Effects of zinc status on age-related T cell dysfunction and chronic inflammation

Abstract

Age-related T cell dysfunction contributes to immunosenescence and chronic inflammation. Aging is also associated with a progressive decline in zinc status. Zinc is an essential micronutrient critical for immune function. A significant portion of the older populations are at risk for marginal zinc deficiency. The combined impact of dietary zinc deficiency and age on immune dysfunction has not been well explored despite the common occurrence together in the elderly population. We hypothesize that age-related zinc loss contributes to T cell dysfunction and chronic inflammation in the elderly and is exacerbated by inadequate dietary intake and improved with zinc supplementation. Using an aging mouse model, the effects of marginal zinc deficiency and zinc supplementation on Th1/Th17/proinflammatory cytokine profiles and CD4+ T cell naïve/memory phenotypes were examined. In the first study, young (2 months) and old (24 months) C57BL/6 mice were fed a zinc adequate (ZA) or marginally zinc deficient (MZD) diets for 6 weeks. In the second study, mice were fed a ZA or zinc supplemented (ZS) diet for 6 weeks. MZD old mice had significant increase in LPS-induced IL6 compared to ZA old mice. In contrast, ZS old mice had significantly reduced plasma MCP1 levels, reduced T cell activation-induced IFNγ, IL17, and TNFα response, as well as increased naïve CD4+ T-cell subset compared to ZA old mice. Our data suggest that zinc deficiency is an important contributing factor in immune aging, and improving zinc status can in part reverse immune dysfunction and reduce chronic inflammation associated with aging.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data availability

Available upon request.

Abbreviations

CBA:

Cytometric bead array

ICP-OES:

Inductively coupled plasma-optical emission spectroscopy

LN:

Lymph nodes

MZD:

Marginally zinc deficient

NIA:

National Institute of Aging

Treg:

Regulatory T cells

ZA:

Zinc adequate

ZS:

Zinc supplemented

References

  1. Aspinall R, Lang PO (2018) Interventions to restore appropriate immune function in the elderly. Immun Ageing 15:5. https://doi.org/10.1186/s12979-017-0111-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. August D, Janghorbani M, Young VR (1989) Determination of zinc and copper absorption at three dietary Zn-Cu ratios by using stable isotope methods in young adult and elderly subjects. Am J Clin Nutr 50:1457–1463. https://doi.org/10.1093/ajcn/50.6.1457

    CAS  Article  PubMed  Google Scholar 

  3. Bogden JD et al (1988) Zinc and immunocompetence in elderly people: effects of zinc supplementation for 3 months. Am J Clin Nutr 48:655–663. https://doi.org/10.1093/ajcn/48.3.655

    CAS  Article  PubMed  Google Scholar 

  4. Bruins MJ, Van Dael P, Eggersdorfer M (2019) The role of nutrients in reducing the risk for noncommunicable diseases during aging. Nutrients 11:85. https://doi.org/10.3390/nu11010085

    CAS  Article  PubMed Central  Google Scholar 

  5. Coder BD, Wang H, Ruan L, Su DM (2015) Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation. J Immunol 194:5825–5837. https://doi.org/10.4049/jimmunol.1500082

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Conley MN, Wong CP, Duyck KM, Hord N, Ho E, Sharpton TJ (2016) Aging and serum MCP-1 are associated with gut microbiome composition in a murine model. PeerJ 4:e1854. https://doi.org/10.7717/peerj.1854

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Dardenne M, Boukaiba N, Gagnerault MC, Homo-Delarche F, Chappuis P, Lemonnier D, Savino W (1993) Restoration of the thymus in aging mice by in vivo zinc supplementation. Clin Immunol Immunopathol 66:127–135. https://doi.org/10.1006/clin.1993.1016

    CAS  Article  PubMed  Google Scholar 

  8. Day KJ, Adamski MM, Dordevic AL, Murgia C (2017) Genetic variations as modifying factors to dietary zinc requirements-a systematic review. Nutrients. https://doi.org/10.3390/nu9020148

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dixon LB, Winkleby MA, Radimer KL (2001) Dietary intakes and serum nutrients differ between adults from food-insufficient and food-sufficient families: Third National Health and Nutrition Examination Survey, 1988–1994. J Nutr 131:1232–1246. https://doi.org/10.1093/jn/131.4.1232

    CAS  Article  PubMed  Google Scholar 

  10. Elyahu Y et al (2019) Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci Adv 5:eaaw8330. https://doi.org/10.1126/sciadv.aaw8330

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Ervin RB, Kennedy-Stephenson J (2002) Mineral intakes of elderly adult supplement and non-supplement users in the third national health and nutrition examination survey. J Nutr 132:3422–3427. https://doi.org/10.1093/jn/132.11.3422

    CAS  Article  PubMed  Google Scholar 

  12. Fischer Walker C, Black RE (2004) Zinc and the risk for infectious disease. Annu Rev Nutr 24:255–275. https://doi.org/10.1146/annurev.nutr.23.011702.073054

    CAS  Article  PubMed  Google Scholar 

  13. Fortes C et al (1998) The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc 46:19–26. https://doi.org/10.1111/j.1532-5415.1998.tb01008.x

    CAS  Article  PubMed  Google Scholar 

  14. Fraker PJ, King LE (2004) Reprogramming of the immune system during zinc deficiency. Annu Rev Nutr 24:277–298. https://doi.org/10.1146/annurev.nutr.24.012003.132454

    CAS  Article  PubMed  Google Scholar 

  15. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C (2017) Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 8:1960. https://doi.org/10.3389/fimmu.2017.01960

    CAS  Article  PubMed  Google Scholar 

  16. Gammoh NZ, Rink L (2017) Zinc in Infection and Inflammation. Nutrients 9:624. https://doi.org/10.3390/nu9060624

    CAS  Article  PubMed Central  Google Scholar 

  17. Girodon F, Lombard M, Galan P, Brunet-Lecomte P, Monget AL, Arnaud J, Preziosi P, Hercberg S (1997) Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial. Ann Nutr Metab 41:98–107. https://doi.org/10.1159/000177984

    CAS  Article  PubMed  Google Scholar 

  18. Girodon F, Galan P, Monget AL, Boutron-Ruault MC, Brunet-Lecomte P, Preziosi P, Arnaud J, Manuguerra JC, Herchberg S (1999) Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT AOX. geriatric network. Arch Intern Med 159:748–754. https://doi.org/10.1001/archinte.159.7.748

    CAS  Article  PubMed  Google Scholar 

  19. Goronzy JJ, Weyand CM (2017) Successful and maladaptive T cell aging. Immunity 46:364–378. https://doi.org/10.1016/j.immuni.2017.03.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Haase H, Rink L (2009) The immune system and the impact of zinc during aging. Immun Ageing 6:9. https://doi.org/10.1186/1742-4933-6-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Haase H, Mocchegiani E, Rink L (2006) Correlation between zinc status and immune function in the elderly. Biogerontology 7:421–428. https://doi.org/10.1007/s10522-006-9057-3

    CAS  Article  PubMed  Google Scholar 

  22. Harpaz I, Bhattacharya U, Elyahu Y, Strominger I, Monsonego A (2017) Old mice accumulate activated effector CD4 T cells refractory to regulatory T cell-induced immunosuppression. Front Immunol 8:283. https://doi.org/10.3389/fimmu.2017.00283

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. High KP (2001) Nutritional strategies to boost immunity and prevent infection in elderly individuals. Clin Infect Dis 33:1892–1900. https://doi.org/10.1086/324509

    CAS  Article  PubMed  Google Scholar 

  24. Hodkinson CF et al (2007) Effect of zinc supplementation on the immune status of healthy older individuals aged 55–70 years: the ZENITH Study. J Gerontol A 62:598–608. https://doi.org/10.1093/gerona/62.6.598

    Article  Google Scholar 

  25. Kim S, Jazwinski SM (2018) The gut microbiota and healthy aging: a mini-review. Gerontology 64:513–520. https://doi.org/10.1159/000490615

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. King JC, Brown KH, Gibson RS, Krebs NF, Lowe NM, Siekmann JH, Raiten DJ (2015) Biomarkers of nutrition for development (BOND)-zinc review. J Nutr 146:858S-885S. https://doi.org/10.3945/jn.115.220079

    Article  PubMed  Google Scholar 

  27. Kohman RA, Crowell B, Kusnecov AW (2010) Differential sensitivity to endotoxin exposure in young and middle-age mice. Brain Behav Immun 24:486–492. https://doi.org/10.1016/j.bbi.2009.12.004

    CAS  Article  PubMed  Google Scholar 

  28. Maue AC, Yager EJ, Swain SL, Woodland DL, Blackman MA, Haynes L (2009) T-cell immunosenescence: lessons learned from mouse models of aging. Trends Immunol 30:301–305. https://doi.org/10.1016/j.it.2009.04.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738. https://doi.org/10.4049/jimmunol.172.5.2731

    CAS  Article  PubMed  Google Scholar 

  30. Meydani SN, Barnett JB, Dallal GE, Fine BC, Jacques PF, Leka LS, Hamer DH (2007) Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr 86:1167–1173. https://doi.org/10.1093/ajcn/86.4.1167

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Nikolich-Zugich J (2014) Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol 193:2622–2629. https://doi.org/10.4049/jimmunol.1401174

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Pae M, Wu D (2017) Nutritional modulation of age-related changes in the immune system and risk of infection. Nutr Res 41:14–35. https://doi.org/10.1016/j.nutres.2017.02.001

    CAS  Article  PubMed  Google Scholar 

  33. Pae M, Meydani SN, Wu D (2012) The role of nutrition in enhancing immunity in aging. Aging Dis 3:91–129

    PubMed  Google Scholar 

  34. Pinchuk LM, Filipov NM (2008) Differential effects of age on circulating and splenic leukocyte populations in C57BL/6 and BALB/c male mice. Immun Ageing 5:1. https://doi.org/10.1186/1742-4933-5-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Provinciali M et al (1998) Effect of zinc or zinc plus arginine supplementation on antibody titre and lymphocyte subsets after influenza vaccination in elderly subjects: a randomized controlled trial. Age Ageing 27:715–722. https://doi.org/10.1093/ageing/27.6.715

    CAS  Article  PubMed  Google Scholar 

  36. Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA (2018) Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol 9:586. https://doi.org/10.3389/fimmu.2018.00586

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Reider CA, Chung RY, Devarshi PP, Grant RW, Hazels Mitmesser S (2020) Inadequacy of immune health nutrients: intakes in US adults, the 2005–2016 NHANES. Nutrients. https://doi.org/10.3390/nu12061735

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rodriguez-Caballero A, Garcia-Montero AC, Bueno C, Almeida J, Varro R, Chen R, Pandiella A, Orfao A (2004) A new simple whole blood flow cytometry-based method for simultaneous identification of activated cells and quantitative evaluation of cytokines released during activation. Lab Invest 84:1387–1398. https://doi.org/10.1038/labinvest.3700162

    CAS  Article  PubMed  Google Scholar 

  39. Schuerwegh AJ, De Clerck LS, Bridts CH, Stevens WJ (2003) Comparison of intracellular cytokine production with extracellular cytokine levels using two flow cytometric techniques. Cytometry B 55:52–58. https://doi.org/10.1002/cyto.b.10041

    CAS  Article  Google Scholar 

  40. Shlisky J et al (2017) Nutritional considerations for healthy aging and reduction in age-related chronic disease. Adv Nutr 8:17–26. https://doi.org/10.3945/an.116.013474

    Article  PubMed  PubMed Central  Google Scholar 

  41. Song Y, Leonard SW, Traber MG, Ho E (2009) Zinc deficiency affects DNA damage, oxidative stress, antioxidant defenses, and DNA repair in rats. J Nutr 139:1626–1631. https://doi.org/10.3945/jn.109.106369

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Swain S, Clise-Dwyer K, Haynes L (2005) Homeostasis and the age-associated defect of CD4 T cells. Semin Immunol 17:370–377. https://doi.org/10.1016/j.smim.2005.05.007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Tateda K, Matsumoto T, Miyazaki S, Yamaguchi K (1996) Lipopolysaccharide-induced lethality and cytokine production in aged mice. Infect Immun 64:769–774

    CAS  Article  Google Scholar 

  44. Thevaranjan N et al (2017) Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21(455–466):e454. https://doi.org/10.1016/j.chom.2017.03.002

    CAS  Article  Google Scholar 

  45. Thomas R, Wang W, Su DM (2020) Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun Ageing 17:2. https://doi.org/10.1186/s12979-020-0173-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Tibbs TN, Lopez LR, Arthur JC (2019) The influence of the microbiota on immune development, chronic inflammation, and cancer in the context of aging. Microb Cell 6:324–334. https://doi.org/10.15698/mic2019.08.685

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Tsukamoto H, Senju S, Matsumura K, Swain SL, Nishimura Y (2015) IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age. Nat Commun 6:6702. https://doi.org/10.1038/ncomms7702

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Turnlund JR, Durkin N, Costa F, Margen S (1986) Stable isotope studies of zinc absorption and retention in young and elderly men. J Nutr 116:1239–1247. https://doi.org/10.1093/jn/116.7.1239

    CAS  Article  PubMed  Google Scholar 

  49. Wang H et al (2020) BRD4 contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake. Aging (Albany NY) 12:9240–9259. https://doi.org/10.18632/aging.103200

    CAS  Article  Google Scholar 

  50. Wessells KR, Brown KH (2012) Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting. PLoS ONE 7:e50568. https://doi.org/10.1371/journal.pone.0050568

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Wong CP, Magnusson KR, Ho E (2013) Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation. J Nutr Biochem 24:353–359. https://doi.org/10.1016/j.jnutbio.2012.07.005

    CAS  Article  PubMed  Google Scholar 

  52. Wong CP, Song Y, Elias VD, Magnusson KR, Ho E (2009) Zinc supplementation increases zinc status and thymopoiesis in aged mice. J Nutr 139:1393–1397. https://doi.org/10.3945/jn.109.106021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Wong CP, Rinaldi NA, Ho E (2015) Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation. Mol Nutr Food Res 59:991–999. https://doi.org/10.1002/mnfr.201400761

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Wong CP, Dashner-Titus EJ, Alvarez SC, Chase TT, Hudson LG, Ho E (2019) Zinc deficiency and arsenic exposure can act both independently or cooperatively to affect zinc status, oxidative stress, and inflammatory response. Biol Trace Elem Res 191:370–381. https://doi.org/10.1007/s12011-019-1631-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Wu D, Lewis ED, Pae M, Meydani SN (2018) Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance. Front Immunol 9:3160. https://doi.org/10.3389/fimmu.2018.03160

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Adam Branscum, Professor and Program Director of Biostatistics at Oregon State University for providing expert consultation regarding statistical analysis approach and data interpretation. This work was supported by United States Department of Agriculture National Institute of Food and Agriculture (NIFA-2018-67017-27358), as well as funding from Oregon Agricultural Experimental Station (OR00735).

Funding

United States Department of Agriculture National Institute of Food and Agriculture (NIFA-2018-67017-27358), and Oregon Agricultural Experimental Station (OR00735).

Author information

Affiliations

Authors

Contributions

CPW: conceptualization, methodology, investigation, validation, formal analysis, writing—original draft preparation; KRM: conceptualization, writing—original draft preparation; TJS: conceptualization, funding acquisition, methodology, writing—original draft preparation; EH: conceptualization, funding acquisition, supervision, methodology, writing—original draft preparation.

Corresponding author

Correspondence to Emily Ho.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The animal protocol was approved by the Oregon State University Institutional Laboratory Animal Care and Use Committee, and adhered to the international standards of animal care as established by the Association for Assessment and Accreditation of Laboratory Animal Care International.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wong, C.P., Magnusson, K.R., Sharpton, T.J. et al. Effects of zinc status on age-related T cell dysfunction and chronic inflammation. Biometals 34, 291–301 (2021). https://doi.org/10.1007/s10534-020-00279-5

Download citation

Keywords

  • Zinc
  • Aging
  • Inflammation
  • Immune dysfunction
  • T cells