFN, T-bet, and IL-12Rbb2 mRNAs. These mRNAs are crucial regulators in T cell differentiation. 
In conclusion, zinc is a major player in the immune system by way of influencing T cell populations. The way zinc modulates T cell differentiation and T cell subpopulations is by modulating mRNAs in the cell. These alterations of T cell differentiation and subpopulations lead to increased T cell numbers. 
Dosage and Daily Intake
The current recommended daily intake (RDI) is 11 mg for adult men and 8 mg for adult women. For context, 8 oz of 93% lean ground beef contains around 11.2 mg of zinc. The RDI is extremely low considering the upper limit is set at 40 mg/day. Since 12% of the population is reported to be zinc-deficient proper nutritional advice throughout the public education system should be encouraged. Those individuals who do not enjoy eating certain foods rich in zinc may opt to take a zinc supplement. Even through proper nutrition, a zinc supplement may still be taken on top of an 11 mg/day dietary intake to reach optimal zinc intake. An additional 8-12 mg of zinc through a supplement can provide benefits as listed previously in “Findings from the Literature." 
Formulations 
A zinc supplement can be found in many formulations, such as zinc picolinate, zinc gluconate, zinc citrate, and zinc sulfate. Individual tolerability is required for the most easily absorbed form of zinc, which is zinc picolinate. Simply put, zinc supplementation should be tested per individual to analyze gastric tolerability and serum levels of zinc.  
Concluding Remarks
At physiological doses, zinc is critical to immune function, glucose metabolism, and even neurological progression. As an essential trace mineral, the recommended daily intake for zinc is set at 11 mg, yet many Americans fail to meet this due to poor food choices, socioeconomic factors, and the decreasing nutritional density of foods. With this, zinc supplementation has gained the public's interest due to its ability to improve factors in the immune system. Not only does zinc supplementation improve symptoms associated with zinc deficiency, but it may enhance glucose metabolism and improve symptoms associated with obesity and depression. Zinc supplementation may not only be beneficial to those not obtaining enough zinc from their diet but to those looking to obtain some of the benefits listed above. 


 

Meet The Author


Hello everyone, 

My name is Joshua Giblin. I am a post-bachelor researcher/research technician at USC. My interests range from nutrition to nanomedicine and also practical science to improve everyday life. Through this blog, I aim to communicate practical scientific research and present it to curious individuals so that an educated decision can be made. Thank you for reading the blog and showing your support.

 
 

Editors

A special thanks to the people involved behind the scenes. Without them, these informative and influential posts would not be what they are.
Anna Richardson - Undergraduate
Molly Giblin - High School Student 
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