Zinc and immunity is a well-studied area with thousands of studies and hundreds of RCTs (Randomised Controlled Trials) showing the impact that the micronutrient zinc can have in relation to the immune response. In the midst of an easing of lockdown measures in the UK and around the world and the potential threat of increased infection rates, a second wave, we take a deep dive into some of the science surrounding this essential nutrient.
Zinc is a trace mineral that is essential for growth, reproduction, and good health throughout life. It is required for the structure and function of literally thousands of different proteins, including enzymes, transporters, and transcription factors. One of the most important roles of zinc is as a gatekeeper of the immune system. Zinc supports innate and acquired immunity through direct, indirect, and antioxidant mechanisms, all of which help the body fight infections.
Mouse models have shown, for example, that just 30 days of suboptimal zinc intake can lead to a 30-80% loss of immune capacity. Notably, an investigation of the nutritional status of patients admitted to a hospital’s infectious disease ward revealed that two-thirds of the patients were deficient in zinc.
Zinc and immunity
Zinc deficiency not only compromises immunity but also shifts the immune system toward an inflammatory state that can predispose the body for damage to the lungs and other organs. Low levels of zinc, for example, are associated with greater disease severity in patients with sepsis, a life-threatening complicated infection.
Even mild zinc deficiencies can increase the risk and severity of viral infections, including respiratory infections such as influenza and pneumonia. Moreover, studies have shown that zinc can inhibit the replication (and thus the potential burden of infection that the body has to fight in other ways) of influenza, coronavirus, rhinovirus, and respiratory syncytial virus in vitro.
As we all know, the risk of respiratory infections increases with age, due to a decline in immune function known as “immunosenescence”. The process of immunosenescence is controlled in part by thymulin, a zinc-containing hormone produced by the thymus gland that regulates the production and maturation of a type of white blood cell known as the T-lymphocyte, or simply, T cell.
Deficiencies of zinc and other necessary immune system nutrients also become more prevalent as we age. Prolonged zinc deficiency leads to thymic atrophy, a reduction in T-cell populations, and diminished immunity. Fortunately, animal models have shown that the thymic atrophy associated with ageing can be reversed by supplementing with zinc, suggesting that immunosenescence may not be inevitable. Human studies support the animal data, one such study finding that zinc supplementation (30 mg per day for three months) boosted T cell populations in elderly individuals.
A fascinating study published many years ago showed that white blood cells (WBCs) collected from elderly individuals produced less interferon (IFN) – a cytokine involved in viral killing – than those from young adults. Again, the IFN-producing capacity was not permanently lost: when WBCs from the elderly were incubated with physiologic concentrations of zinc, they produced IFN in amounts comparable to those from the younger subjects.
Zinc supplementation reduced the risk of pneumonia by 64% in critical care patients on ventilators.
Several clinical trials have been done to determine if supplemental zinc could influence the risk of infections such as pneumonia in the elderly. In one randomized, double-blind, placebo-controlled trial, study participants were given a daily multivitamin and mineral supplement, including zinc, for one year. Individuals who developed normal zinc levels had a lower incidence and duration of pneumonia and less need for antibiotics compared to subjects with low serum zinc concentrations. Similarly, another study showed that zinc supplementation reduced the risk of pneumonia by 64% in critical care patients on ventilators.
Notably, the impact of zinc for healthspan extends beyond immunity, because zinc deficiency is associated with an increase in the risk for Alzheimer’s disease, atherosclerosis (hardening of the arteries), diabetes, osteoporosis, and certain cancers, including pancreatic cancer. Conversely, the maintenance of adequate zinc levels throughout life may help protect against chronic diseases of ageing. Growing evidence suggests that individuals with adequate serum zinc concentrations have a reduced risk of mortality from all causes – suggesting zinc impacts lifespan as well as healthspan.
Zinc supplementation can improve blood glucose control in both prediabetic and diabetic patients.
Zinc also plays a role in insulin signalling, helping to regulate blood glucose levels. An RCT in individuals with prediabetes showed that zinc supplementation lowered blood glucose and cholesterol levels, and reduced the number of individuals who progressed to full-blown diabetes. A meta-analysis of 32 studies, involving 1,700 participants, concluded that zinc supplementation can improve blood glucose control in both prediabetic and diabetic patients. The effective doses of zinc in the meta-analysis generally ranged from 20 to 50 mg per day.
Interestingly, obesity and/or diabetes are underlying conditions that can increase a person’s risk for respiratory infections. Zinc may be one of the common links: obesity and/or diabetes increase the risk for zinc deficiency, which in turn increases the risk of infections. However, zinc is not alone in this regard: inadequate vitamin D levels also are associated with obesity, diabetes, and infections.
Who is at risk for zinc deficiency?
The body has no specialized storage system for zinc, so it is necessary to consume this mineral every day to maintain adequate levels. Population studies suggest that the prevalence of marginal zinc intakes ranges from 12% of younger adults to 30% or more of individuals over the age of 60.
Zinc is found in many different foods but it is particularly concentrated in meat, poultry, and shellfish. Vegetarians, and especially vegans who consume no animal products, have an increased risk of zinc deficiency, particularly if they also avoid nuts and seeds which contain relatively high levels of zinc. The zinc present in plant-based foods is also less bioavailable due to the presence of phytates, which strongly bind zinc and prevent its absorption.
Individuals with celiac disease who are consuming gluten-free (GF) diets may also be at risk for a deficiency of zinc and several other nutrients. One study reported that 67% of newly diagnosed adult patients with celiac disease had suboptimal serum zinc levels, while another study observed that 40% of individuals consuming long-term GF diets still were deficient in zinc. Zinc supplementation (25 to 40 mg per day) was recommended for nutritional support.
While diet is one factor, studies also show that intestinal malabsorption (which often exists in celiac disease), inflammatory bowel disease, autoimmune disease, kidney or liver disease, cancer or cancer treatments, and the use of medications (including antibiotics, statins, and blood pressure medications), can all contribute to zinc deficiency.
How much zinc do we need?
Zinc is a micronutrient, meaning that small amounts are needed every day. The RDA for zinc is 8–12 mg daily depending on age and gender. One study suggested that supplementation with 10 mg of zinc daily may increase the quantity of IFN-producing cells and thereby strengthen the immune system against viral infections. More recent studies indicate that 30 mg per day may be a better target intake for immune support.
Nutrigold zinc citrate delivers 15mg elemental zinc per capsule in a highly bioavailable and bioactive citrate form. Zinc contributes to normal immune system function, normal carbohydrate metabolism, normal cognitive function, normal fertility and reproduction as well as maintenance of normal bones, hair, nails and skin.
Chasapis CT, et al. Zinc and human health: an update. Arch Toxicol. 2012 Apr;86(4):521-34.
Abdollahi M, et al. Zinc supplementation is an effective and feasible strategy to prevent growth retardation in 6 to 24 month children: a pragmatic double blind, randomized trial. Heliyon. 2019 Nov 1;5(11):e02581.
Tomas-Sanchez C, et al. Prophylactic zinc and therapeutic selenium administration increases the antioxidant enzyme activity in the rat temporoparietal cortex and improves memory after a transient hypoxia-ischemia. Oxid Med Cell Longev. 2018 Sep 6;2018:9416432.
Andreini C, et al. Counting the zinc-proteins encoded in the human genome. J Proteome Res. 2006 Jan;5(1):196-201.
Maret W. Zinc biochemistry: from a single zinc enzyme to a key element of life. Adv Nutr. 2013 Jan 1;4(1):82-91.
Wessels I, et al. Zinc as a gatekeeper of immune function. Nutrients. 2017 Nov 25;9(12):1286.
Reider CA, et al. Inadequacy of immune health nutrients: intakes in US adults, the 2005-2016 NHANES. Nutrients. 2020 Jun 10;12(6):E1735.
Pyo CW, et al. Alteration of copper–zinc superoxide dismutase 1 expression by influenza A virus is correlated with virus replication. Biochem Biophys Res Commun. 2014;450(1):711-6.
Sapkota M, Knoell DL. Essential role of zinc and zinc transporters in myeloid cell function and host defense against infection. J Immunol Res. 2018 Oct 17;2018:4315140.
Prasad AS, Bao B. Molecular mechanisms of zinc as a pro-antioxidant mediator: clinical therapeutic implications. Antioxidants (Basel). 2019 Jun 6;8(6):164.
Gao H, et al. The role of zinc and zinc homeostasis in macrophage function. J Immunol Res. 2018 Dec 6;2018:6872621.
Fraker PJ, King LE. Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr. 2004;24:277-98.
Dizdar OS, et al. Nutritional risk, micronutrient status and clinical outcomes: a prospective observational study in an infectious disease clinic. Nutrients. 2016 Feb 29;8(3):124.
Kido T, et al. Inflammatory response under zinc deficiency is exacerbated by dysfunction of the T Helper type 2 lymphocyte-M2 macrophage pathway. Immunology. 2019 Apr;156(4):356-72.
Gammoh NZ, Rink L. Zinc in infection and inflammation. Nutrients. 2017 Jun 17;9(6):624.
Wong HR, et al. Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcome. Physiol Genomics. 2007 Jul 18;30(2):146-55.
Besecker BY, et al. A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. Am J Clin Nutr. 2011 Jun;93(6):1356-64.
Hoeger J, et al. Persistent low serum zinc is associated with recurrent sepsis in critically ill patients – a pilot study. PLoS One. 2017; 12(5):e0176069.
Mocchegiani E, Muzzioli M. Therapeutic application of zinc in human immunodeficiency virus against opportunistic infections. J Nutr. 2000 May;130(5S Suppl):1424S-31S.
Read SA, et al. The role of zinc in antiviral immunity. Adv Nutr. 2019 Jul 1;10(4):696-710.
Eijelkamp BA, et al. Dietary zinc and the control of Streptococcus pneumoniae infection. PLoS Pathog. 2019 Aug 22;15(8):e1007957.
McCarty MF, DiNicolantonio JJ. Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus. Prog Cardiovasc Dis. 2020 Feb 12 [online ahead of print.]
te Velthuis AJW, et al. Zn(2+) Inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010 Nov 4;6(11):e1001176.
Suara RO, Crowe JE. Effect of zinc salts on respiratory syncytial virus replication. Antimicrob Agents Chemother. 2004 Mar;48(3):783-90.
Geist FC, et al. In vitro activity of zinc salts against human rhinoviruses. Antimicrob Agents Chemother. 1987 Apr;31(4):622-4.
Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc with capsid polypeptides. J Virol. 1976 Apr;18(1):298-306.
Merluzzi VJ, et al. Evaluation of zinc complexes on the replication of rhinovirus 2 in vitro. Res Commun Chem Pathol Pharmacol. 1989 Dec;66(3):425-40.
Khan NA, et al. Respiratory syncytial virus-induced oxidative stress leads to an increase in labile zinc pools in lung epithelial cells. mSphere. 2020 May 27;5(3):e00447-20.
Tang Q, et al. The short form of the zinc finger antiviral protein inhibits influenza A virus protein expression and is antagonized by the virus-encoded NS1. J Virol. 2017 Jan 3;91(2):e01909-16.
Cabrera AJR. Zinc, aging, and immunosenescence: an overview. Pathobiol Aging Age Relat Dis. 2015 Feb 5;5:25592.
Crooke SN, et al. Immunosenescence: a systems-level overview of immune cell biology and strategies for improving vaccine responses. Exp Gerontol. 2019 Sep;124:110632.
Berzins SP, et al. Thymic regeneration: teaching an old immune system new tricks. Trends Mol Med. 2002 Oct;8(10):469-76.
Wong CP, et al. Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation. J Nutr Biochem. 2013 Jan 1;24(1):353-9.
Prasad AS. Lessons learned from experimental human model of zinc deficiency. J Immunol Res. 2020 Jan 9;2020:9207279.
Mitchell WA, et al. Thymic output, ageing and zinc. Biogerontology. Oct-Dec 2006;7(5-6):461-70.
Di Silvestro RA, et al. Comparison of thymulin activity with other measures of marginal zinc deficiency. Biol Trace Elem Res. 2020 May 3. [online ahead of print.]
Haase H, Rink L. The immune system and the impact of zinc during aging. Immun Ageing. 2009 Jun 12;6:9.
Maggini S, et al. Immune function and micronutrient requirements change over the life course. Nutrients. 2018 Oct 17;10(10):1531.
Wong CP, Ho E. Zinc and its role in age-related inflammation and immune dysfunction. Mol Nutr Food Res. 2012 Jan;56(1):77-87.
Giacconi R, et al. Main biomarkers associated with age-related plasma zinc decrease and copper/zinc ratio in healthy elderly from ZincAge study. Eur J Nutr. 2017 Dec;56(8):2457-66.
Fraker PJ, et al. Regeneration of T-cell helper function in zinc-deficient adult mice. Proc Natl Acad Sci. 1978 Nov 1;75(11):5660-4.
Mocchegiani E, et al. Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice. Int J Immunopharmacol. 1995 Sep;17(9):703-18.
Mocchegiani E, et al. Plasticity of neuroendocrine-thymus interactions during ontogeny and ageing: role of zinc and arginine. Ageing Res Rev. 2006 Aug;5(3):281-309.
Dardenne M, et al. Restoration of the thymus in aging mice by in vivo zinc supplementation. Clin Immunol Immunopathol. 1993 Feb;66(2):127-35.
Barnett JB, et al. Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2016 Mar;103(3):942-51.
Cakman I, et al. Zinc supplementation reconstitutes the production of interferon-alpha by leukocytes from elderly persons. J Interferon Cytokine Res. 1997 Aug;17(8):469-72.
Barnett JB, et al. Low zinc status: a new risk factor for pneumonia in the elderly? Nutr Rev. 2010 Jan;68(1):30-7.
Yasuda H, Tsutsui T. Infants and elderlies are susceptible to zinc deficiency. Sci Rep. 2016 Feb 25;6:21850.
Meydani SN, et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr. 2007 Oct;86(4):1167-73.
Kiabi FH, et al. Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: a secondary analysis of a prospective, observational study. Indian J Crit Care Med. 2017 Jan; 21(1):34–9.
Bredesen DE. Metabolic profiling distinguishes three subtypes of Alzheimer’s disease. Aging (Albany NY). 2015 Aug;7(8):595-600.
Choi S, et al. Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases. Acta Pharmacol Sin. 2018 Jul;39(7):1120-32.
Wang X, et al. Zinc supplementation improves glycemic control for diabetes prevention and management: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2019 Jul 1;110(1):76-90.
O’Connor JP, et al. Zinc as a therapeutic agent in bone regeneration. Materials (Basel). 2020 May 12;13(10):2211.
Costello LC, et al. Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma. Cancer Biol Ther. 2011 Aug 15;12(4):297-303.
Prasad AS. Zinc: mechanisms of host defense. J Nutr. 2007 May;137(5):1345-9.
Bao B, et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr. 2010 Jun;91(6):1634-41.
Malavolta M, et al. Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population. Biogerontology. 2010 Jun;11(3):309-19.
Mocchegiani E, et al. Cu to Zn ratio, physical function, disability, and mortality risk in older elderly (ilSIRENTE Study). Age (Dordr). 2012 Jun;34(3):539-52.
Fukunaka A, Fujitani Y. Role of zinc homeostasis in the pathogenesis of diabetes and obesity. Int J Mol Sci. 2018 Feb 6;19(2):476.
Tuncay E, et al. Hyperglycemia-induced changes in ZIP7 and ZnT7 expression cause Zn 2+ release from the sarco(endo)plasmic reticulum and mediate ER stress in the heart. Diabetes. 2017 May;66(5):1346-58.
Fernández-Cao JC, et al. Dietary zinc intake and whole blood zinc concentration in subjects with type 2 diabetes versus healthy subjects: a systematic review, meta-analysis and meta-regression. J Trace Elem Med Biol. 2018 Sep;49:241-51.
Chausmer AB. Zinc, insulin and diabetes. J Am Coll Nutr. 1998 Apr;17(2):109-15.
Beattie JH, et al. Suboptimal dietary zinc intake promotes vascular inflammation and atherogenesis in a mouse model of atherosclerosis. Mol Nutr Food Res. 2012 Jul;56(7):1097-105.
Yang YJ, et al. Dietary zinc intake is inversely related to subclinical atherosclerosis measured by carotid intima-media thickness. Br J Nutr. 2010 Oct;104(8):1202-11.
Olechnowicz J, et al. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J Physiol Sci. 2018 Jan;68(1):19-31.
Koliaki C, et al. Obesity and cardiovascular disease: revisiting an old relationship. Metabolism. 2019 Mar;92:98-107.
Kim J, Ahn J. Effect of zinc supplementation on inflammatory markers and adipokines in young obese women. Biol Trace Elem Res. 2014 Feb;157(2):101-6.
Khorsandi H, et al. Zinc supplementation improves body weight management, inflammatory biomarkers and insulin resistance in individuals with obesity: a randomized, placebo-controlled, double-blind trial. Diabetol Metab Syndr. 2019 Dec 2;11:101.
Norouzi S, et al. Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines. PLoS One. 2018 Jan 26;13(1):e0191727.
Adulcikas J, et al. Targeting the zinc transporter ZIP7 in the treatment of insulin resistance and type 2 diabetes. Nutrients. 2019 Feb 15;11(2):408.
Jansen J, et al. Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc. J Nutr Biochem. 2012 Nov;23(11):1458-66.
Ranasinghe P, et al. Zinc supplementation in prediabetes: a randomized double-blind placebo-controlled clinical trial. J Diabetes. 2018 May;10(5):386-97.
Maccioni L, et al. Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study. BMC Public Health. 2018;18:271.
Casqueiro J, et al. Infections in patients with diabetes mellitus: a review of pathogenesis. Indian J Endocrinol Metab. 2012 Mar;16(Suppl1):S27–36.
Parohan M, et al. Risk factors for mortality in patients with coronavirus disease 2019 (COVID-19) infection: a systematic review and meta-analysis of observational studies. Aging Male. 2020 Jun 8;1-9.
McGill AT, et al. Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutr J. 2008 Jan 28;7:4.
Ginde AA, et al. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):384-90.
Rink L, Gabriel P. Zinc and the immune system. Proc Nutr Soc. 2000 Nov;59(4):541-52.
Blumberg JB, et al. Contribution of dietary supplements to nutritional adequacy in various adult age groups. Nutrients. 2017 Dec 6;9(12):1325.
Ervin RB, Kennedy-Stephenson J. Mineral intakes of elderly adult supplement and non-supplement users in the Third National Health and Nutrition Examination Survey. J Nutr. 2002 Nov;132(11):3422-7.
Vural Z, et al. Trace mineral intake and deficiencies in older adults living in the community and institutions: a systematic review. Nutrients. 2020 Apr 13;12(4):1072.
Sharma S, et al. Contribution of meat to vitamin B₁₂, iron and zinc intakes in five ethnic groups in the USA: implications for developing food-based dietary guidelines. J Hum Nutr Diet. 2013 Apr;26(2):156-68.
Wapnir RA. Zinc deficiency, malnutrition and the gastrointestinal tract. J Nutr. 2000 May;130(5S Suppl):1388S-92S.
Farmer B. Nutritional adequacy of plant-based diets for weight management: observations from the NHANES. Am J Clin Nutr. 2014 Jul;100 Suppl 1:365S-8S.
Foster M, Samman S. Vegetarian diets across the lifecycle: impact on zinc intake and status. Adv Food Nutr Res. 2015;74:93-131.
Lönnerdal B. Dietary factors influencing zinc absorption. J Nutr. 2000 May;130(5S Suppl):1378S-83S.
Fredlund K, et al. Absorption of zinc and retention of calcium: dose-dependent inhibition by phytate. J Trace Elem Med Biol. 2006;20(1):49-57.
Hambridge KM, et al. Dietary reference intakes for zinc may require adjustment for phytate intake based upon model predictions. J Nutr. 2008 Dec;138(12):2363-6.
Vici G, Belli L, Biondi M, Polzonetti V. Gluten free diet and nutrient deficiencies: a review. Clin Nutr. 2016 Dec 1;35(6):1236-41.
Wierdsma NJ, et al. Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients. Nutrients. 2013 Sep 30;5(10):3975-92.
Rondanelli M, et al. Micronutrients dietary supplementation advices for celiac patients on long-term gluten-free diet with good compliance: a review. Medicina (Kaunas). 2019 Jul 3;55(7):337.
Holt PR. Intestinal malabsorption in the elderly. Dig Dis. 2007;25(2):144-50.
Frustaci A, et al. Selenium- and zinc-deficient cardiomyopathy in human intestinal malabsorption: preliminary results of selenium/zinc infusion. Eur J Heart Fail. 2012 Feb;14(2):202-10.
Siva S, et al. Zinc deficiency is associated with poor clinical outcomes in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2017 Jan;23(1):152-7.
Sanna A, et al. Zinc status and autoimmunity: a systematic review and meta-analysis. Nutrients. 2018 Jan 11;10(1):68.
Damianaki K, et al. Renal handling of zinc in chronic kidney disease patients and the role of circulating zinc levels in renal function decline. Nephrol Dial Transplant. 2019 Apr 21;gfz065.
Himoto T, Masaki T. Associations between zinc deficiency and metabolic abnormalities in patients with chronic liver disease. Nutrients. 2018 Jan;10(1):88.
Ozeki I, et al. The association between serum zinc levels and subjective symptoms in zinc deficiency patients with chronic liver disease. J Clin Biochem Nutr. 2020 May;66(3):253-61.
Kandaz M, et al. Zinc sulfate and/or growth hormone administration for the prevention of radiation-induced dermatitis: a placebo-controlled rat model study. Biol Trace Elem Res. 2017 Sep;179(1):110-6.
Suliburska J, et al. Effect of hypotensive therapy combined with modified diet or zinc supplementation on biochemical parameters and mineral status in hypertensive patients. J Trace Elem Med Biol. 2018 May;47:140-8.
Ghayour-Mobarhan M, et al. Effect of statin therapy on serum trace element status in dyslipidaemic subjects. J Trace Elem Med Biol. 2005;19(1):61-7.
National Institutes of Health. Zinc fact sheet for health professionals [Internet]. Bethesda (MD): U S Department of Health and Human Services; 2020 [cited 2020 July 6]. Available from: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/
Metz CHD, et al. T-helper type 1 cytokine release is enhanced by in vitro zinc supplementation due to increased natural killer cells. Nutrition. 2007 Feb;23(2):157-63.
