Role of the Immune System in Aging

  • Takashi Makinodan
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 129)


Since the turn of the century, there has been a continuum of medical breakthroughs controlling life-shortening diseases. As a consequence, more people are now living longer than they were at the turn of the century. Unfortunately, life extension means chronic disorders to many of the elderly. This has created a trememdous socio-economic burden throughout the world. Thus, during the past decade, there has been a growing emphasis in biomedical research towards control of age-related chronic disorders, in order to enable the elderly to extend their healthy years of life.


Spleen Cell Aged Mouse Bone Marrow Stem Cell Cell Grafting Dwarf Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    I. R. Mackay, Ageing and immunological function in man, Gerontologia 18:285 (1972).PubMedCrossRefGoogle Scholar
  2. 2.
    H. Baer and R. T. owser, Antibody production and development of contact skin sensitivity in guinea pigs of various ages, Science 140:1211 (1963).PubMedCrossRefGoogle Scholar
  3. 3.
    G. E. Bilder, Studies on immune competence in the rat: Changes with age, sex, and strain, J. Gerontol. 30:641 (1975).PubMedGoogle Scholar
  4. 4.
    B. N. Jaroslow, K. M. Suhrbier, and T. E. Fritz, Decline and restoration of antibody forming capacity in aging beagle dogs, J. Immunol. 112:1467 (1974).PubMedGoogle Scholar
  5. 5.
    T. Makinodan, and W. J. Peterson, Relative antibody-forming capacity of spleen cells as a function of age, Proc. Nat. Acad. Sci. U.S. 48:234 (1962).CrossRefGoogle Scholar
  6. 6.
    M. Mathies, L. Lipps, G. S. Smith, and R. L. Walford, Age related decline in response to phytohemagglutinin and pokeweed mitogen by spleen cells from hamster and a longlived mouse strain, J. Gerontol. 28:425 (1973).PubMedGoogle Scholar
  7. 7.
    T. A. Nomaguchi, Y. Okuma-Sakurai, and I. Kimura, Changes in immunological potential between juvenile and presenile rabbits, Mech. Ageing Dev. 5:409 (1976).PubMedCrossRefGoogle Scholar
  8. 8.
    H. H. Fudenberg, R. A. Good, H. C. Goodman, W. Hitzig, H. G. Kunkel, I. M. Roitt, F. S. Rosen, D. S. Rowe, M. Seligmann, and J. R. Soothill, Primary immunodeficiencies, Bull. WHO 45:125 (1975).Google Scholar
  9. 9.
    I. Penn, and T. E. Starzl, Malignant tumors arising de novo in immunosuppressed organ transplant recipients, Transplantation 14:407 (1972).PubMedCrossRefGoogle Scholar
  10. 10.
    M. M. B. Kay, and T. Makinodan, Immunobiology of aging: Evaluation of current status, Clin. Immunol. Immunopathol. 6:394 (1976).PubMedCrossRefGoogle Scholar
  11. 11.
    “Tolerance, Autoimmunity and Aging,” M. M. Seigel, and R. A. Good, eds., Charles C. Thomas, Springfield, Ill. (1972).Google Scholar
  12. 12.
    R. L. Walford, The immunologic theory of aging, current status. Fed. Proc. 33:2020 (1974).PubMedGoogle Scholar
  13. 13.
    “Immunology and Aging,” T. Makinodan, and E. J. Yunis, eds., Plenum Medical Book Company, New York (1977).Google Scholar
  14. 14.
    D. Segre, and M. Segre, Age-related changes in B and T lymphocytes and decline of humoral immune responsiveness in aged mice, Mech. Ageing Dev. 6:115–129 (1977).PubMedCrossRefGoogle Scholar
  15. 15.
    G. B. Price, and T. Makinodan, Immunologic deficiencies in senescence. II. Characterization of extrinsic deficiencies. J. Immunol. 108:413 (1972).PubMedGoogle Scholar
  16. 16.
    B. Rivnay, A. Globerson, and M. Shinitzky, Viscosity of lymphocyte plasma membrane in aging mice and its possible relation to serum cholesterol, Mech. Ageing Dev. 10:71 (1979).PubMedCrossRefGoogle Scholar
  17. 17.
    F. J. Bach, M. Dardenne, and J. C. Solomon, Studies on thymus products. IV. Absence of serum thymic activity in adult NZB and (NZB x NZW)F1 mice, Clin. Exp. Immunol. 14:247 (1973).PubMedGoogle Scholar
  18. 18.
    G. E. Bilder, and W. D. Denckla, Restoration of ability to reject xenografts and clear carbon after hypophysectomy of adult rats, Mech. Ageing Dev. 6:153 (1977).PubMedCrossRefGoogle Scholar
  19. 19.
    L. Hayflick, and P. S. Moorhead, The serial cultivation of human diploid cell strains, Exp. Cell Res. 25:585 (1961).CrossRefGoogle Scholar
  20. 20.
    P. C. Brennan, and B. N. Jaroslow, Age-associated decline in theta antigen on spleen thymus-derived lymphocytes of B6CF1 mice, Cell. Immunol. 15:51 (1975).PubMedCrossRefGoogle Scholar
  21. 21.
    P. A. Jacobs, and W. M. Court Brown, Distribution of human chromosome counts in relation to age, Nature 191:1178 (1961).PubMedCrossRefGoogle Scholar
  22. 22.
    A. M. Preumont, P. Van Gansen, and J. Brachet, Cytochemical study of human lymphocytes stimulated by PHA in function of donor age, Mech. Ageing Dev. 7:25 (1978).PubMedCrossRefGoogle Scholar
  23. 23.
    Y. H. Oh, and R. A. Conrad, Effect of aging on acetate incorporation in nuclei of lymphocytes stimulated with phytohemagglutinin. Life Sciences 11:677 (1972).CrossRefGoogle Scholar
  24. 24.
    M. G. Chen, Impaired Elkind recovery in hematopoeitic colony-forming cells of aged mice. Proc. Soc. Exp. Biol. Med. 145:1181 (1974)PubMedGoogle Scholar
  25. 25.
    D. J. Scribner, H. L. Weiner, and J. W. Moorhead, Anti-immunoglobulin stimulation of murine lymphocytes. V. Age-related decline in Fc receptor-mediated immunoregulation. J. Immunol. 121:377 (1978).PubMedGoogle Scholar
  26. 26.
    C.F. Tarn, and R. L. Walford, Cyclic nucleotide levels in resting and mitogen-stimulated spleen cell suspensions from young and old mice, Mech. Ageing Dev. 7:309 (1978).CrossRefGoogle Scholar
  27. 27.
    G. B. Price, and T. Makinodan, Immunologic deficiencies in senescence. I. Characterization of intrinsic deficiencies. J. Immunol. 108:403 (1972).PubMedGoogle Scholar
  28. 28.
    R. E. Callard, and A. Basten, Immune function in aged mice. IV. Loss of T cell and B cell function in thymus-dependent antibody response, Eur. J. Immunol. 8:552 (1978).PubMedCrossRefGoogle Scholar
  29. 29.
    T. Makinodan, J. W. Albright, P. I. Good, C. P. Peter, and M. L. Heidrick, Reduced humoral immune activity in long-lived old mice: An approach to elucidating its mechanisms, Immunology 31:903 (1976).PubMedGoogle Scholar
  30. 30.
    D. Segre, and M. Segre, Humoral immunity in aged mice. II. Increased suppressor T cell activity in immunologically deficient old mice, J. Immunol. 116:735 (1976).PubMedGoogle Scholar
  31. 31.
    N. L. Gerber, J. A. Hardin, T. M. Chused, and A. D. Steinberg, Loss with age in NZB/W mice of thymic suppressor cells in the graft-versus-host reaction, J. Immunol. 113:1618 (1974).PubMedGoogle Scholar
  32. 32.
    H. M. Hallgren, and E. J. Yunis, Suppressor lymphocytes in young and aged humans, J. Immunol. 118:2004 (1977).PubMedGoogle Scholar
  33. 33.
    S. Gupta, and R. A. Good, Subpopulations of human T lymphocytes. X. Alterations in T, B, third population cells, and T cells with receptors for immunoglobulin M(tγ) or G(Tμ) in aging humans, J. Immunol. 122:1214 (1979).PubMedGoogle Scholar
  34. 34.
    R. L. Krogsrud, and E. H. Perkins, Age-related changes in T cell function, J. Immunol. 118:1607 (1977).PubMedGoogle Scholar
  35. 35.
    G. Doria, G. D’Agostaro, and A. Poretti, Age-dependent variation of antibody avidity, Immunology 38:601 (1978).Google Scholar
  36. 36.
    R. K. Liu, and R. L. Walford, Mid-life temperature-transfer effects on life span of annual fish, J. Gerontol. 30:129 (1975).PubMedGoogle Scholar
  37. 37.
    J. Furth, Prolongation of life with prevention of leukemia by thymectomy in mice, J. Gerontol. 1:46 (1946).PubMedGoogle Scholar
  38. 38.
    J. W. Albright, T. Makinodan, and J. W. Deitchman, Presence of life-shortening factors in spleens of aged mice of long life span and extension of life expectancy by splenectomy, Exp. Gerontol. 4:267 (1969).PubMedCrossRefGoogle Scholar
  39. 39.
    F. Chino, T. Makinodan, W. E. Lever, and W. J. Peterson, The immune systems of mice reared in clean and in dirty conventional laboratory farms. I. Life expectancy and pathology of mice with long life spans, J. Gerontol. 26:497 (1971).PubMedGoogle Scholar
  40. 40.
    R. L. Walford, The immunologic theory of aging, current status, Fed. Proc. 33:2020 (1974).PubMedGoogle Scholar
  41. 41.
    “Immunogenetics and Immunodeficiency,” B. Benacerraf, ed., University Park Press, Baltimore (1975).Google Scholar
  42. 42.
    G. S. Smith, and R. L. Walford, Influence of the main histocompatibility complex on aging in mice, Nature 270:727 (1977).PubMedCrossRefGoogle Scholar
  43. 43.
    P. J. Meredith, and R. L. Walford, Effect of age on response to T and B cell mitogens in mice congenic at the H-2 locus, Immunogenetics 5:109 (1978).CrossRefGoogle Scholar
  44. 44.
    G. Fernandes, R. A. Good, and E. J. Yunis, Attempts to correct age-related immunodeficiency and autoimmunity by cellular and dietary manipulation in inbred mice, in:“Immunology and Aging,” T. Makinodan and E. J. Yunis, eds., Plenum Medical Book Company, New York (1977).Google Scholar
  45. 45.
    L. J. Greenberg, and E. J. Yunis, Histocompatibility determinants, immune responsiveness and aging in mice, Fed. Proc. 37:1258 (1978).PubMedGoogle Scholar
  46. 46.
    C. M. McCay, M. F. Crowell, and L. A. Maynard, The effect of retarded growth upon the length of life span and upon the ultimate body size, J. Nutrition 10:63 (1935).Google Scholar
  47. 47.
    M. H. Ross, Aging, nutrition, and hepatic enzyme activity patterns in the rat, J. Nutrition Suppl 1, part 2, 97:565 (1969).Google Scholar
  48. 48.
    M. H. Ross, and G. Bras, Lasting influence of early caloric restriction on prevalence of neoplasia in the rat, J. Nat. Cancer Inst. 47:1095 (1971).PubMedGoogle Scholar
  49. 49.
    R. L. Walford, R. K. Liu, M. Mathies, M. Gerbase-DeLima, and G. S. Smith, Response to sheep red blood cells and to mitogenio agents, Meoh. Ageing Dev. 2:447 (1974).CrossRefGoogle Scholar
  50. 50.
    G. Fernandes, E. J. Yunis, D. G. Jose, and R. A. Good, Dietary influence on antinuclear antibodies and cell-mediated immunity in NZB mice, Int. Arch, Allergy Appi. Immunol. 44:770 (1973).CrossRefGoogle Scholar
  51. 51.
    B. Fernandes, E. J. Yunis, J. Smith, and R. A. Good, Dietary influence on breeding behavior, hemolytic anemia, and longevity in NZB mice, Proc. Soc. Exp. Biol. Med. 139:1189 (1972).PubMedGoogle Scholar
  52. 52.
    G. Fernandes, E. J. Yunis, and R. A. Good, Influence of diet on survival of mice, Proc. Nat. Acad. Sci. USA 73:1279 (1976).PubMedCrossRefGoogle Scholar
  53. 53.
    W. D. Denckla, Role of pituitary and thyroid glands in the decline of minimal O2 consumption with age, J. Clin. Invest. 53:572 (1974).PubMedCrossRefGoogle Scholar
  54. 54.
    N. Fabris, W. Pierpaoli, and E. Sorkin, Lymphocytes, hormones and aging, Nature 240:557 (1972).PubMedCrossRefGoogle Scholar
  55. 55.
    P. O. Teague, and G. J. Friou, Antinuclear antibodies in mice. II. Transformation with spleen cells, inhibition or prevention with thymus or spleen cells, Immunology 17:665 (1969).PubMedGoogle Scholar
  56. 56.
    E. J. Yunis, and L. J. Greenberg, Immunopathology of aging, Fed. Proc. 33:2017 (1974).Google Scholar
  57. 57.
    S. Kysela, and A. D. Steinberg, Increased survival of NZB/W mice given multiple syngeneic young thymus grafts, Clin. Immunol. Immunopath. 2:133 (1973).CrossRefGoogle Scholar
  58. 58.
    E. J. Yunis, G. Fernandes, and O. Stutman, Susceptibility to involution of the thymus-dependent lymphoid system and autoimmunity, Am. J. Clin. Path. 56:280 (1971).PubMedGoogle Scholar
  59. 59.
    J. F. Albright, and T. Makinodan, Growth and senescence of antibody-forming cells, J. Cell Comp. Physiol. 67(Suppl. 1): 185 (1966).Google Scholar
  60. 60.
    D. Metcalf, R. Moulds, and B. Pike, Influence of the spleen and thymus on immune responses in aging mice, Clin. Exp. Immunol. 2:109 (1966).Google Scholar
  61. 61.
    T. Makinodan, and W. H. Adler, The effects of aging on the differentiation and proliferation potentials of cells of the immune system, Fed. Proc. 34:153 (1975).PubMedGoogle Scholar
  62. 62.
    J. W. Albright, and T. Makinodan, Decline in the growth potential of spleen-colonizing bone marrow stem cells of long lived aging mice, J. Exp. Med. 144:1204 (1976).PubMedCrossRefGoogle Scholar
  63. 63.
    K. Hirokawa, and T. Makinodan, Thymic involution: Effect on T cell differentiation, J. Immunol. 114:1659 (1975).PubMedGoogle Scholar
  64. 64.
    K. Hirokawa, J. W. Albright, and T. Makinodan, Restoration of impaired immune functions in aging animals. I. Effect of syngeneic thymus and bone marrow cells, Clin. Immunol. Immunopathol. 5:371–376 (1976).PubMedCrossRefGoogle Scholar
  65. 65.
    E. H. Perkins, T. Makinodan, and C. Seibert, Model approach to immunological rejuvenation of the aged, Infect. Immunity 6:518 (1972).Google Scholar
  66. 66.
    D. Friedman, V. Keiser, and A. Globerson, Reactivation of immunocompetence in spleen cells of aged mice, Nature 251:545 (1974).PubMedCrossRefGoogle Scholar
  67. 67.
    M.-A. Bach, Lymphocyte-mediated cytotoxicity: Effects of ageing, adult thymectomy and thymic factor, J. Immunol. 119:641 (1977).PubMedGoogle Scholar
  68. 68.
    M. E. Weksler, J. B. Innes, and G. Goldstein, G. Immunological studies of aging. IV. The contribution of thymic involution to the immune deficiencies of aging mice and reversal with thymopoietin, J. Exp. Med. 148:996 (1978).PubMedCrossRefGoogle Scholar
  69. 69.
    D. Martinez, A. K. Field, H. Schwam, A. A. Tytell, and M. R. Hilleman, Failure of thymopoietin, ubiquitin and synthetic serum thymic factor to restore immunocompetence in T cell deficient mice, Proc. Soc. Exp. Biol. Med. 159:195 (1978).PubMedGoogle Scholar
  70. 70.
    A. L. Goldstein, G. B. Thurman, T. L. Low, G. E. Trivers, and J. L. Rossie, Thymosin: The endocrine thymus and its role in the aging process, in:“Physiology and Cell Biology of Aging,” A. Cherkin, C. E. Finch, N. Kharasch, T. Makinodan, F. L. Scott, and B. L. Strehler, eds., Raven Press, New York (1979).Google Scholar
  71. 71.
    J. Rovensky, A. L. Goldstein, P. J. L. Holt, J. Pwkarek, and T. Mistina, Obnova funkcie T lymfocytor tymosinom u klinicky zdravych asob vyssieho veku, Cas. Lek. Ces. 116:1063 (1977).Google Scholar
  72. 72.
    B. Strehler, “Time, Cells and Aging,” Academic Press, New York (1977).Google Scholar
  73. 73.
    D. Harman, Prolongation of life: Role of free radical reactions in aging, J. Am. Geriatrics Soc. 17:721 (1969).Google Scholar
  74. 74.
    D. Harman, M. L. Heidrick, and D. E. Eddy, Free radical theory of aging: Effect of free-radical-reaction inhibitors on the immune response, J. Am. Geriatrics Soc. 25:400 (1977).Google Scholar
  75. 75.
    E. G. Bliznakov, Immunological senescence in mice and its reversal by coenzyme Q10, Mech. Ageing Dev. 7:189 (1978).PubMedCrossRefGoogle Scholar
  76. 76.
    W. Braun, Y. Yajima, and M. Ishizuka, Synthetic polynucleotides as restorers of normal antibody formation capacities in aged mice, J. Reticuloendothel. Soc. 7:418 (1970).PubMedGoogle Scholar
  77. 77.
    I. H. Han, and A. G. Johnson, Regulation of the immune system by synthetic polynucleotides. VII. Amplification of the immune response in young and aged mice, J. Immunol. 117:423 (1976).PubMedGoogle Scholar
  78. 78.
    M. E. Schmidt, and S. D. Douglas, Effects of synthetic single and multistranded polynucleotides on human monocyte IgG receptor activity in vitro, Proc. Soc. Exp. Biol. Med. 151:376 (1979).Google Scholar
  79. 79.
    W. Braun, W. M. Lichtenstein, and C. Parker, eds., “Cyclic AMP, Cell Growth and the Immune Response,” Springer-Verlag, New York (1974).Google Scholar
  80. 80.
    J. D. Broome, and M. W. Jeng, Promotion of replication in lymphoid cells by specific thiols and disulfides in vitro, J. Exp. Med. 138:574 (1973).PubMedCrossRefGoogle Scholar
  81. 81.
    C. Chen, and J. G. Hirsch, The effects of mercaptoethanol and of peritoneal macrophages on the antibody forming capacity of nonadherent mouse spleen cells in vitro, J. Exp. Med. 136:604 (1972).PubMedCrossRefGoogle Scholar
  82. 82.
    M. W. Fanger, D. A. Hart, J. V. Wells, and A. Nisonoff, Enhancement by reducing agents of the transformation of human and rabbit peripheral lymphocytes, J. Immunol. 105:1043 (1970).PubMedGoogle Scholar
  83. 83.
    E. Heber-Katz, and R. E. Click, Immune responses in vitro. V. Role of mercaptoethanol in the mixed-leukocyte reaction, Cell. Immunol. 5:410 (1972).PubMedCrossRefGoogle Scholar
  84. 84.
    N. Johnson, R. Jessup, and P. W. Ramwell, The significance of protein disulfide and sulphonyl groups in prostaglandin action, Prostaglandins 5:125 (1974).CrossRefGoogle Scholar
  85. 85.
    W. Lands, R. Lee, and W. Smith, Factors regulating the biosynthesis of various prostaglandins, Ann. N.Y. Acad. Sci. 180:107 (1971).PubMedCrossRefGoogle Scholar
  86. 86.
    T. Makinodan, J. W. Deitchman, G. H. Stoltzner, M. M. Kay, and K. Hirokawa, Restoration of the declining normal immune functions of aging mice, Proc. 10th Internat. Cong. Gerontol. 2:23 (1975).Google Scholar
  87. 87.
    T. Makinodan, Control of immunologic abnormalities associated with aging, Mech. Ageing Dev. 9:7 (1979).PubMedCrossRefGoogle Scholar
  88. 88.
    T. Makinodan, and J. F. Albright, Restoration of impaired immune functions in aging animals. II. Effect of mercaptoethanol in enhancing the reduced primary antibody responsiveness in vitro, Mech. Ageing Dev. 10:325 (1979).PubMedCrossRefGoogle Scholar
  89. 89.
    T. Makinodan, and J. F. Albright, Restoration of impaired immune functions in aging animals. III. Effect of mercaptoethanol in enhancing the reduced primary antibody responsiveness in vivo, Mech. Ageing Dev., in press.Google Scholar
  90. 90.
    M. G. Goodman, and W. O. Weigle, Nonspecific activation of murine lymphocytes. I. Proliferation and polyclonal activation induced by 2-mercaptoethanol and a-thioglycerol, J. Exp. Med. 145:473 (1977).PubMedCrossRefGoogle Scholar
  91. 91.
    D. Metcalf, Role of mercaptoethanol and endotoxin in stimulation of B lymphocyte colony formation in vitro, J. Immunol. 116:635 (1976).PubMedGoogle Scholar
  92. 92.
    M. J. Bevan, R. Epstein, and M. Cohn, The effect of 2-mercaptoethanol on murine mixed lymphocyte cultures, J. Exp. Med. 139:1025 (1974).PubMedCrossRefGoogle Scholar
  93. 93.
    H. D. Engers, H. R. MacDonald, J. C. Cerottini, and K. T. Brunner, Effect of delayed addition of 2-mercaptoethanol on the generation of mouse cytotoxic T-lymphocytes in mixed leukocyte cultures, Eur. J. Immunol. 5:223 (1975).PubMedCrossRefGoogle Scholar
  94. 94.
    T. Igarashi, M. Okada, T. Kishimoto, and Y. Yamamura, In vitro induction of polyclonal killer T cells with 2-mercaptoethanol and the essential role of macrophages in this process, J. Immunol. 118:1697 (1977).PubMedGoogle Scholar
  95. 95.
    H. G. Opitz, U. Opitz, H. Lemke, H. D. Flad, G. Hewlett, and H. D. Schlumberger, Humoral primary immune response in vitro in a homologous mouse system: Replacement of fetal calf serum by a 2-mercaptoethanol or macrophage-activated fraction of mouse serum, J. Immunol. 119:2089 (1977).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1980

Authors and Affiliations

  • Takashi Makinodan
    • 1
    • 2
  1. 1.Geriatric Research, Education and Clinical Center (GRECC)Wadsworth Medical CenterLos AngelesUSA
  2. 2.Department of MedicineUCLALos AngelesUSA

Personalised recommendations