Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®

Immune function in older adults

Antoine Azar, MD
Zuhair K Ballas, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Anna M Feldweg, MD


Normal functions of the immune system include defense against infections and detection and destruction of malignant or autoreactive cells. As the immune system ages and these capabilities decline, there is increased susceptibility to infections and cancer and an increased incidence of autoimmune disorders. The study of age-related changes in immune function is a relatively new area of investigation, which is limited by incomplete understanding of the complexities of immune mechanisms in general [1]. At present, most research is focused on defining normal changes in immune function at the basic science level, and much of the available data are from animal studies. In addition, there are no clinical interventions that have been definitively shown to counter immunologic aging.

This topic will review the changes observed in different components of the immune system with aging. The theoretical implications of these changes on health maintenance and vaccination of older adults are also discussed. Normal aging of other systems, nutrition in older adults, infections in older adults, and geriatric health maintenance (including current recommendations for vaccination) are reviewed elsewhere. (See "Normal aging" and "Geriatric nutrition: Nutritional issues in older adults" and "Evaluation of infection in the older adult" and "Geriatric health maintenance".)


Immunosenescence refers to the changes that occur in the immune system with increasing age. The clinical consequences of immunosenescence include an increased risk of infections, malignancy, and autoimmune disorders.

Infections — Pneumonia and influenza are among the top 10 causes of death in individuals aged 65 and older [2]. Nosocomial infections are also significantly increased in older adults. This could be the result of decreased immunologic function in addition to a decreased efficacy of vaccines in older adults. However, there are several other factors that are likely to contribute to increased infections in older adults, including malnutrition, comorbid conditions (eg, diabetes, chronic obstructive pulmonary disease), diminished mucosal barriers, decreased cough reflex, and mechanical changes to the urinary tract system, among others [3].

The clinical presentation of infections in older patients may be different from that in younger patients. Older adults with severe infections tend to have fewer symptoms and fever is absent or blunted in 20 to 30 percent. This suggests a decreased ability to mount inflammatory cytokine responses in the face of infection. Signs of infection in older adults can be nonspecific and include falls, delirium, anorexia, or generalized weakness [4]. (See "Evaluation of infection in the older adult".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2014. | This topic last updated: Jan 5, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2015 UpToDate, Inc.
  1. Agarwal S, Busse PJ. Innate and adaptive immunosenescence. Ann Allergy Asthma Immunol 2010; 104:183.
  2. Heron M, Hoyert DL, Murphy SL, et al. Deaths: final data for 2006. Natl Vital Stat Rep 2009; 57:1.
  3. Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis 2002; 2:659.
  4. Norman DC. Fever in the elderly. Clin Infect Dis 2000; 31:148.
  5. Robertson RG, Montagnini M. Geriatric failure to thrive. Am Fam Physician 2004; 70:343.
  6. Egbert AM. The dwindles: failure to thrive in older patients. Nutr Rev 1996; 54:S25.
  7. Malaguarnera L, Cristaldi E, Malaguarnera M. The role of immunity in elderly cancer. Crit Rev Oncol Hematol 2010; 74:40.
  8. Aprahamian T, Takemura Y, Goukassian D, Walsh K. Ageing is associated with diminished apoptotic cell clearance in vivo. Clin Exp Immunol 2008; 152:448.
  9. Ramos-Casals M, Brito-Zerón P, López-Soto A, Font J. Systemic autoimmune diseases in elderly patients: atypical presentation and association with neoplasia. Autoimmun Rev 2004; 3:376.
  10. Deal CL, Meenan RF, Goldenberg DL, et al. The clinical features of elderly-onset rheumatoid arthritis. A comparison with younger-onset disease of similar duration. Arthritis Rheum 1985; 28:987.
  11. Drey M, Kaiser MJ. [Malnutrition in the elderly]. Dtsch Med Wochenschr 2011; 136:176.
  12. Fülöp T, Larbi A, Hirokawa K, et al. Immunosupportive therapies in aging. Clin Interv Aging 2007; 2:33.
  13. Persson MD, Brismar KE, Katzarski KS, et al. Nutritional status using mini nutritional assessment and subjective global assessment predict mortality in geriatric patients. J Am Geriatr Soc 2002; 50:1996.
  14. Volkert D, Saeglitz C, Gueldenzoph H, et al. Undiagnosed malnutrition and nutrition-related problems in geriatric patients. J Nutr Health Aging 2010; 14:387.
  15. Kawakami K, Kadota J, Iida K, et al. Reduced immune function and malnutrition in the elderly. Tohoku J Exp Med 1999; 187:157.
  16. Chandra RK. Nutrition and the immune system from birth to old age. Eur J Clin Nutr 2002; 56 Suppl 3:S73.
  17. Cunha DF, Cunha SF, Unamuno MR, Vannucchi H. Serum levels assessment of vitamin A, E, C, B2 and carotenoids in malnourished and non-malnourished hospitalized elderly patients. Clin Nutr 2001; 20:167.
  18. Heseker H, Schneider R. Requirement and supply of vitamin C, E and beta-carotene for elderly men and women. Eur J Clin Nutr 1994; 48:118.
  19. Clarke R, Refsum H, Birks J, et al. Screening for vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr 2003; 77:1241.
  20. Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004; 171:251.
  21. Spinneker A, Sola R, Lemmen V, et al. Vitamin B6 status, deficiency and its consequences--an overview. Nutr Hosp 2007; 22:7.
  22. Gloth FM 3rd, Gundberg CM, Hollis BW, et al. Vitamin D deficiency in homebound elderly persons. JAMA 1995; 274:1683.
  23. Vaquero MP. Magnesium and trace elements in the elderly: intake, status and recommendations. J Nutr Health Aging 2002; 6:147.
  24. Carmel R. Nutritional anemias and the elderly. Semin Hematol 2008; 45:225.
  25. Geiger H, Rudolph KL. Aging in the lympho-hematopoietic stem cell compartment. Trends Immunol 2009; 30:360.
  26. Vaziri H, Dragowska W, Allsopp RC, et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci U S A 1994; 91:9857.
  27. Cancro MP, Hao Y, Scholz JL, et al. B cells and aging: molecules and mechanisms. Trends Immunol 2009; 30:313.
  28. Chambers SM, Goodell MA. Hematopoietic stem cell aging: wrinkles in stem cell potential. Stem Cell Rev 2007; 3:201.
  29. Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int 2009; 22:1041.
  30. Shaw AC, Joshi S, Greenwood H, et al. Aging of the innate immune system. Curr Opin Immunol 2010; 22:507.
  31. Boehmer ED, Goral J, Faunce DE, Kovacs EJ. Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 2004; 75:342.
  32. van Duin D, Mohanty S, Thomas V, et al. Age-associated defect in human TLR-1/2 function. J Immunol 2007; 178:970.
  33. Ogawa T, Kitagawa M, Hirokawa K. Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mech Ageing Dev 2000; 117:57.
  34. Plowden J, Renshaw-Hoelscher M, Engleman C, et al. Innate immunity in aging: impact on macrophage function. Aging Cell 2004; 3:161.
  35. Agius E, Lacy KE, Vukmanovic-Stejic M, et al. Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J Exp Med 2009; 206:1929.
  36. Gomez CR, Nomellini V, Faunce DE, Kovacs EJ. Innate immunity and aging. Exp Gerontol 2008; 43:718.
  37. Wessels I, Jansen J, Rink L, Uciechowski P. Immunosenescence of polymorphonuclear neutrophils. ScientificWorldJournal 2010; 10:145.
  38. Panda A, Arjona A, Sapey E, et al. Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 2009; 30:325.
  39. Borrego F, Alonso MC, Galiani MD, et al. NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol 1999; 34:253.
  40. Hayhoe RP, Henson SM, Akbar AN, Palmer DB. Variation of human natural killer cell phenotypes with age: identification of a unique KLRG1-negative subset. Hum Immunol 2010; 71:676.
  41. Le Garff-Tavernier M, Béziat V, Decocq J, et al. Human NK cells display major phenotypic and functional changes over the life span. Aging Cell 2010; 9:527.
  42. Ogata K, An E, Shioi Y, et al. Association between natural killer cell activity and infection in immunologically normal elderly people. Clin Exp Immunol 2001; 124:392.
  43. Sansoni P, Cossarizza A, Brianti V, et al. Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 1993; 82:2767.
  44. Berzins SP, Smyth MJ, Baxter AG. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 2011; 11:131.
  45. Zajonc DM, Kronenberg M. Carbohydrate specificity of the recognition of diverse glycolipids by natural killer T cells. Immunol Rev 2009; 230:188.
  46. DelaRosa O, Tarazona R, Casado JG, et al. Valpha24+ NKT cells are decreased in elderly humans. Exp Gerontol 2002; 37:213.
  47. Jing Y, Gravenstein S, Chaganty NR, et al. Aging is associated with a rapid decline in frequency, alterations in subset composition, and enhanced Th2 response in CD1d-restricted NKT cells from human peripheral blood. Exp Gerontol 2007; 42:719.
  48. Peralbo E, DelaRosa O, Gayoso I, et al. Decreased frequency and proliferative response of invariant Valpha24Vbeta11 natural killer T (iNKT) cells in healthy elderly. Biogerontology 2006; 7:483.
  49. Agrawal A, Agrawal S, Gupta S. Dendritic cells in human aging. Exp Gerontol 2007; 42:421.
  50. Jing Y, Shaheen E, Drake RR, et al. Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol 2009; 70:777.
  51. Panda A, Qian F, Mohanty S, et al. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol 2010; 184:2518.
  52. Flores KG, Li J, Sempowski GD, et al. Analysis of the human thymic perivascular space during aging. J Clin Invest 1999; 104:1031.
  53. Naylor K, Li G, Vallejo AN, et al. The influence of age on T cell generation and TCR diversity. J Immunol 2005; 174:7446.
  54. Nasi M, Troiano L, Lugli E, et al. Thymic output and functionality of the IL-7/IL-7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging Cell 2006; 5:167.
  55. Li G, Yu M, Lee WW, et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med 2012; 18:1518.
  56. Kaltoft K. Cytokine-driven immortalization of in vitro activated human T lymphocytes. CD28 expression correlates inversely with cell population doublings. Exp Clin Immunogenet 1998; 15:84.
  57. Haynes L, Maue AC. Effects of aging on T cell function. Curr Opin Immunol 2009; 21:414.
  58. Tsaknaridis L, Spencer L, Culbertson N, et al. Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res 2003; 74:296.
  59. Uciechowski P, Kahmann L, Plümäkers B, et al. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation. Exp Gerontol 2008; 43:493.
  60. Cakman I, Rohwer J, Schütz RM, et al. Dysregulation between TH1 and TH2 T cell subpopulations in the elderly. Mech Ageing Dev 1996; 87:197.
  61. Mansfield AS, Nevala WK, Dronca RS, et al. Normal ageing is associated with an increase in Th2 cells, MCP-1 (CCL1) and RANTES (CCL5), with differences in sCD40L and PDGF-AA between sexes. Clin Exp Immunol 2012; 170:186.
  62. Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, et al. Altered Th1/Th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol 2000; 120:267.
  63. Frasca D, Blomberg BB. Effects of aging on B cell function. Curr Opin Immunol 2009; 21:425.
  64. Frasca D, Landin AM, Lechner SC, et al. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol 2008; 180:5283.
  65. Lazuardi L, Jenewein B, Wolf AM, et al. Age-related loss of naïve T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology 2005; 114:37.
  66. Gibson KL, Wu YC, Barnett Y, et al. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 2009; 8:18.
  67. Henson SM, Akbar AN. Memory T-cell homeostasis and senescence during aging. Adv Exp Med Biol 2010; 684:189.
  68. Stacy S, Krolick KA, Infante AJ, Kraig E. Immunological memory and late onset autoimmunity. Mech Ageing Dev 2002; 123:975.
  69. Kovaiou RD, Weiskirchner I, Keller M, et al. Age-related differences in phenotype and function of CD4+ T cells are due to a phenotypic shift from naive to memory effector CD4+ T cells. Int Immunol 2005; 17:1359.
  70. Hancock K, Veguilla V, Lu X, et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N Engl J Med 2009; 361:1945.
  71. Monsalvo AC, Batalle JP, Lopez MF, et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med 2011; 17:195.
  72. Haynes L, Eaton SM, Burns EM, et al. Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen. J Exp Med 2005; 201:845.
  73. Kaszubowska L. Telomere shortening and ageing of the immune system. J Physiol Pharmacol 2008; 59 Suppl 9:169.
  74. Risques RA, Arbeev KG, Yashin AI, et al. Leukocyte telomere length is associated with disability in older u.s. Population. J Am Geriatr Soc 2010; 58:1289.
  75. Koch S, Larbi A, Ozcelik D, et al. Cytomegalovirus infection: a driving force in human T cell immunosenescence. Ann N Y Acad Sci 2007; 1114:23.
  76. Pawelec G, Ferguson FG, Wikby A. The SENIEUR protocol after 16 years. Mech Ageing Dev 2001; 122:132.
  77. Wikby A, Johansson B, Ferguson F, Olsson J. Age-related changes in immune parameters in a very old population of Swedish people: a longitudinal study. Exp Gerontol 1994; 29:531.
  78. Pawelec G, Ouyang Q, Colonna-Romano G, et al. Is human immunosenescence clinically relevant? Looking for 'immunological risk phenotypes'. Trends Immunol 2002; 23:330.
  79. Derhovanessian E, Maier AB, Beck R, et al. Hallmark features of immunosenescence are absent in familial longevity. J Immunol 2010; 185:4618.
  80. Strindhall J, Nilsson BO, Löfgren S, et al. No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol 2007; 42:753.
  81. Collerton J, Martin-Ruiz C, Davies K, et al. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study. Mech Ageing Dev 2012; 133:456.
  82. Adriaensen W, Derhovanessian E, Vaes B, et al. CD4:8 Ratio >5 Is Associated With a Dominant Naive T-Cell Phenotype and Impaired Physical Functioning in CMV-Seropositive Very Elderly People: Results From the BELFRAIL Study. J Gerontol A Biol Sci Med Sci 2014.
  83. Strindhall J, Skog M, Ernerudh J, et al. The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age (Dordr) 2013; 35:985.
  84. Maggini S, Wintergerst ES, Beveridge S, Hornig DH. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. Br J Nutr 2007; 98 Suppl 1:S29.
  85. High KP. Micronutrient supplementation and immune function in the elderly. Clin Infect Dis 1999; 28:717.
  86. Chandra RK. Impact of nutritional status and nutrient supplements on immune responses and incidence of infection in older individuals. Ageing Res Rev 2004; 3:91.
  87. Gibson A, Edgar JD, Neville CE, et al. Effect of fruit and vegetable consumption on immune function in older people: a randomized controlled trial. Am J Clin Nutr 2012; 96:1429.
  88. DiPenta JM, Johnson JG, Murphy RJ. Natural killer cells and exercise training in the elderly: a review. Can J Appl Physiol 2004; 29:419.
  89. Ogawa K, Oka J, Yamakawa J, Higuchi M. A single bout of exercise influences natural killer cells in elderly women, especially those who are habitually active. J Strength Cond Res 2005; 19:45.
  90. Kohut ML, Arntson BA, Lee W, et al. Moderate exercise improves antibody response to influenza immunization in older adults. Vaccine 2004; 22:2298.
  91. Haaland DA, Sabljic TF, Baribeau DA, et al. Is regular exercise a friend or foe of the aging immune system? A systematic review. Clin J Sport Med 2008; 18:539.
  92. Bauer ME, Muller GC, Correa BL, et al. Psychoneuroendocrine interventions aimed at attenuating immunosenescence: a review. Biogerontology 2013; 14:9.
  93. Busse WW, Peters SP, Fenton MJ, et al. Vaccination of patients with mild and severe asthma with a 2009 pandemic H1N1 influenza virus vaccine. J Allergy Clin Immunol 2011; 127:130.
  94. Iob A, Brianti G, Zamparo E, Gallo T. Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy. Epidemiol Infect 2005; 133:687.
  95. Li R, Fang H, Li Y, et al. Safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine in elderly Chinese subjects. Immun Ageing 2008; 5:2.
  96. de Roux A, Schmöle-Thoma B, Siber GR, et al. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin Infect Dis 2008; 46:1015.
  97. Hsu HE, Shutt KA, Moore MR, et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N Engl J Med 2009; 360:244.
  98. Roos D, Homan-Müller JW, Weening RS. Effect of cytochalasin B on the oxidative metabolism of human peripheral blood granulocytes. Biochem Biophys Res Commun 1976; 68:43.
  99. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014; 63:822.
  100. Sankilampi U, Honkanen PO, Bloigu A, et al. Antibody response to pneumococcal capsular polysaccharide vaccine in the elderly. J Infect Dis 1996; 173:387.
  101. Romero-Steiner S, Musher DM, Cetron MS, et al. Reduction in functional antibody activity against Streptococcus pneumoniae in vaccinated elderly individuals highly correlates with decreased IgG antibody avidity. Clin Infect Dis 1999; 29:281.
  102. Andrews NJ, Waight PA, George RC, et al. Impact and effectiveness of 23-valent pneumococcal polysaccharide vaccine against invasive pneumococcal disease in the elderly in England and Wales. Vaccine 2012; 30:6802.
  103. Schubert C. New vaccine tailored to the weakened elderly immune system. Nat Med 2010; 16:137.
  104. Kaml M, Weiskirchner I, Keller M, et al. Booster vaccination in the elderly: their success depends on the vaccine type applied earlier in life as well as on pre-vaccination antibody titers. Vaccine 2006; 24:6808.
  105. Couch RB, Bayas JM, Caso C, et al. Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older. BMC Infect Dis 2014; 14:425.
  106. Steinhagen F, Kinjo T, Bode C, Klinman DM. TLR-based immune adjuvants. Vaccine 2011; 29:3341.
  107. Holland D, Booy R, De Looze F, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis 2008; 198:650.
  108. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011; 11:330.
  109. Sportès C, Hakim FT, Memon SA, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 2008; 205:1701.
  110. Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 2009; 119:997.
  111. Davaro F, Forde SD, Garfield M, et al. 3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1β interferes with mature IL-1β signaling. J Biol Chem 2014; 289:16214.
  112. Ruiz-Limon P, Barbarroja N, Perez-Sanchez C, et al. Atherosclerosis and cardiovascular disease in systemic lupus erythematosus: effects of in vivo statin treatment. Ann Rheum Dis 2014.
  113. Lyons A, Murphy KJ, Clarke R, Lynch MA. Atorvastatin prevents age-related and amyloid-β-induced microglial activation by blocking interferon-γ release from natural killer cells in the brain. J Neuroinflammation 2011; 8:27.
  114. Olivieri F, Mazzanti I, Abbatecola AM, et al. Telomere/Telomerase system: a new target of statins pleiotropic effect? Curr Vasc Pharmacol 2012; 10:216.
  115. Siegrist CA, Aspinall R. B-cell responses to vaccination at the extremes of age. Nat Rev Immunol 2009; 9:185.
  116. Weinberger B, Herndler-Brandstetter D, Schwanninger A, et al. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis 2008; 46:1078.
  117. Schenkein JG, Park S, Nahm MH. Pneumococcal vaccination in older adults induces antibodies with low opsonic capacity and reduced antibody potency. Vaccine 2008; 26:5521.
  118. Musher DM, Manof SB, Liss C, et al. Safety and antibody response, including antibody persistence for 5 years, after primary vaccination or revaccination with pneumococcal polysaccharide vaccine in middle-aged and older adults. J Infect Dis 2010; 201:516.
  119. Ridda I, Macintyre CR, Lindley R, et al. Immunological responses to pneumococcal vaccine in frail older people. Vaccine 2009; 27:1628.