, Volume 5, Issue 6, pp 389–400

Changes with ageing in several leukocyte functions of male and female rats

  • Mónica De La Fuente
  • Isabel Baeza
  • Noelia Guayerbas
  • Marta Puerto
  • Carmen Castillo
  • Veronica Salazar
  • Carmen Ariznavarreta
  • Jesus A. F-tresguerres
Research Article


The impairment of the immune system with aging, or ‘immunosenescence’, appears to contribute to the increased morbidity and mortality of aged subjects. T cell functions and Natural Killer activity seem to be the immune responses most affected by ageing. Since the immune system works more efficiently in females than in males, we have studied the changes of several immune functions with age in rats of both sexes. In addition, we have investigated if ovariectomy, a model of menopause in rats, produces a loss of this gender-related advantage. In the present work, the changes with age (2, 6, 12, 14, 18, 22 and 24 months old) in lymphocyte chemotaxis, T lymphoproliferative response to the mitogen ConA, IL-2 release and Natural Killer activity of cells from axillary nodes and spleen of male and female rats as well as of females ovariectomized at 12 months of age have been studied. An age-related decrease was found in all investigated functions, with a slightly different evolution depending on the immune organ and gender considered. In general, the data obtained show that a certain degree of immunosenescence takes place with age in rats, with males being less immunocompetent than intact age-matched females, but showing an immune response similar to that of ovariectomized animals.


ageing chemotaxis IL-2 lymphoproliferation Natural Killer activity ovariectomy 



Chemotaxis index


Concanavalin A


Interleuquin 2


major histocompatibility complex


Interleuquin 2


major histocompatibility complex


male control


Natural Killer






Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Asdell, SA, Doornenbal, H, Joshi, SR, Sperling, GA 1967The effects of sex steroid hormones upon longevity in ratsJ Reprod Fertil14113120Google Scholar
  2. Aspinall, R 2000Longevity and the immune responseBiogerontology1273278Google Scholar
  3. Bonacho, MG, Cardinali, DP, Castrillón, P, Cutrera, RA, Esquifino, AI 2001Aging-induced changes in 24-h rhythms of mitogenic responses, lymphocyte subset population and neurotransmitter and amino acid content in rat submaxillary lymph nodes during Freund’s adjuvant arthritisExp Gerontol36267282Google Scholar
  4. Borrás, C, Sastre, J, García-Sala, D, Lloret, A, Pallardó, FV, Viña, J 2003Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than malesFree Rad Biol Med34546552Google Scholar
  5. Borrego, F, Alonso, MC, Galiani, MD, Carracedo, J, Ramirez, R, Ostos, B, Peña, J, Solana, R 1999NK phenotypic markers and IL-2 response in NK cells from elderly peopleExp Gerontol34253265Google Scholar
  6. Boyden, SV 1962The chemotaxis effect of mixtures of antibody and antigen on polymorphonuclear leukocytesJ Exp Med115453466Google Scholar
  7. Cannon, JG, St.Pierre, B 1997Gender differences in host defense mechanismsJ Psychiat Res3199113Google Scholar
  8. Chakravarti, B, Abraham, GN 1999Aging and T-cell mediated immunityMech Ageing Dev180183206Google Scholar
  9. Chen, J, Mo, R, Lescure, PA, Misek, DE, Hanash, S, Rochford, R, Hobbs, M, Yung, RL 2003Aging is associated with increased T-cell chemokine expression in C57BL/6 miceJ Gerontol A Biol Sci Med Sci58975983Google Scholar
  10. Damjanovich, S, Gáspár, R Jr, Lászlo, B, Attila, J, Lázslo, M 2003Signal transduction in T lymphocytes and agingExp Gerontol38231236Google Scholar
  11. Davila, DR, Kelley, KW 1988Sex differences in lectin-induced interleukin-2 synthesis in aging ratsMech. Ageing Dev44231240Google Scholar
  12. De, la Fuente M 2002Effects of antioxidants on immune system ageingEur J Clin Nutr565154Google Scholar
  13. De la Fuente , M, Carazo, M, Correa, R, Del Río, M 2000Changes in macrophage and lymphocyte functions in guinea-pigs after different amount of vitamin E ingestionBritish J Nutr842529Google Scholar
  14. De la Fuente , M, Del Río,  M, Víctor, VM, Medina, S 2001Neuropeptide Y effects on murine natural killer activity: changes with ageing and cAMP involvementReg Pept1017379Google Scholar
  15. Del Río , M, Hernanz, A, De la Fuente , M 1994Bombesin, gastrin-releasing peptide, and neuromedin C modulate murine lymphocyte proliferation through adherent accesory cells and activate protein kinase CPeptides151522Google Scholar
  16. Di Lorenzo , G, Balistreri, CR, Candore, G, Cigna, D, Colombo, A, Colonna-Romano, G, Colucci, AT, Gervasi, F, Listi, F, Potestio, M, Caruso, C 1999Granulocyte and natural killer activity in the elderlyMech Ageing Dev1082538Google Scholar
  17. Doherty, DE, Haslett, C, Fonnesen, MG, Henson, PM 1987Human monocyte adherence: a primary effect of chemotactic factors on the monocyte to stimulate adherence to human endotheliumJ Immunol13817621771Google Scholar
  18. Douziech, N, Seres, I, Larbi, A, Szikszay, E, Roy, PM, Arcand, M, Dupuis, G, Fulop, TJr 2002Modulation of human lymphocyte proliferative response with agingExp Gerontol37369387Google Scholar
  19. Fabris, N, Mocchegiani, E, Provinciali, M 1997Plasticity of neuroendocrine interactions during agingExp Gerontol32415429Google Scholar
  20. Fagiolo, U, Amadori, A, Biselli, R, Paganelli, R, Nisini, R, Cozzi, E, Zamarchi, R, D’Amelio, R 1993Quantitative and qualitative analysis of anti-tetanus toxoid antibody response in the elderlyHumoral immune response enhanced by thymostimulin. Vaccine1111361340Google Scholar
  21. Ferrández, MD, Correa, R, Del Río,  M, De la Fuente,  M 1999Effect in vitro of several antioxidants on the natural killer function of aging miceExp Gerontol34675685Google Scholar
  22. Franceshi, C, Valensin, S, Bonafé, M, Paolisso, G, Yashin, AI, Monti, D, De Benedictis , G 2000The network and the remodeling theories of aging: historical background and new perspectivesExp Gerontol35879896Google Scholar
  23. Gaillard, RC, Spinedi, E 1998Sex- and stress–steroids interactions and the immune system: evidence for a neuroendocrine-immunological sexual dimorphismDomestic Anim Endocrinol15345352Google Scholar
  24. Ginaldi, L, De Martinis, M, D’Ostilio, A, Marini, L, Loreto, MF, Quaglino, D 1999The immune system in the elderlyImmunologic Res2021172126Google Scholar
  25. Ginaldi, L, De Martinis , M, D’Ostilio, A, Marini, L, Loreto, MF, Modesti, M, Quaglino, D 2001Changes in the expression of surface receptors on lymphocyte subsets in the elderly: quantitative flow cytometric analysisAm J Hematol676372Google Scholar
  26. Globerson, A, Effros, RB 2000Ageing of lymphocytes and lymphocytes in the agedImmunol. Today21515521Google Scholar
  27. Goya, RG 1991A comparison between hormone levels and T lymphocyte function in young and old ratsMech Ageing Dev61275285Google Scholar
  28. Grossman, C 1989Possible underlying mechanisms of sexual dimorphism in the immune response, fact and hypothesisJ Steroid Biochem34241251Google Scholar
  29. Guayerbas, N, De la Fuente , M 2003An impairment of phagocytic function is linked to a shorter life span in two strains of prematurely aging miceDev Comp Immunol27339350Google Scholar
  30. Guayerbas, N, Puerto, M, Victor, VM, Miquel, J, De la Fuente , M 2002Leukocyte function and life span in a murine model of premature immunosenescenceExp Gerontol37249256Google Scholar
  31. Hirokawa, K 1999Age-related changes of signal transduction in T cellsExp Gerontol34718Google Scholar
  32. Hobbs, MV, Ernst, DN 1997T cell differentiation and cytokine expression in late lifeDev Comp Immunol21161170Google Scholar
  33. Holbrook, NJ, Chopra, RK, McCoy, MT, Nagel, JE, Powers, DC, Adler, WH, Schneider, EL 1989Expression of interleukin 2 and the interleukin 2 receptor in aging ratsCell Immunol12019Google Scholar
  34. Hugli, TE 1989ChemotaxisCurr Opin Immunol21927Google Scholar
  35. Kamada, M, Irahara, M, Maegawa, M, Yasui, T, Yamano, S, Yamada, M, Tezuka, M, Kasai, Y, Deguchi, K, Ohmoto, Y, Aono, T 2001B cell subsets in postmenopausal women and the effect of hormone replacement therapyMaturitas37173179Google Scholar
  36. Keller, ET, Zhang, J, Yao, Z, Qi, Y 2001The impact of chronic estrogen deprivation on immunologic parameters in the ovariectomized rhesus monkey (Macaca mulatta) model of menopauseJ Reprod Immunol504155Google Scholar
  37. Kutza, I, Murasko, DM 1994Effects of aging on natural killer activity and activation by interleukin-2 and IFN-αCell Immunol155195204Google Scholar
  38. Kutza, I, Murasko, DM 1996Age-associated decline in IL-2 and IL-12 induction of LAK cell activity of human PBMCMech Ageing Dev90209222Google Scholar
  39. Leal, AM, Ruiz-Larrea, MB, Martinez, R, Lacort, M 1998Cytoprotective actions of estrogens against tert-butyl hydroperoxide-induced toxicity in hepatocytesBiochem Pharmacol5614631469Google Scholar
  40. Levy, SM, Fernstrom, J, Herberman, RB, Whiteside, T, Lee, J, Ward, M, Massoudi, M 1991Persistently low natural killer cell activity and circulating levels of plasma beta endorphin: risk factors for infectious diseaseLife Sci48107116Google Scholar
  41. Losonczy, G, Kriston, T, Szabo, A, Muller, V, Harvey, J, Hamar, P, Heeman, V, Baylis, C 2000Male gender predisposes to development of endotoxic shock in the ratCardiov Res47183191Google Scholar
  42. Lu, KH, Hopper, BR, Vargo, TM, Yen, SS 1979Chronological changes in sex steroids gonadotropin and prolactin secretion in aging female rats displaying different reproductive statesBiol Reprod21193203Google Scholar
  43. Makinodan, T 1998Studies on the influence of age on immune response to understand the biology of immunosenescenceExp Gerontol332738Google Scholar
  44. Malaguarnera, L, Ferlito, L, Imbesi, RM, Gulizia, GS, Di Mauro, S, Maugeri, D, Malaguarnera, M, Messina, A 2001Immunosenescence: a reviewArch Gerontol Geriatr32114Google Scholar
  45. Mariani, E, Pulsatelli, L, Neri, S, Dolzani, P, Meneghetti, A, Silvestri, T, Ravaglia, G, Forti, P, Cattini, L, Facchini, A 2002RANTES and MIP-1α production by T lymphocytes, monocytes and NK cells from nonagenarian subjectsExp Gerontol37219226Google Scholar
  46. Medina, S, Del Rio, M, Hernanz, A, De la Fuente, M 2000aAge-related changes in the neuropeptide Y effects on murine lymphoproliferation and interleukin-2 productionPeptides2114031409Google Scholar
  47. Medina, S, Del Río , M, Hernánz, A, De la Fuente , M 2000bThe NPY effects on murine leukocyte adherence and chemotaxis change with age Adherent cell implication. Reg Peptides953545Google Scholar
  48. Medina, S, Del Río, M, Víctor, VM, Hernánz, A, De la Fuente , M 1998Changes with ageing in the modulation of murine lymphocyte chemotaxis by CCK-8s, GRP and NPYMech Ageing Dev102249261Google Scholar
  49. Miller, RA 1991Aging and the immune functionInt Rev Cytol124187215Google Scholar
  50. Odio, M, Brodish, A, Ricardo, MJ ,Jr 1987Effects on immune responses by crhonic stress are modulated by agingBrain Behav Immun1204215Google Scholar
  51. Offner, PJ, Moore, EE, Biffl, WL 1999Male gender is a risk factor for major infections after surgeryArch Surg Chicago134935938Google Scholar
  52. Olsen, NJ, Kovacs, WJ 1996Gonadal steroids and immunityEndocrin Rev17369384Google Scholar
  53. Ortega, E, García, JJ, De la Fuente,  M 2000Modulation of adherence and chemotaxis of macrophage by norepinephrine Influence of ageing. Mol Cell Biochem203113117Google Scholar
  54. Pahlavani, MA, Richardson, A 1996The effect of age on the expression of interleukin-2Mech Ageing Dev89125154Google Scholar
  55. Pawelec, G, Barnett, Y, Forsey, R, Frasca, D, Globerson, A, McLeod, J, Caruso, C, Franceschi, C, Fülop, T, Gupta, S, Mariani, E, Mocchegiani, E, Solana, R 2002T cells and agingFrontiers Biosci 7D1056D1183Google Scholar
  56. Persky, AM, Green, PS, Stubley, L, Howell, CO, Zaulyanov, L, Brazeau, GA, Simpkins, JW 2000Protective effect of estrogens against oxidative damage to heart and skeletal muscle in␣vivo and in vitroProc Soc Exp Biol Med2235966Google Scholar
  57. Pfeilschifter, J, Köditz, R, Pfohl, M, Schatz, H 2002Changes in proinflammatory cytokine activity after menopauseEndocrin Rev2390119Google Scholar
  58. Ruiz-Larrea, MB, Leal, AM, Martin, C, Martinez, R, Lacort, M 1997Antioxidant action of estrogens in rat hepatocytesRev Esp Fisiol53225229Google Scholar
  59. Schindowski, K, Fröhlich, L, Maurer, K, Müller, WE, Eckert, A 2002Age-related impairment of human T lymphocytes activation: specific differences between CD4+ and CD8+ subsetsMech Ageing Dev123375390Google Scholar
  60. Shames, RS 2002Gender differences in the development and function of the immune systemJ Adol Health305970Google Scholar
  61. Sharon, N 1983Lectin receptors as lymphocyte surface markersAdv Immunol34213298Google Scholar
  62. Solana, R, Mariani, E 2000NK and NK/T cells in human senescenceVaccine1816131620Google Scholar
  63. Solana, R, Pawelec, G 1998Molecular and cellular basis of immunosenescenceMech Ageing Dev102115129Google Scholar
  64. Solana, R, Alonso, MC, Peña, J 1999Natural killer cells in healthy agingExp Gerontol34435443Google Scholar
  65. Verthelyi, D 2001Sex hormones as immunomodulators in health and diseaseInt Immunopharmacol1983993Google Scholar
  66. Vom Saal, FS, CE, Finch, JF, Nelson 1994

    Natural history and mechanisms of reproductive aging in humans, laboratory rodents and other selected vertebrates

    Knobil, ENeill, JD eds. The Physiology of Reproduction2Raven PressNew York12131314
    Google Scholar
  67. Wayne, SJ, Rhyne, RL, Garry, PJ, Goodwin, JS 1990Cell-mediated immunity as a predictor of morbility and mortality in subjects over 60J Gerontol454548Google Scholar
  68. Wight, E, Kung, CF, Moreau, P, Takase, H, Bersinger, NA, Luscher, TF 2000Aging, serum estradiol levels, and pregnancy differentially affect vascular reactivity of the rat uterine arteryJ Soc Gynecol Investig7106113Google Scholar
  69. Windmill, KF, Lee, VM 1998Effects of castration on the lymphocytes of the thymus, spleen and lymph nodesTiss Cell30104111Google Scholar
  70. Wu, WT, Pahlavani, M, Cheung, HT, Richardson, A 1986The effect of aging on the expression of interleukin 2 messenger ribonucleid acidCell Immunol100224231Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Mónica De La Fuente
    • 1
  • Isabel Baeza
    • 1
  • Noelia Guayerbas
    • 1
  • Marta Puerto
    • 1
  • Carmen Castillo
    • 2
  • Veronica Salazar
    • 2
  • Carmen Ariznavarreta
    • 2
  • Jesus A. F-tresguerres
    • 2
  1. 1.Department of Animal Physiology, Faculty of Biological SciencesComplutense UniversityMadridSpain
  2. 2.Department of Physiology, Faculty of MedicineComplutense UniversityMadridSpain

Personalised recommendations