Biogerontology

, Volume 7, Issue 5–6, pp 399–408 | Cite as

The heat shock proteins in cellular aging: is zinc the missing link?

  • Anis Larbi
  • Juergen Kempf
  • Kilian Wistuba-Hamprecht
  • Constantin Haug
  • Graham Pawelec
Review Article

Abstract

T-cell functions are critical for the efficiency of the adaptive immune response. It is now clear that aging is associated with changes in the T-cell response to antigenic stimulation, one of the many changes collectively resulting in immune senescence. Several hypotheses have been proposed to explain such changes. We believe that chronic stimulation of T-cells enhances the appearance of apoptosis-resistant anergic dysfunctional cells; in humans in vivo these are predominantly specific for antigens of persistent viruses, especially CMV. Concomitantly, age-associated zinc deficiency is common and one hypothesis is that lack of zinc bioavailability contributes to impaired T-cell function. This could further compromise the integrity of T-cells under chronic antigenic stress, which can be modelled in long-term clonal cultures in vitro. Newly synthesized heat-shock proteins (HSPs) protect the cellular proteins from degradation under such conditions. In this short review we will briefly outline the role of heat-shock proteins and zinc deficiency in aging in order to finally discuss our own results in the context of a link between HSPs, aging and zinc.

Notes

Acknowledgement

This work was supported by Zincage, contract FOOD–CT–2003-506850.

References

  1. Adewoye AH, McMahon L (2005) Chaperones and disease. N Engl J Med 353:2821–2822PubMedCrossRefGoogle Scholar
  2. Alsbury S, Papageorgiou K, Latchman DS (2004) Heat shock proteins can protect aged human and rodent cells from different stressful stimuli. Mech Ageing Dev 125:201–209PubMedCrossRefGoogle Scholar
  3. Beck FW, Kaplan J, Fine N, Handschu W, Prasad AS (1997a) Decreased expression of CD73 (ecto-5’-nucleotidase) in the CD8+ subset is associated with zinc deficiency in human patients. J Lab Clin Med 130:147–156CrossRefGoogle Scholar
  4. Beck FW, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ (1997b) Changes in cytokine production and T-cell subpopulations in experimentally induced zinc-deficient humans. Am J Physiol 272:E1002–1007Google Scholar
  5. Bijur GN, Jope RS (2000) Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3beta in the regulation of HSF-1 activity. J Neurochem 75:2401–2408PubMedCrossRefGoogle Scholar
  6. Burdon RH (1987) Temperature and animal cell protein synthesis. Symp Soc Exp Biol 41:113–133PubMedGoogle Scholar
  7. Chang KM, Thimme R, Melpolder JJ, Oldach D, Pemberton J, Moorhead-Loudis J, McHutchison JG, Alter HJ, Chisari FV (2001) Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection. Hepatology 33:267–276PubMedCrossRefGoogle Scholar
  8. Chaplin DD (2006) Overview of the human immune response. J Allergy Clin Immunol 117:S430-S435PubMedCrossRefGoogle Scholar
  9. Chaudhuri S, Jana B, Basu T (2006) Why does ethanol induce cellular heat-shock response? Cell Biol Toxicol 22:29–37PubMedCrossRefGoogle Scholar
  10. Chazot G, Broussolle E (1993) Alterations in trace elements during brain aging and in Alzheimer’s dementia. Prog Clin Biol Res 380:269–281PubMedGoogle Scholar
  11. Chiu PY, Leung HY, Poon MK, Ko KM (2006) Chronic schisandrin B treatment improves mitochondrial antioxidant status and tissue heat shock protein production in various tissues of young adult and middle-aged rats. Biogerontology (in press)Google Scholar
  12. Christians ES, Zhou Q, Renard J, Benjamin IJ (2003) Heat shock proteins in mammalian development. Semin Cell Dev Biol 14:283–290PubMedCrossRefGoogle Scholar
  13. Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103PubMedCrossRefGoogle Scholar
  14. Dai R, Frejtag W, He B, Zhang Y, Mivechi NF (2000) c-Jun NH2-terminal kinase targeting and phosphorylation of heat shock factor-1 suppress its transcriptional activity. J Biol Chem 275:18210–18218PubMedCrossRefGoogle Scholar
  15. Deguchi Y, Negoro S, Kishimoto S (1988) Age-related changes of heat shock protein gene transcription in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 157:580–584PubMedCrossRefGoogle Scholar
  16. DeVeale B, Brummel T, Seroude L (2004) Immunity and aging: the enemy within? Aging Cell 3:195–208PubMedCrossRefGoogle Scholar
  17. Dickey CA, Dunmore J, Lu B, Wang JW, Lee WC, Kamal A, Burrows F, Eckman C, Hutton M, Petrucelli L (2006) HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J 20:753–755PubMedGoogle Scholar
  18. Effros RB, Pawelec G (1997) Replicative senescence of T cells: does the Hayflick limit lead to immune exhaustion? Immunol Today 18:450–454PubMedCrossRefGoogle Scholar
  19. Effros RB, Zhu X, Walford RL (1994) Stress response of senescent T lymphocytes: reduced hsp70 is independent of the proliferative block. J Gerontol 49:B65–B70PubMedGoogle Scholar
  20. Eustace BK, Jay DG (2004) Extracellular roles for the molecular chaperone, hsp90. Cell Cycle 3:1098–1100PubMedGoogle Scholar
  21. Fabris N (1994) Neuroendocrine-immune aging: an integrative view on the role of zinc. Ann N Y Acad Sci 719:353–368PubMedGoogle Scholar
  22. Fonager J, Beedholm R, Clark BF, Rattan SI (2002) Mild stress-induced stimulation of heat-shock protein synthesis and improved functional ability of human fibroblasts undergoing aging in vitro. Exp Gerontol 37:1223–1228PubMedCrossRefGoogle Scholar
  23. Gabai VL, Meriin AB, Yaglom JA, Volloch VZ, Sherman MY (1998) Role of Hsp70 in regulation of stress-kinase JNK: implications in apoptosis and aging. FEBS Lett 438:1–4PubMedCrossRefGoogle Scholar
  24. Garrido C, Solary E (2003) A role of HSPs in apoptosis through “protein triage”? Cell Death Differ 10:619–620PubMedCrossRefGoogle Scholar
  25. Ginaldi L, De Martinis M, Monti D, Franceschi C (2004) The immune system in the elderly: activation-induced and damage-induced apoptosis. Immunol Res 30:81–94PubMedCrossRefGoogle Scholar
  26. Good RA (1981) Nutrition and immunity. J Clin Immunol 1:3–11PubMedCrossRefGoogle Scholar
  27. Gothard LQ, Ruffner ME, Woodward JG, Park-Sarge OK, Sarge KD (2003) Lowered temperature set point for activation of the cellular stress response in T-lymphocytes. J Biol Chem 278:9322–9326PubMedCrossRefGoogle Scholar
  28. Gupta S, Bi R, Kim C, Chiplunkar S, Yel L, Gollapudi S (2005) Role of NF-kappaB signaling pathway in increased tumor necrosis factor-alpha-induced apoptosis of lymphocytes in aged humans. Cell Death Differ 12:177–183PubMedCrossRefGoogle Scholar
  29. Hampel B, Fortschegger K, Ressler S, Chang MW, Unterluggauer H, Breitwieser A, Sommergruber W, Fitzky B, Lepperdinger G, Jansen-Durr P, Voglauer R, Grillari J (2006) Increased expression of extracellular proteins as a hallmark of human endothelial cell in vitro senesence. Exp Gerontol (in press)Google Scholar
  30. Hansen MA, Fernandes G, Good RA (1982) Nutrition and immunity: the influence of diet on autoimmunity and the role of zinc in the immune response. Annu Rev Nutr 2:151–177PubMedCrossRefGoogle Scholar
  31. Hardcastle A, Boxall K, Richards J, Tomlin P, Sharp S, Clarke P, Workman P, Aherne W (2005) Solid-phase immunoassays in mechanism-based drug discovery: their application in the development of inhibitors of the molecular chaperone heat-shock protein 90. Assay Drug Dev Technol 3:273–285PubMedCrossRefGoogle Scholar
  32. Hatayama T, Hayakawa M (1999) Differential temperature dependency of chemical stressors in HSF1-mediated stress response in mammalian cells. Biochem Biophys Res Commun 265:763–769PubMedCrossRefGoogle Scholar
  33. He HT, Lellouch A, Marguet D (2005) Lipid rafts and the initiation of T-cell receptor signaling. Semin Immunol 17:23–33PubMedCrossRefGoogle Scholar
  34. Higashi T, Takechi H, Uemura Y, Kikuchi H, Nagata K (1994) Differential induction of mRNA species encoding several classes of stress proteins following focal cerebral ischemia in rats. Brain Res 650:239–248PubMedCrossRefGoogle Scholar
  35. Holtkamp W, Brodersen HP, Stollberg T, Thiery J, Falkner C (1993) Zinc supplementation stimulates tetanus antibody formation and soluble interleukin-2 receptor levels in chronic hemodialysis patients. Clin Investig 71:537–541PubMedCrossRefGoogle Scholar
  36. Hunter-Lavin C, Davies EL, Bacelar MM, Marshall MJ, Andrew SM, Williams JH (2004) Hsp70 release from peripheral blood mononuclear cells. Biochem Biophys Res Commun 324:511–517PubMedCrossRefGoogle Scholar
  37. Imai J, Yashiroda H, Maruya M, Yahara I, Tanaka K (2003) Proteasomes and molecular chaperones: cellular machinery responsible for folding and destruction of unfolded proteins. Cell Cycle 2:585–590PubMedGoogle Scholar
  38. Jin X, Wang R, Xiao C, Cheng L, Wang F, Yang L, Feng T, Chen M, Chen S, Fu X, Deng J, Wang R, Tang F, Wei Q, Tanguay RM, Wu T (2004) Serum and lymphocyte levels of heat shock protein 70 in aging: a study in the normal Chinese population. Cell Stress Chaperones 9:69–75PubMedCrossRefGoogle Scholar
  39. Kelly KJ (2005) Heat shock (stress response) proteins and renal ischemia/reperfusion injury. Contrib Nephrol 148:86–106PubMedCrossRefGoogle Scholar
  40. Killilea DW, Atamna H, Liao C, Ames BN (2003) Iron accumulation during cellular senescence in human fibroblasts in vitro. Antioxid Redox Signal 5:507–516PubMedCrossRefGoogle Scholar
  41. King LE, Frentzel JW, Mann JJ, Fraker PJ (2005) Chronic zinc deficiency in mice disrupted T-cell lymphopoiesis and erythropoiesis while B cell lymphopoiesis and myelopoiesis were maintained. J Am Coll Nutr 24:494–502PubMedGoogle Scholar
  42. Larbi A, Douziech N, Dupuis G, Khalil A, Pelletier H, Guerard KP, Fulop T Jr (2004) Age-associated alterations in the recruitment of signal-transduction proteins to lipid rafts in human T lymphocytes. J Leuk Biol 75:373–381CrossRefGoogle Scholar
  43. Larbi A, Dupuis G, Khalil A, Douziech N, Fortin C, Fulop T Jr (2006) Differential role of lipid rafts in the functions of CD4+ and CD8+ human T lymphocytes with aging. Cell Signal 18:1017–1030PubMedCrossRefGoogle Scholar
  44. Leis HP Jr (1991) The relationship of diet to cancer, cardiovascular disease and longevity. Int Surg 76:1–5PubMedGoogle Scholar
  45. Lepage LM, Giesbrecht JA, Taylor CG (1999) Expression of T lymphocyte p56(lck), a zinc-finger signal transduction protein, is elevated by dietary zinc deficiency and diet restriction in mice. J Nutr 129:620–627PubMedGoogle Scholar
  46. Lindeman RD, Clark ML, Colmore JP (1971) Influence of age and sex on plasma and red-cell zinc concentrations. J Gerontol 26:358–363PubMedGoogle Scholar
  47. Lindholm H (1956) Studies in normal adults for variation in zinc turbidity test with sex and age. Scand J Clin Lab Invest 8:340–1PubMedGoogle Scholar
  48. Liu AY, Bae-Lee MS, Choi HS, Li BS (1989) Heat shock induction of HSP89 is regulated in cellular aging. Biochem Biophys Res Commun 162: 1302–1310PubMedCrossRefGoogle Scholar
  49. Macario AJ (1995) Heat-shock proteins and molecular chaperones: implications for pathogenesis, diagnostics, and therapeutics. Int J Clin Lab Res 25:59–70PubMedGoogle Scholar
  50. Maczek C, Bock G, Jurgens G, Schonitzer D, Dietrich H, Wick G (1998) Environmental influence on age-related changes of human lymphocyte membrane viscosity using severe combined immunodeficiency mice as an in vivo model. Exp Gerontol 33:485–498PubMedCrossRefGoogle Scholar
  51. Maglara AA, Vasilaki A, Jackson MJ, McArdle A (2003) Damage to developing mouse skeletal muscle myotubes in culture: protective effect of heat shock proteins. J Physiol 548:837–846PubMedCrossRefGoogle Scholar
  52. Mocchegiani E, Santarelli L, Muzzioli M, Fabris N (1995) Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice. Int J Immunopharmacol 17:703–718PubMedCrossRefGoogle Scholar
  53. Morley JE, Mooradian AD, Silver AJ, Heber D, Alfin-Slater RB (1988) Nutrition in the elderly. Ann Intern Med 109:890–904PubMedGoogle Scholar
  54. Muramatsu T, Hatoko M, Tada H, Shirai T, Ohnishi T (1996) Age-related decrease in the inductability of heat shock protein 72 in normal human skin. Br J Dermatol 134:1035–1038PubMedCrossRefGoogle Scholar
  55. Nagayama S, Jono H, Suzaki H, Sakai K, Tsuruya E, Yamatsu I, Isohama Y, Miyata T, Kai H (2001) Carbenoxolone, a new inducer of heat shock protein 70. Life Sci 69:2867–2873PubMedCrossRefGoogle Scholar
  56. Nilsson BO, Ernerudh J, Johansson B, Evrin PE, Lofgren S, Ferguson FG, Wikby A (2003) Morbidity does not influence the T-cell immune risk phenotype in the elderly: findings in the Swedish NONA Immune Study using sample selection protocols. Mech Ageing Dev 124:469–476PubMedCrossRefGoogle Scholar
  57. Nizard C, Noblesse E, Boisde C, Moreau M, Faussat AM, Schnebert S, Mahe C (2004) Heat shock protein 47 expression in aged normal human fibroblasts: modulation by Salix alba extract. Ann N Y Acad Sci 1019:223–227PubMedCrossRefGoogle Scholar
  58. Njemini R, Abeele MV, Demanet C, Lambert M, Vandebosch S, Mets T (2002) Age-related decrease in the inducibility of heat-shock protein 70 in human peripheral blood mononuclear cells. J Clin Immunol 22:195–205PubMedCrossRefGoogle Scholar
  59. Njemini R, Lambert M, Demanet C, Vanden Abeele M, Vandebosch S, Mets T (2003) The induction of heat shock protein 70 in peripheral mononuclear blood cells in elderly patients: a role for inflammatory markers. Hum Immunol 64:575–585PubMedGoogle Scholar
  60. Ohsawa M, Otsuka F, Sugizaki S (1992) Zinc status in proliferative response of T lymphocytes. J Nutr Sci Vitaminol 518–521Google Scholar
  61. Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G (2004) Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol 39:607–613PubMedCrossRefGoogle Scholar
  62. Pawelec G, Akbar A, Caruso C, Effros R, Grubeck-Loebenstein B, Wikby A (2004) Is immunosenescence infectious? Trends Immunol 25:406–410PubMedCrossRefGoogle Scholar
  63. Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A, McLeod J, Caruso C, Franceschi C, Fulop T, Gupta S, Mariani E, Mocchegiani E, Solana R (2002) T cells and aging, January 2002 update. Front Biosci 7:1056–1183Google Scholar
  64. Pawelec G, Rehbein A, Haehnel K, Merl A, Adibzadeh M (1997) Human T-cell clones in long-term culture as a model of immunosenescence. Immunol Rev 160:31–42PubMedCrossRefGoogle Scholar
  65. Pawelec G, Remarque E, Barnett Y, Solana R (1998) T cells and aging. Front Biosci 3:59–99Google Scholar
  66. Plowden J, Renshaw-Hoelscher M, Gangappa S, Engleman C, Katz JM, Sambhara S (2004) Impaired antigen-induced CD8+ T-cell clonal expansion in aging is due to defects in antigen presenting cell function. Cell Immunol 229:86–92PubMedCrossRefGoogle Scholar
  67. Prasad AS (1985) Clinical and biochemical manifestation zinc deficiency in human subjects. J Pharmacol 16:344–352PubMedGoogle Scholar
  68. Prasad AS, Bao B, Beck FW, Sarkar FH (2002) Zinc enhances the expression of interleukin-2 and interleukin-2 receptors in HUT-78 cells by way of NF-kappaB activation. J Lab Clin Med 140:272–289PubMedCrossRefGoogle Scholar
  69. Prelog M (2006) Aging of the immune system: a risk factor for autoimmunity? Autoimmun Rev 5:136–139PubMedCrossRefGoogle Scholar
  70. Rao DV, Watson K, Jones GL (1999) Age-related attenuation in the expression of the major heat shock proteins in human peripheral lymphocytes. Mech Ageing Dev 107:105–118PubMedCrossRefGoogle Scholar
  71. Ryan M, Levy MM (2003) Clinical review: fever in intensive care unit patients. Crit Care 7:221–225PubMedCrossRefGoogle Scholar
  72. Samali A, Robertson JD, Peterson E, Manero F, van Zeijl L, Paul C, Cotgreave IA, Arrigo AP, Orrenius S. (2001) Hsp27 protects mitochondria of thermotolerant cells against apoptotic stimuli. Cell Stress Chaperones 6: 49–58PubMedCrossRefGoogle Scholar
  73. Santos-Neto L, Tosta CE, Dorea JG (1992) Zinc reverses the increased sensitivity of lymphocytes from aged subjects to the antiproliferative effect of prostaglandin E2. Clin Immunol Immunopathol 64:184–187PubMedCrossRefGoogle Scholar
  74. Savarino L, Granchi D, Ciapetti G, Cenni E, Ravaglia G, Forti P, Maioli F, Mattioli R (2001) Serum concentrations of zinc and selenium in elderly people: results in healthy nonagenarians/centenarians. Exp Gerontol 36:327–339PubMedCrossRefGoogle Scholar
  75. Shaw AR, Li L (2003) Exploration of the functional proteome: lessons from lipid rafts. Curr Opin Mol Ther 5:294–301PubMedGoogle Scholar
  76. Solana R, Pawelec G, Tarazona R (2006) Aging and Innate Immunity. Immunity 24:1–4CrossRefGoogle Scholar
  77. Sprietsma JE (1997) Zinc-controlled Th1/Th2 switch significantly determines development of diseases. Med Hypotheses 49:1–14PubMedCrossRefGoogle Scholar
  78. Sreedhar AS, Csermely P (2004) Heat shock proteins in the regulation of apoptosis: new strategies in tumor therapy: a comprehensive review. Pharmacol Ther 101:227–257PubMedCrossRefGoogle Scholar
  79. Stephanou A, Latchman DS, Isenberg DA (1998) The regulation of heat shock proteins and their role in systemic lupus erythematosus. Semin Arthritis Rheum 28:155–162PubMedCrossRefGoogle Scholar
  80. Terry DF, McCormick M, Andersen S, Pennington J, Schoenhofen E, Palaima E, Bausero M, Ogawa K, Perls TT, Asea A (2004) Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann N Y Acad 1019:502–505CrossRefGoogle Scholar
  81. Trinklein ND, Chen WC, Kingston RE, Myers RM (2004) Transcriptional regulation and binding of heat shock factor 1 and heat shock factor 2 to 32 human heat shock genes during thermal stress and differentiation. Cell Stress Chaperones 9:21–28PubMedCrossRefGoogle Scholar
  82. Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118PubMedGoogle Scholar
  83. Verbeke P, Clark BF, Rattan SI (2000) Modulating cellular aging in vitro: hormetic effects of repeated mild heat stress on protein oxidation and glycation. Exp Gerontol 35:787–794PubMedCrossRefGoogle Scholar
  84. Verbeke P, Clark BF, Rattan SI (2001) Reduced levels of oxidized and glycoxidized proteins in human fibroblasts exposed to repeated mild heat shock during serial passaging in vitro. Free Radic Biol Med 31:1593–1602PubMedCrossRefGoogle Scholar
  85. Verstraeten SV, Zago MP, MacKenzie GG, Keen CL, Oteiza PI (2004) Influence of zinc deficiency on cell-membrane fluidity in Jurkat, 3T3 and IMR-32 cells. Biochem J 378:579–587PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Anis Larbi
    • 1
  • Juergen Kempf
    • 1
  • Kilian Wistuba-Hamprecht
    • 1
  • Constantin Haug
    • 1
  • Graham Pawelec
    • 1
  1. 1.Center for Medical Research, Tüebingen Aging and Tumor Immunology groupUniversity of TüebingenTüebingenGermany

Personalised recommendations