Skip to main content

Advertisement

Log in

Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity

  • Review Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ″immune risk phenotype” (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abo T, Kawamura T, Watanabe H (2000) Physiological responses of extrathymic T cells in the liver. Immunol Rev 174:135–149

    Article  PubMed  CAS  Google Scholar 

  • Aspinall R (2000) Longevity and the immune response. Biogerontology 1:273–278

    Article  PubMed  CAS  Google Scholar 

  • Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, Pena J, Solana R (1999) NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol 34:253–265

    Article  PubMed  CAS  Google Scholar 

  • Bottino C, Moretta L, Moretta A (2006) NK cell activating receptors and tumor recognition in humans. Curr Top Microbiol Immunol 298:175–182

    PubMed  CAS  Google Scholar 

  • Bruunsgaard H, Pedersen AN, Schroll M, Skinhoj P, Pedersen BK (2001) Decreased natural killer cell activity is associated with atherosclerosis in elderly humans. Exp Gerontol 37:127–136

    Article  PubMed  CAS  Google Scholar 

  • Cakman I, Kirchner H, Rink L (1997) Zinc supplementation reconstitutes the production of interferon-alpha by leukocytes from elderly persons. J Interferon Cytokine Res 17:469–472

    Article  PubMed  CAS  Google Scholar 

  • Colonna-Romano G, Potestio M, Aquino A, Candore G, Lio D, Caruso C (2002) Gamma/delta T lymphocytes are affected in the elderly. Exp Gerontol 37:205–211

    Article  PubMed  CAS  Google Scholar 

  • Cumberbatch M, Dearman RJ, Kimber I (2002) Influence of ageing on Langerhans cell migration in mice: identification of a putative deficiency of epidermal interleukin-1beta. Immunology 105:466–477

    Article  PubMed  CAS  Google Scholar 

  • Dunne PJ, Faint JM, Gudgeon NH, Fletcher JM, Plunkett FJ, Soares MV, Hislop AD, Annels NE, Rickinson AB, Salmon M, Akbar AN (2002) Epstein–Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood 100:933–940

    Article  PubMed  CAS  Google Scholar 

  • Effros RB, Dagarag M, Spaulding C, Man J (2005) The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 205:147–157

    Article  PubMed  CAS  Google Scholar 

  • Fann M, Chiu WK, Wood WH III, Levine BL, Becker KG, Weng NP (2005) Gene expression characteristics of CD28 null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev 205:190–206

    Article  PubMed  CAS  Google Scholar 

  • Ferguson FG, Wikby A, Maxson P, Olsson J, Johansson B (1995) Immune parameters in a longitudinal study of a very old population of Swedish people: a comparison between survivors and nonsurvivors. J Gerontol A Biol Sci Med Sci 50:B378–B382

    PubMed  CAS  Google Scholar 

  • Fosmire GJ (1990) Zinc toxicity. Am J Clin Nutr 51:225–227

    PubMed  CAS  Google Scholar 

  • Franceschi C, Monti D, Sansoni P, Cossarizza A (1995) The immunology of exceptional individuals: the lesson of centenarians. Immunol Today 16:12–16

    Article  PubMed  CAS  Google Scholar 

  • Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafe M (1999) Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load. Exp Gerontol 34:911–921

    Article  PubMed  CAS  Google Scholar 

  • Goronzy JJ, Weyand CM (2005) T cell development and receptor diversity during aging. Curr Opin Immunol 17:468–475

    PubMed  CAS  Google Scholar 

  • Guma M, Angulo A, Lopez-Botet M (2006) NK cell receptors involved in the response to human cytomegalovirus infection. Curr Top Microbiol Immunol 298:207–223

    PubMed  CAS  Google Scholar 

  • Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G, thorStraten P, Wikby A (2006) Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol 176:2645–2653

    PubMed  CAS  Google Scholar 

  • Heller DA, Ahern FM, Stout JT, McClearn GE (1998) Mortality and biomarkers of aging in heterogeneous stock (HS) mice. J Gerontol Ser A Biol Sci Med 53:B217–B230

    CAS  Google Scholar 

  • Herrero C, Marques L, Lloberas J, Celada A (2001) IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest 107:485–493

    Article  PubMed  CAS  Google Scholar 

  • Herrero C, Sebastian C, Marques L, Comalada M, Xaus J, Valledor AF, Lloberas J, Celada A (2002) Immunosenescence of macrophages: reduced MHC class II gene expression. Exp Gerontol 37:389–394

    Article  PubMed  CAS  Google Scholar 

  • Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA (2002) Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 169:1984–1992

    PubMed  CAS  Google Scholar 

  • Koch S, Solana R, Rosa OD, Pawelec G (2006) Human cytomegalovirus infection and T cell immunosenescence. Mech Ageing Dev 127:538–543

    Article  PubMed  CAS  Google Scholar 

  • Kutza J, Murasko DM (1994) Effects of aging on natural killer cell activity and activation by interleukin-2 and IFN-alpha. Cell Immunol 155:195–204

    Article  PubMed  CAS  Google Scholar 

  • Kutza J, Murasko DM (1996) Age-associated decline in IL-2 and IL-12 induction of LAK cell activity of human PBMC samples. Mech Ageing Dev 90:209–222

    Article  PubMed  CAS  Google Scholar 

  • Linton PJ, Li SP, Zhang Y, Bautista B, Huynh Q, Trinh T (2005) Intrinsic versus environmental influences on T-cell responses in aging. Immunol Rev 205:207–219

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Botet M, Angulo A, Guma M (2004) Natural killer cell receptors for major histocompatibility complex class I and related molecules in cytomegalovirus infection. Tissue Antigens 63:195–203

    Article  PubMed  CAS  Google Scholar 

  • Lung TL, Saurwein-Teissl M, Parson W, Schonitzer D, Grubeck-Loebenstein B (2000) Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells. Vaccine 18:1606–1612

    Article  PubMed  CAS  Google Scholar 

  • Lutz CT, Moore MB, Bradley S, Shelton BJ, Lutgendorf SK (2005) Reciprocal age related change in natural killer cell receptors for MHC class I. Mech Ageing Dev 126:722–731

    Article  PubMed  CAS  Google Scholar 

  • Mariani E, Monaco MC, Cattini L, Sinoppi M, Facchini A (1994) Distribution and lytic activity of NK cell subsets in the elderly. Mech Ageing Dev 76:177–187

    Article  PubMed  CAS  Google Scholar 

  • Mariani E, Mariani AR, Meneghetti A, Tarozzi A, Cocco L, Facchini A (1998a) Age-dependent decreases of NK cell phosphoinositide turnover during spontaneous but not Fc-mediated cytolytic activity. Int Immunol 10:981–989

    Article  PubMed  CAS  Google Scholar 

  • Mariani E, Ravaglia G, Meneghetti A, Tarozzi A, Forti P, Maioli F, Boschi F, Facchini A (1998b) Natural immunity and bone and muscle remodelling hormones in the elderly. Mech Ageing Dev 102:279–292

    Article  PubMed  CAS  Google Scholar 

  • Mariani E, Ravaglia G, Forti P, Meneghetti A, Tarozzi A, Maioli F, Boschi F, Pratelli L, Pizzoferrato A, Piras F, Facchini A (1999) Vitamin D, thyroid hormones and muscle mass influence natural killer (NK) innate immunity in healthy nonagenarians and centenarians. Clin Exp Immunol 116:19–27

    Article  PubMed  CAS  Google Scholar 

  • Mariani E, Meneghetti A, Neri S, Ravaglia G, Forti P, Cattini L, Facchini A (2002) Chemokine production by natural killer cells from nonagenarians. Eur J Immunol 32:1524–1529

    Article  PubMed  CAS  Google Scholar 

  • Miyaji C, Watanabe H, Toma H, Akisaka M, Tomiyama K, Sato Y, Abo T (2000) Functional alteration of granulocytes, NK cells, and natural killer T cells in centenarians. Hum Immunol 61:908–916

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Muzzioli M (2000a) Therapeutic application of zinc in human immunodeficiency virus against opportunistic infections. J Nutr 130(5S Suppl):1424S–1431S

    PubMed  CAS  Google Scholar 

  • Mocchegiani E, Muzzioli M, Giacconi R (2000b) Zinc, metallothioneins, immune responses, survival and ageing. Biogerontology 1:133–143

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Malavolta M (2004) NK and NKT cell functions in immunosenescence. Aging Cell 3:177–184

    Article  PubMed  CAS  Google Scholar 

  • 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 17:703–718

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Muzzioli M, Cipriano C, Giacconi R (1998) Zinc, T-cell pathways, aging: role of metallothioneins. Mech Ageing Dev 106:183–204

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Muzzioli M, Giacconi R, Cipriano C, Gasparini N, Franceschi C, Gaetti R, Cavalieri E, Suzuki H (2003) Metallothioneins/PARP-1/IL-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. Effect of zinc supply. Mech Ageing Dev 124:459–468

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Giacconi R, Muti E, Rogo C, Bracci M, Muzzioli M, Cipriano C, Malavolta M (2004a) Zinc, immune plasticity, aging, and successful aging: role of metallothionein. Ann N Y Acad Sci 1019:127–134

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Giacconi R, Cipriano C, Gasparini N, Bernardini G, Malavolta M, Menegazzi M, Cavalieri E, Muzzioli M, Ciampa AR, Suzuki H (2004b) The variations during the circadian cycle of liver CD1d-unrestricted NK1.1 + TCR gamma/delta+ cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice. Exp Gerontol 39:775–788

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Marcellini F, Pawelec G (2004c) Nutritional zinc, oxidative stress and immunosenescence: biochemical, genetic, and lifestyle implications for healthy ageing. Biogerontology 5:271–273

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, Costarelli L, Giacconi R, Cipriano C, Muti E, Tesei S, Malavolta M (2006) Nutrient-gene interaction in ageing and successful ageing A single nutrient (zinc) and some target genes related to inflammatory/immune response. Mech Ageing Dev 127:517–525

    Article  PubMed  CAS  Google Scholar 

  • Murasko DM, Jiang J (2005) Response of aged mice to primary virus infections. Immunol Rev 205:285–296

    Article  PubMed  CAS  Google Scholar 

  • Mysliwska J, Trzonkowski P, Szmit E, Brydak LB, Machala M, Mysliwski A (2004) Immunomodulating effect of influenza vaccination in the elderly differing in health status. Exp Gerontol 39:1447–1458

    Article  PubMed  CAS  Google Scholar 

  • 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 124:469–476

    Article  PubMed  Google Scholar 

  • Ogata K, Yokose N, Tamura H, An E, Nakamura K, Dan K, Nomura T (1997) Natural killer cells in the late decades of human life. Clin Immunol Immunopathol 84:269–275

    Article  PubMed  CAS  Google Scholar 

  • Ogata K, An E, Shioi Y, Nakamura K, Luo S, Yokose N, Minami S, Dan K (2001) Association between natural killer cell activity and infection in immunologically normal elderly people. Clin Exp Immunol 124:392–397

    Article  PubMed  CAS  Google Scholar 

  • Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, Muller CA, Pircher H, Pawelec G (2003a) Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp Gerontol 38:911–920

    Article  PubMed  CAS  Google Scholar 

  • Ouyang Q, Wagner WM, Wikby A, Walter S, Aubert G, Dodi AI, Travers P, Pawelec G (2003b) Large numbers of dysfunctional CD8+ T lymphocytes bearing receptors for a single dominant CMV epitope in the very old. J Clin Immunol 23:247–257

    Article  PubMed  CAS  Google Scholar 

  • 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 39:607–613

    Article  PubMed  CAS  Google Scholar 

  • Pawelec G, Solana R, Remarque E, Mariani E (1998) Impact of aging on innate immunity. J Leukoc Biol 64:703–712

    PubMed  CAS  Google Scholar 

  • 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:d1056–d1183

    PubMed  CAS  Google Scholar 

  • Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A (2005) Human immunosenescence: is it infectious? Immunol Rev 205:257–268

    Article  PubMed  CAS  Google Scholar 

  • Piantanelli L, Fabris N (1978) Hypopituitary dwarf and athymic nude mice and the study of the relationships among thymus, hormones and aging. In: Bergsma D, Harrison DE (eds) Genetic effect of aging. Alan R. Liss Inc., New York, pp 315–333

    Google Scholar 

  • Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S (2004) Innate immunity in aging: impact on macrophage function. Aging Cell 3:161–167

    Article  PubMed  CAS  Google Scholar 

  • Ravaglia G, Forti P, Maioli F, Bastagli L, Facchini A, Mariani E, Savarino L, Sassi S, Cucinotta D, Lenaz G (2000) Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged >/=90 y. Am J Clin Nutr 71:590–598

    PubMed  CAS  Google Scholar 

  • Remarque E, Pawelec G (1998) T cell immunosenescence and its clinical relevance in man. Rev Clin Gerontol 8:5–14

    Article  Google Scholar 

  • Rink L, Kirchner H (2000) Zinc-altered immune function and cytokine production. J Nutr 130(5S Suppl):1407S–1411S

    PubMed  CAS  Google Scholar 

  • Sansoni P, Brianti V, Fagnoni F, Snelli G, Marcato A, Passeri G, Monti D, Cossarizza A, Franceschi C (1992) NK cell activity and T-lymphocyte proliferation in healthy centenarians. Ann NY Acad Sci 663:505–507

    PubMed  CAS  Google Scholar 

  • Sansoni P, Cossarizza A, Brianti V, Fagnoni F, Snelli G, Monti D, Marcato A, Passeri G, Ortolani C, Forti E, Franceschi C (1993) Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 82:2767–2773

    PubMed  CAS  Google Scholar 

  • Saurwein-Teissl M, Romani N, Grubeck-Loebenstein B (2000) Dendritic cells in old age—neglected by gerontology? Mech Ageing Dev 121:123–130

    Article  PubMed  CAS  Google Scholar 

  • Sebastian C, Espia M, Serra M, Celada A, Lloberas J (2005) MacrophAging: a cellular and molecular review. Immunobiology 210:121–126

    Article  PubMed  CAS  Google Scholar 

  • Solana R, Mariani E (2000) NK and NK/T cells in human senescence. Vaccine 18:1613–1620

    Article  PubMed  CAS  Google Scholar 

  • Solana R, Alonso MC, Pena J (1999) Natural killer cells in healthy aging. Exp Gerontol 34:435–443

    Article  PubMed  CAS  Google Scholar 

  • Solana R, Pawelec G, Tarazona R (2006) Aging and innate immunity. Immunity 24:491–494

    Article  PubMed  CAS  Google Scholar 

  • Spaulding C, Guo W, Effros RB (1999) Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 34:633–644

    Article  PubMed  CAS  Google Scholar 

  • Stout RD, Suttles J (2005) Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev 205:60–71

    Article  PubMed  CAS  Google Scholar 

  • Tarazona R, Delarosa O, Alonso C, Ostos B, Espejo J, Pena J, Solana R (2000) Increased expression of NK cell markers on T lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T cells. Mech Ageing Dev 121:77–88

    Article  PubMed  CAS  Google Scholar 

  • Tarazona R, Solana R, Ouyang Q, Pawelec G (2002) Basic biology and clinical impact of immunosenescence. Exp Gerontol 37:183–189

    Article  PubMed  Google Scholar 

  • Uyemura K, Castle SC, Makinodan T (2002) The frail elderly: role of dendritic cells in the susceptibility of infection. Mech Ageing Dev 123:955–962

    Article  PubMed  CAS  Google Scholar 

  • Vescovini R, Telera A, Fagnoni FF, Biasini C, Medici MC, Valcavi P, Lucchini G, Zanlari L, Passeri G, Zanni F, Chezzi C, Franceschi C, Sansoni P (2004) Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. Exp Gerontol 39:1233–1243

    Article  PubMed  Google Scholar 

  • Villanueva JL, Solana R, Alonso MC, Pena J (1990) Changes in the expression of HLA-class II antigens on peripheral blood monocytes from aged humans. Dis Markers 8:85–91

    PubMed  CAS  Google Scholar 

  • Voehringer D, Koschella M, Pircher H (2002) Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood 100:3698–3702

    Article  PubMed  CAS  Google Scholar 

  • Wellinghausen N, Kirchner H, Rink L (1997) The immunobiology of zinc. Immunol Today 18:519–521

    Article  PubMed  CAS  Google Scholar 

  • Weng NP (2006) Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24:495–499

    Article  PubMed  CAS  Google Scholar 

  • Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B (2005) An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci 60:556–565

    PubMed  Google Scholar 

  • Zissel G, Schlaak M, Muller-Quernheim J (1999) Age-related decrease in accessory cell function of human alveolar macrophages. J Investig Med 47:51–56

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Work in the laboratories of R.S., G.P. and R.T. was supported by grants FIS03/1383, DFG-SFB685-B4 and SAF03/05184, respectively and by the 5th Framework Program project T-CIA (EU-QLK6-CT-2002-02283) (O.R., R.S., G.P., A.W.) and the 6th FP project ZINCAGE (FOOD-CT-2003-506850) (E.M., G.P., E.M.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rafael Solana.

Rights and permissions

Reprints and permissions

About this article

Cite this article

DelaRosa, O., Pawelec, G., Peralbo, E. et al. Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology 7, 471–481 (2006). https://doi.org/10.1007/s10522-006-9062-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-006-9062-6

Keywords

Navigation