Skip to main content

Advertisement

Log in

Cell proliferation and apoptosis in the immune system in the elderly

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Loss of the cell proliferative capability and involution of tissues and organs are among the most important phenomena that characterize the aging process. Some of the aged-linked immune dysfunctions could be partly due to a dysregulation of apoptotic processes and to a lower responsiveness of aged lymphoid cells to activation and proliferation signals. The main changes in proliferative activity and cell death during aging and their impact on the process of immunosenescence are discussed. In fact, a very important function that has been suggested to deteriorate with age and to play a major role in the aging process is the capability of cells from aged subjects to respond to mitogenic stimuli and, consequently, to undergo cell proliferation. However, the cellular activation processes are very complex and the proliferative responses can follow different interconnected signal transduction pathways, and only some of them appear to be modified during age. Moreover, cell growth, immunosenescence, and longevity are strictly interconnected and deeply related to programmed cell death or apoptosis. The cellular equilibrium between cell survival and proliferation, on the one hand, and programmed cell death, on the other hand, seems to be unbalanced with advancing age, although in each type of immune cell it could be differentially modulated, resulting in a variety of clincopathological consequences. Thus, cell proliferation and cell death are two physiologically active phenomena closely linked and regulated and a failure of these mechanisms determines profound dysregulations of cell homeostasis with major consequences in immune functioning and the onset of autoimmune diseases and cancer, whose incidence appears to be increased in the elderly.

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.

Similar content being viewed by others

References

  1. Franceschi C: Cell proliferation, cell death and aging. Aging 1989;1:3–15.

    PubMed  CAS  Google Scholar 

  2. Franceschi C, Monti D, Sansoni P, Cossarizza A: The immunology of exceptional individuals: the lesson of centerarians. Immunol Today 1995;16:12–16.

    Article  PubMed  CAS  Google Scholar 

  3. Quaglino D, Ginaldi L, Furia N, De Martinis M: The effect of age on hemopoiesis. Aging Clin Exp Res 1996;8:1–12.

    CAS  Google Scholar 

  4. Wakikawa A, Utsuyama M, Hirokawa K: Altered expression of various receptors on T cells in young and old mice after mitogenics stimulation: a flow cytometric analysis. Mech Ageing Dev 1997;94:113–122.

    Article  PubMed  CAS  Google Scholar 

  5. Cristofalo VJ, Pignolo RJ: Replicative senescence of human fibroblast-like cells in culture. Phisiol, 1992;Rev 73:795–808.

    Google Scholar 

  6. Cossarizza A, Ortolani C, Monti D, Franceschi C: Cytometric analysis of immunosenescence. Cytometry 1997;27:297–213.

    Article  PubMed  CAS  Google Scholar 

  7. Pawelec G, Rehbein A, Haehnel K, Merl A, Adibzadeh M: Human T-cell clones in long-term culture as a model of immunosenescence. Immunol Rev 1997;160:31–42.

    Article  PubMed  CAS  Google Scholar 

  8. Weng N, Palmer LD, Levine BL, Lane HC, June CH, Hodes RJ: Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activational aging. Immunol Rev 1997;160:43–54.

    Article  PubMed  CAS  Google Scholar 

  9. Pawelec G, Adidzadeh M, Solana R, Beckman I: The T cell in the ageing individual. Mech Ageing Dev 1997;93:35–45.

    Article  PubMed  CAS  Google Scholar 

  10. Adibzadeh M, Pohla H, Rehbein A, Pawelec G: Long-term culture of monoclonal human T-lymphocytes: models for immunosenescence. Mech Ageing Dev 1995;83:171–183.

    Article  PubMed  CAS  Google Scholar 

  11. Weng NP, Levine BL, June CH, Hodes RJ: Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc Natl Acad Sci USA 1995;92:11,091–11,094.

    CAS  Google Scholar 

  12. Effros RB: Insights on immunological aging derived from the T lymphocyte cellular senescence model. Exp Gerontol 1996;31:21–27.

    Article  PubMed  CAS  Google Scholar 

  13. Posnett DN, Sinha R, Kabak S, Russo C: Clonal populations of T cells in normal elderly humans— the T cell equivalent to benign monoclonal gammopathy. J Exp Med 1994;179:609–618.

    Article  PubMed  CAS  Google Scholar 

  14. Kannerer R, Iten A, Frei PC, Burgisser P: Expansion of T cells negative for CD28 expression in HIV infection. Relation to activation markers and cell adhesio molecules, and correlation with prognostic markers. Med Microbiol Immunol 1996;185:19–25.

    Article  Google Scholar 

  15. Rossi E, Matutes E, Morilla R, Owusu-Ankomah K, Heffernan AM, Catovsky D: Zeta chain and CD28 are poorly expressed on T lymphocytes from chronic lymphocytic leukemia. Leukemia 1996;10:494–497.

    PubMed  CAS  Google Scholar 

  16. Schmidt D, Goronzy JJ, Weyand CM: CD4+ CD7-CD28-T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 1996;97:2027–2037.

    PubMed  CAS  Google Scholar 

  17. Roman LI, Manzano L, Delahera A, Abreu L, Rossi I, Alvarezmon M: Expanded CD4+CD45RO+ phenotype and defective proliferative response in T lymphocytes from patients with Crohn's disease. Gastroenterology 1996;110:1008–1019.

    Article  PubMed  CAS  Google Scholar 

  18. Flurkey K, Stadecker M, Miller RA: Memory T lymphocyte hyporesponsiveness to non-cognate stimuli: a key factor in age-related immunodeficiency. Eur J Immunol 1992;22:931–935.

    Article  PubMed  CAS  Google Scholar 

  19. Engwenda CR, Handwerger BS, Fox BS: Aged T cells are hyporesponsive to costimulation mediated by CD28. J Immunol 1994;152:3740–3747.

    Google Scholar 

  20. Powers DG, Manning MC, Morley JE, Flood JF: Age-related changes in thymphoproliferation, cytotoxic T lymphocyte responses, and natural killer activity of senescence-accelerated mouse (SAM)-P/8 and SAM-R/1 substrains. Aging Immunol Infect Dis 1995;6:43–52.

    Google Scholar 

  21. Utsuyama M, Hirokawa K: Age-related changes of splenic T cells in mice. Flow cytometric analysis. Mech Ageing Dev 1987;40:89–102.

    Article  PubMed  CAS  Google Scholar 

  22. Zeng YX, Wu J, Yee ST, NariuchiH, Hirokawa K: Abnormality in the early signal transduction pathways is responsible for the impaired proliferative response and low K+ currentina T cell clone by stimulation with anti-CD3 antibody. Cell Signal 1996;8:263–267.

    Article  PubMed  CAS  Google Scholar 

  23. Utsuyama M, Wakikawa T, Tamura T, Nariuchi H, Hirokawa K: Impairment of signal transduction in T cells from old mice. Mech Ageing Dev 1997;93:131–144.

    Article  PubMed  CAS  Google Scholar 

  24. Franceschi C, Monti D, Sansoni P, Cossarizza A: The immunology of exceptional individual: the lesson of centenarians. Immunol Today 1995;16:12–16.

    Article  PubMed  CAS  Google Scholar 

  25. Franceschi C, Monti D, Barbieri DSS, Negro P, Capri M, Guido M, Azzi RPS, Paganelli R, Fagiolo U, Baggio G, Dorazzan S, Mariotti S, D'Addato S, Gaddi A, Ortolani C, Cossarizza A: Immunosenescence in humans: deterioration or remodelling? Int Rev Immunol 1995;12:57–74.

    PubMed  CAS  Google Scholar 

  26. Sansoni P, Fagnoni F, Vescovini R, Mazzola M, Brianti V, Bologna G, Nigro E, Lavagetto G, Cossarizza A, Monti E, Lavagetto G, Passeri M: T lymphocyte proliferative capability to defined stimuli and costinulatory CD28 pathway is not impaired in healthy centenarians. Mech Ageing Dev 1997;96:127–136.

    Article  PubMed  CAS  Google Scholar 

  27. Franceschi C, Monti D, Cossarizza A, Fagnoni F, Passeri G, Sansoni P: Aging, longevity and cancer: studies in Down's syndrome and in centerarians. Ann NY Acad Sci 1991;621:428–440.

    Article  PubMed  CAS  Google Scholar 

  28. Holt PR, Tierney AR, Kotler DP: Delayed enzyme expression: a defect of aging rat gut. Gastroenterology 1985;89:1026–1034.

    PubMed  CAS  Google Scholar 

  29. Holt PR, Yeh KY, Kotler DP: Altered controls of proliferation in proxymal small intestine of the senescent rat. Proc Natl Acad Sci 1988;85:2771–2775.

    Article  PubMed  CAS  Google Scholar 

  30. Corazza GR, Ginaldi L, Quaglione G, Ponzielli F, Vecchio L, Biagi F, Quaglino D: Proliferating cell nuclear antigen expression is increased in small how elepithelium in the elderly? Mech Ageing Dev 1998;104:1–9.

    Article  PubMed  CAS  Google Scholar 

  31. Monti D, Troiano L, Grassilli E, Agnesini C, Tropea F, Barbieri D, Capri M, Salvioli S, Ronchetti I, Bellomo G, Cossarizza A, Franceschi C: Cell proliferation and cell death in immunosenescence. Ann NY Acad Sci 1992;663:250–261.

    Article  PubMed  CAS  Google Scholar 

  32. Monti D, Grassilli E, Troiano L, Cossarizza A, Salvioli S, Barbieri D, Agnesini C, Bettizzi S, Ingletti MC, Corti A, Franceschi C: Senescence, immortalization and apoptosis: an intriguing relationship. Ann NY Acad Sci 1992;663:250–261.

    Article  PubMed  CAS  Google Scholar 

  33. Cohen JJ: Programmed cell death in the immune system. Adv Immunol 1991;50:55–85.

    Article  PubMed  CAS  Google Scholar 

  34. Monti D, Troiano L, Tropea F, Grassilli E, Cossarizza A, Barozzi D, Pelloni MC, Tamassia MG, Franceschi C: A poptosis—Programmed cell death: a role in the aging process? Am J Clin Nutr 1992;55:1208–1214.

    Google Scholar 

  35. Oehm A, Behrmann I, Falk W, Pawlita M, Maier G, Klas C, Li-Weber M, Richards S, Dhein J, Trauth BC, Ponstingl H, Krammer PH: Purification and molecular cloning of the APQ-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor family. J Biol Chem 1992;267:10,709–10,715.

    CAS  Google Scholar 

  36. Yonehara S, Ishii A, Yonehara M: A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-down regulated with the receptor for tumor necrosis factor. J Exp Med 1989;169:1747–1756.

    Article  PubMed  CAS  Google Scholar 

  37. Rathmell JC, Goodnow CC: Effect of the Ipr mutation on elimination and inactivation of self-reactive B cells. J Immunol 1994;153:2831–2842.

    PubMed  CAS  Google Scholar 

  38. Gamble DA, Schwab R, Weksler ME, Szabo P: Decreased steadystate c-myc mRNA in activated T cell cultures from old humans is caused by a smaller proportion of T cells that transcribe the c-myc gene. J Immunol 1990;144:3569–3573.

    PubMed  CAS  Google Scholar 

  39. Pieri C, Recchioni R, Moroni F, Marcheselli F, Lipponi G: Phytohemagglutinin-induced changes of membrane lipid packing c-myc and c-mybercoded protein expression in human lymphocytes during aging. Mech Ageing Dev 1992;64:177–187.

    Article  PubMed  CAS  Google Scholar 

  40. Song I, Stephens JM, Kittur S, Collins GD, Nagel JE, Pekala PH, Adler WH: Mech. Ageing Dev 1992;65:149–156.

    Article  PubMed  CAS  Google Scholar 

  41. Venable ME, Lee JY, Smith MJ, Bielawska A, Obeid L: Role of ceramide in cellular senescence. J Biol Chem 1995;270:30,701–30,708.

    CAS  Google Scholar 

  42. Whisler RL, Liu BQ, Chen M: Agerelated decrease in IL-2 production by human T cellsareassociated with impaired activation of nuclear transcription factors AP-1 and NF-AT. Cell Immunol 1996;169:185–195.

    Article  PubMed  CAS  Google Scholar 

  43. Phelouzat MA, Arbogast A, Laforge T, Quadri RA, Proust JJ: Excessive apoptosis of mature T lymphocytes is a characteristic feature of human immune senescence. Mech Ageing Dev 1996;88:25–38.

    Article  PubMed  CAS  Google Scholar 

  44. Phelouzat MA, Laforge T, Arbogast A, Quadri RA, Boutet S, Proust JJ: Susceptibility to apoptosis of T lymphocytes from elderly humans is associated with increased in vivo expression of functional Fas receptors. Mech Ageing Dev 1977;96:35–46.

    Article  Google Scholar 

  45. Dhein J, Daniel PT, Trauth BC, Oehm A, Moller P, Krammer PH: Induction of apoptosis by monoclonal antibody anti-APO-I class switch variants is dependent on cross-linking of APO-I cell surface antigens. J Immunol 1992;149:3116–3173.

    Google Scholar 

  46. Brunner T, Mogil RJ, LaFace D, Yoo NJ, Mahboubi A, Echeverri F, Martin SJ, Force WR, Lynch DH, Ware CF, Green D: Cell-autonomous Fas (CD95/Fas-ligand) interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 1995;373:441–444.

    Article  PubMed  CAS  Google Scholar 

  47. Suda T, Nagata S: Purification and characterization of the Fas-ligand that induces apoptosis. J Exp Med 1994;179:873–879.

    Article  PubMed  CAS  Google Scholar 

  48. Alderson MR, Armitage RJ, Maraskovski E, Tough TW, Roux E, Schooley K, Ramsdell F, Lynch D: Fas transduces activation signals in normal human T lymphocytes. J Exp Med 1993;178:2231–2235.

    Article  PubMed  CAS  Google Scholar 

  49. Oltvai ZN, Korsmeyer SJ: Checkpoint of dueling dimers foil death wishes. Cell 1994;19:189–192.

    Article  Google Scholar 

  50. Lyrch DH, Ramsdell F, Alderson MR: Fasand Fasl in the bomeostatic regulation of immune responses. Immunol Today 1995;16:569–574.

    Article  Google Scholar 

  51. Phelouzat MA, Arbogast A, Laforge T, Quadri RA, Proust JJ: Excessive apoptosis of mature T lymphocytes is a characteristic feature of human immune senescence. Mech Ageing Dev 1996;88:25–38.

    Article  PubMed  CAS  Google Scholar 

  52. Herndon FJ, Hsu HC, Mountz JD: Increased apoptosis of CD45RO-T cells with aging. Mech Ageing Dev 1997;94:123–134.

    Article  PubMed  CAS  Google Scholar 

  53. Mountz JD, Wu J, Zhou T, Hsu HC: Cell death and longevity: implications of Fas-mediated apoptosis in T-cell senescence. Immunol Rev 1997;160:19–30.

    Article  PubMed  CAS  Google Scholar 

  54. Ucker DS, Hebshi LD, Blomquist JF, Toebett BE: Physiological T-cell death: susceptibility is modulated by activation, aging, and transformation, but the mechanism iscorstant. Immunol Rev 1994;142:273–299.

    Article  PubMed  CAS  Google Scholar 

  55. Zhou T, Edwards CK, Mountz JD: Prevention of age-related T cell apoptosis defect in CD2-fas transgenic mice. J Exp Med 1995;182:129–137.

    Article  PubMed  CAS  Google Scholar 

  56. Chrest FJ, Bucholz MA, Kim YH, Kwon TK, Nordin AA: Anti-CD3 induced apoptosis in T cells from young and old mice. Cytometry 1995;20:33–42.

    Article  PubMed  CAS  Google Scholar 

  57. Sancar A: DNA repair in humans. Annu Rev Genet 1993;29:69–105.

    Article  Google Scholar 

  58. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirder GG, Eamshaw WC: Cleavage of poly (ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 1995;346:346–347.

    Google Scholar 

  59. Casciola-Rosen RA, Anhalt GJ, Rosen A: DNA-dependent protein kinase is one of subsets of autoantigens specifically cleaved early during apoptosis. J Exp Med 1995;182:1625–1634.

    Article  PubMed  CAS  Google Scholar 

  60. McConnell KR, Dynan WS, Hardin JA: The DNA-dependent protein kinase (p460) is cleaved during Fas-mediated apoptosis in Jurkat cells. J Immunol 1997;158:2083–2089.

    PubMed  CAS  Google Scholar 

  61. Hayflick L: The limited in vitro life-time of human diploid cell strains. Exp Cell Res 1965;37:614–636.

    Article  PubMed  CAS  Google Scholar 

  62. Souvannavong V, Lemaire C, Andreau K, Brown S, Adam A: Influence of aging on B-cell apoptosis and expression of the activation marker alkaline phosphatase. Aging Immunol Infect Dis 1996;6:197–207.

    Google Scholar 

  63. Wang E: Senescent human fibroblasts resist programmed cell death, and failure to suppress bel2 is involved. Cancer Res 1995;55:2284–2292.

    PubMed  CAS  Google Scholar 

  64. Kane DJ, Saratian TA, Anton R, Hahn H, Gralla EB, Valentine JS, Ord T, Bredesen TE: Bcl-2 inhibition of cell death: decreased generation of reactive oxygen species. Science 1993;262:1274–1277.

    Article  PubMed  CAS  Google Scholar 

  65. Nunez G, Merino G, Grillot D, Gonzales-Garcia M: Bcl-2 and Bcl-x: regulatory switches for lymphoid death and survival. Immunol Today 1994;15:582–588.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ginaldi, L., De Martinis, M., D'Ostilio, A. et al. Cell proliferation and apoptosis in the immune system in the elderly. Immunol Res 21, 31–38 (2000). https://doi.org/10.1385/IR:21:1:31

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/IR:21:1:31

Key words

Navigation