Phenotypic and Functional Changes of Circulating Monocytes in Elderly

  • Lia Ginaldi
  • Massimo De Martinis
Living reference work entry


Aging is characterized by a decline in immune functions with increased susceptibility to infections, which is associated with inflammation and increased risk of chronic diseases. Aging therefore represents a state of paradox where chronic inflammation is associated with declining immune responses. This peculiar finding, known as inflammaging, is mainly sustained by cells of the innate immunity. Immunosenescence might therefore be regarded as a situation in which the specific immune system deteriorates with age, while the innate immunity is negligibly affected and, in some cases, almost upregulated. The innate immune system is composed of a network of cells including neutrophils, NK cells, monocytes/macrophages, and dendritic cells that mediate the earliest interactions with pathogens. Age-associated defects are observed in the activation of all of these cell types, linked to compromised signal transduction pathways. Moreover, ageing is also characterized by a constitutive proinflammatory environment with persistent low-grade innate immune activation that may augment dysfunctions of these cell types. Thus, immunosenescence in the innate immune system reflect dysregulation, rather than exclusively impaired function. One of the key constituents of the innate immune system is monocytes. Circulating monocytes are important mediators of the inflammatory response, acting as a major source of resident tissue antigen presenting cells and serum cytokines. They represent a number of distinct subpopulations whose functional capacity and relative concentrations are known to change with age. Although the age-related changes in the specific immunity are commonly considered the hallmarks of immunosenescence, the central role of the complex remodeling of first-line defense cells, such as monocytes, is gradually emerging. For example, chemotaxis and phagocytosis, as well as antigen processing and presentation, are depressed, whereas cell activation and the secretion of inflammatory cytokines, such as IL-1, IL-6, TNF, are markedly increased. Changes in the expression of functionally important cellular receptors on monocyte surface can also contribute to the modification of immune function characteristic of the elderly. Moreover, significant sex-related differences in innate immune function recently emerged; interestingly, there is a differential impact of age on the phenotype, function, and activation of monocyte subsets in men and women, justifying a gender perspective in the study of monocytes in the elderly.


Monocytes Macrophages Innate Immunity Ageing 


  1. Agius E, Lacy KE, Vukmanovic-Stejic M, Jagger AL et al (2009) Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J Exp Med 206:1929–1940CrossRefPubMedPubMedCentralGoogle Scholar
  2. Agrawal A, Agrawal S, Cao JN et al (2007) Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol 178:6912–6922CrossRefPubMedGoogle Scholar
  3. Ahluwalia N, Mastro AM, Ball R et al (2001) Cytokine production by stimulated mononuclear cells did not change with aging in apparently healthy, well-nourished women. Mech Ageing Dev 122:1269–1279CrossRefPubMedGoogle Scholar
  4. Albright JW, Albright JF (1994) Ageing alters the competence of the immune system to control parasitic infection. Immunol Lett 40:279–285CrossRefPubMedGoogle Scholar
  5. Anderson CF, Mosser DM (2002) A novel phenotype for an activated macrophage: the type 2 activated macrophage. J Leukoc Biol 72:101–106PubMedGoogle Scholar
  6. Antonini JM, Roberts JR, Clarke RW, Yang HM et al (2001) Effect of age on respiratory defense mechanisms: pulmonary bacterial clearance in Fischer 344 rats after intratracheal instillation of Listeria monocytogenes. Chest 120:240–249CrossRefPubMedGoogle Scholar
  7. Artz AS, Fergusson D, Drinka PJ et al (2004) Mechanisms of unexplained anemia in the nursing home. J Am Geriatr Soc 52:423–427CrossRefPubMedGoogle Scholar
  8. Ashcroft GS, Horan MA, Ferguson MW et al (1998) Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest 78:47–58PubMedGoogle Scholar
  9. Asquith M, Kristen Haberthur K, Monica Brown M et al (2012) Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta). Pathobiol Aging Age Relat Dis 2.
  10. Barisione C, Garibaldi S, Ghigliotti G et al (2010) CD14+CD16+ monocyte subset levels in heart failure patients. Dis Markers 28:115–124CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bautmans L, Njemini R, Lambert M et al (2005) Circulating acute phase mediators and skeletal muscle performance in hospitalized geriatric patients. J Gerontol A Biol Sci Med Sci 60:361–367CrossRefPubMedGoogle Scholar
  12. Beenakker KGM, Westendorp RGJ, de Craen AJM et al (2013) Pro-inflammatory capacity of classically activated monocytes relates positively to muscle mass and strength. Aging Cell 12:682–689CrossRefPubMedGoogle Scholar
  13. Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signaling. Nature 430:257–263CrossRefPubMedGoogle Scholar
  14. Boehmer ED, Goral J, Faunce DE, Kovacs EJ (2004) Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75:342–349CrossRefPubMedGoogle Scholar
  15. Boehmer ED, Meehan MJ, Cutro BT, Kovacs EJ (2005) Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway. Mech Ageing Dev 126:1305–1313CrossRefPubMedGoogle Scholar
  16. Bondada S, Wu H, Robertson DA, Chelvarajan RL (2000) Accessory cell defect in unresponsiveness of neonates and aged to polysaccharide vaccines. Vaccine 19:557–565CrossRefPubMedGoogle Scholar
  17. Bradley SF, Kauffman CA (1990) Aging and the response to salmonella infection. Exp Gerontol 25:75–80CrossRefPubMedGoogle Scholar
  18. Bruunsgaard H, Ladelund S, Pedersen AN et al (2003) Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clin Exp Immunol 132:24–31CrossRefPubMedPubMedCentralGoogle Scholar
  19. Castle SC (2000) Clinical relevance of age related immune dysfunction. Clin Infect Dis 31:578–585CrossRefPubMedGoogle Scholar
  20. Chelvarajan RL, Collins SM, Van Willigen JM, Bondada S (2005) The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function. J Leukoc Biol 77:503–512CrossRefPubMedGoogle Scholar
  21. Chelvarajan RL, Liu Y, Popa D, Getchell ML et al (2006) Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages. J Leukoc Biol 79:1314–1327CrossRefPubMedGoogle Scholar
  22. Chinetti G, Fruchart JC, Staels B (2000) Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 49:497–505CrossRefPubMedGoogle Scholar
  23. Chiricolo M, Morini MC, Mancini R et al (1995) Cell adhesion molecules CD11a and CD18 in blood monocytes in old age and the consequences for immunological dysfunction. Preliminary results. Gerontology 41:227–234CrossRefPubMedGoogle Scholar
  24. Clark RB (2002) The role of PPARs in inflammation and immunily. J Leukoc Biol 21:388–400Google Scholar
  25. Corrales-Medina VF, Alvarez KN, Weissfeld LA et al (2015) Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA 313:264–274CrossRefPubMedPubMedCentralGoogle Scholar
  26. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252CrossRefPubMedGoogle Scholar
  27. de Fougerolles AR, Qin X, Springer TA (1994) Characterization of the function of intercellular adhesion molecule (ICAM)-3 and comparison with ICAM-1 and ICAM-2 in immune responses. J Exp Med 179:619–629CrossRefPubMedGoogle Scholar
  28. De Martinis M, Modesti M, Loreto MF et al (2000) Adhesion molecules on peripheral blood lymphocyte subpopulations in the elderly. Life Sci 68:139–151CrossRefPubMedGoogle Scholar
  29. De Martinis M, Modesti M, Ginaldi L (2004) Phenotypic and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol Cell Biol 82:415–420CrossRefPubMedGoogle Scholar
  30. del Pozo MA, Pulido R, Munoz C, Alvarez V et al (1994) Regulation of ICAM-3 (CD50) membrane expression on human neutrophils through proteolytic shedding mechanism. Eur J Immunol 24:2586–2594CrossRefPubMedGoogle Scholar
  31. Della Bella S, Bierti L, Presicce P et al (2007) Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol 122:220–228CrossRefPubMedGoogle Scholar
  32. DeVeale B, Brummet TL, Seroude L et al (2004) Immunity and aging: the enemy within? Aging Cell 3:195–208CrossRefPubMedGoogle Scholar
  33. Dillon S, Agrawal A, Van Dyke T et al (2004) A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol 172:4733–4743CrossRefPubMedGoogle Scholar
  34. Ding A, Hwang S, Schwab R (1994) Effect of aging on murine macrophages. Diminished response to IFN-gamma for enhanced oxidative metabolism. J Immunol 153:2146–2152PubMedGoogle Scholar
  35. Donnelly RP, Dickensheets H, Finbloom DS (1999) The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagacytes. J Interferon Cytokine Res 99:563–573CrossRefGoogle Scholar
  36. Donnini A, Argentati K, Mancini R et al (2002) Phenotype, antigen-presenting capacity, and migration of antigen-presenting cells in young and old age. Exp Gerontol 37:1097–1112CrossRefPubMedGoogle Scholar
  37. ElAli A, LeBlanc NJ (2016) The role of monocytes in ischemic stroke pathobiology: new avenues to explore. Front Aging Neurosci 8:29. Scholar
  38. Elenkov IJ, Chrousos GP (2002) Stress hormones, proinflammatory and anti-inflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 966:290–303CrossRefPubMedGoogle Scholar
  39. Feart C, Pallet V, Boucheron C, Higueret D et al (2005) Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells. Eur J Endocrinol 152:449–458CrossRefPubMedGoogle Scholar
  40. Fernandez S, Jose P, Avdiushko MG et al (2004) Inhibition of IL-10 receptor function in alveolar macrophages by Toll-like receptor agonists. J Immunol 172:2613–2620CrossRefPubMedGoogle Scholar
  41. Fortunel NO, Hatzfeld A, Hatzfeld JA et al (2000) Transforming growth factor-α: pleiotropic role in the regulation of hematopoiesis. Blood 96:2022–2036PubMedGoogle Scholar
  42. Franceschi C, Bonafè M (2003) Centenarians as a model of healthy aging. Biochem Soc Trans 31:457–461CrossRefPubMedGoogle Scholar
  43. Franceschi C, Bonafe M, Valensin S et al (2000a) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18:1717–1720CrossRefPubMedGoogle Scholar
  44. Franceschi C, Bonafe M, Valensin S et al (2000b) Inflammaging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254CrossRefPubMedGoogle Scholar
  45. Friedman G, Ben-Yehuda A, Dabach Y et al (1997) Scavanger receptor activity and expression of apolipoprotein E mRNA in monocyte derived macrophages of young and old healthy men. Atherosclerosis 128:67–73CrossRefPubMedGoogle Scholar
  46. Fuhrmann M, Bittner T, Jung CK et al (2010) Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13:411–413CrossRefPubMedPubMedCentralGoogle Scholar
  47. Gao JJ, Diesl V, Wittmann T et al (2002) Regulation of gene expression in mouse macrophages stimulated with bacterial CpG-DNA and lipopolysaccharide. J Leukoc Biol 72:1234–1245PubMedGoogle Scholar
  48. Garg M, Luo W, Kaplan AM, Bondada S (1996) Cellular basis of decreased immune responses to pneumococcal vaccines in aged mice. Infect Immun 64:4456–4462PubMedPubMedCentralGoogle Scholar
  49. Geiger H, Van Zant G (2002) Thc aging of lympho-hematopoietic stem cells. Nat Immunol 3:329–333CrossRefPubMedGoogle Scholar
  50. Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82CrossRefPubMedGoogle Scholar
  51. Geissmann F, Gordon S, Hume DA et al (2010) Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 10:453–460CrossRefPubMedPubMedCentralGoogle Scholar
  52. Ginaldi L, Sternberg H (2003) The immune system. In: Timiras PS (ed) Physiological basis of aging and geriatrics, 3rd edn. CRC Press, New York, pp 265–283Google Scholar
  53. Ginaldi L, Matutes E, Farahat N et al (1996) Differential expression of T cell antigens in normal peripheral blood lymphocytes: a quantitative analysis by flow cytometry. J Clin Pathol 49:539–544CrossRefPubMedPubMedCentralGoogle Scholar
  54. Ginaldi L, De Martinis M, D’Ostilio A et al (1999) The immune system in the elderly. III. Innate immunity. Immunol Res 20:117–126CrossRefPubMedGoogle Scholar
  55. Ginaldi L, De Martinis M, Modesti M et al (2000) Immunophenotypical changes of T lymphocytes in the elderly. Gerontology 46:242–248CrossRefPubMedGoogle Scholar
  56. Ginaldi L, De Martinis M, D’Ostilio A et al (2001) Changes in the expression of surface receptors on lymphocyte subsets in the elderly: quantitative flow cytometry analysis. Am J Hematol 67:63–72CrossRefPubMedGoogle Scholar
  57. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404CrossRefPubMedGoogle Scholar
  58. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35CrossRefPubMedGoogle Scholar
  59. Gratchev A, Schledzewski K, Guillot P, Goerdt S (2001) Alternatively activated antigen-presenting cells: molecular repertoire, immune regulation, and healing. Skin Pharmacol Appl Skin Physiol 14:272–279CrossRefPubMedGoogle Scholar
  60. Greiwe JS, Cheng B, Rubin DC et al (2001) Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J 15:475–482CrossRefPubMedGoogle Scholar
  61. Hakim FT, Flomerfelt FA, Boyiadiis M, Gress RE (2004) Aging, immunity and cancer. Curr Opin Immunol 16:151–156CrossRefPubMedGoogle Scholar
  62. Hamada K, Vannier E, Sacheck JM et al (2005) Senescence of human skeletal muscle impairs the local inflammatory cytokine response to acute eccentric exercise. FASEB J 19:264–266CrossRefPubMedGoogle Scholar
  63. Hanna RN, Carlin LM, Hubbeling HG et al (2011) The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol 12:778–785CrossRefPubMedPubMedCentralGoogle Scholar
  64. Hausser G, Ludewig B, Gelderblom HR et al (1997) Monocyte-derived dendritic cells represent a transient stage of differentiation in the myeloid lineage. Immunobiology 197:534–542CrossRefPubMedGoogle Scholar
  65. Hayek MG, Mura C, Wu D et al (1997) Enhanced expression of inducible cyclooxygenase with age in murine macrophages. J Immunol 159:2445–2451PubMedGoogle Scholar
  66. Haynes L, Eaton SM, Bums EM et al (2004) Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo. J Immunol 172:5194–5199CrossRefPubMedPubMedCentralGoogle Scholar
  67. Hearps AC, Martin GE, Angelovich TA et al (2012) Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11:867–875CrossRefPubMedGoogle Scholar
  68. Heimbeck I, Hofer TP, Eder C et al (2010) Standardized single-platform assay for human monocyte subpopulations: lower CD14+CD16++ monocytes in females. Cytometry 77:823–830CrossRefPubMedGoogle Scholar
  69. Hochstrasser T, Marksteiner J, Humpel C (2012) Telomere length is age-dependent and reduced in monocytes of Alzheimer patients. Exp Gerontol 47:160–163CrossRefPubMedPubMedCentralGoogle Scholar
  70. Hsu HC, Scott DK, Mountz JD (2005) Impaired apoptosis and immune senescence-cause or effect? Immunol Rev 205:130–146CrossRefPubMedGoogle Scholar
  71. Iwama H, Ohyashiki JH, Hayashi S et al (1998) Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from narmal individuals. Hum Genet 102:397–402CrossRefPubMedGoogle Scholar
  72. Iwasa H, Han J, Ishikawa F (2003) Mitogen-activated protein kinase p38 defines the common senescence-signaling pathway. Genes Cells 8:131–144CrossRefPubMedGoogle Scholar
  73. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216CrossRefPubMedGoogle Scholar
  74. Jozsi AC, Dupont-Versteegden EE, Taylor-Jones JM et al (2001) Molecular characteristics of aged muscle reflect an altered ability to respond to exercise. Int J Sport Nutr Exerc Metab 11:7–13Google Scholar
  75. Kaito M, Araya S-I, Gondo Y et al (2013) Relevance of distinct monocyte subsets to clinical course of ischemic stroke patients. PLoS One 8(8):e69409. Scholar
  76. Kang Y-S, Kim JY, Bmening SA et al (2004) The C-type lectin SIGN-Rl mediates uptake of the capsular polysaccharide of Streptococcus pneumoniae in the marginal zone of mouse spleen. Proc Natl Acad Sci 101:215–220CrossRefPubMedGoogle Scholar
  77. Kang KB, Van Der Zypp A, Iannazzo L, Majewski H (2006) Age-related changes in monocyte and platelet cyclooxygenase expression in healthy male humans and rats. Transl Res 148:289–294CrossRefPubMedGoogle Scholar
  78. Kessel JM, Hayflick J, Weyrich AS et al (1998) Coengagement of ICAM-3 and Fc receptors induces chemokine secretion and spreading by myeloid leucocytes. J Immunol 160:5579–5587PubMedGoogle Scholar
  79. Kiertscher S, Luo J, Dubinett SM, Roth MD (2000) Tumors promote altered maturation and early apoptosis of monocyte-derived dendritic cells. J Immunol 164:1269–1276CrossRefPubMedGoogle Scholar
  80. Kim TS, Lim HK, Lee JY et al (2008) Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 436:196–200CrossRefPubMedGoogle Scholar
  81. Kohut ML, Senchina DS, Madden KS et al (2004) Age effects on macrophage function vary by tissue site, nature of stimulant, and exercise behavior. Exp Gerontol 39:1347–1360CrossRefPubMedGoogle Scholar
  82. Kong KF, Delroux K, Wang X et al (2008) Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly. J Virol 82:7613–7623CrossRefPubMedPubMedCentralGoogle Scholar
  83. Krabbe KS, Pedersen M, Bruunsgaard H (2004) Inflammatory mediators in the elderly. Exp Gerontol 39:687–699CrossRefPubMedGoogle Scholar
  84. Kurt I, Abasli D, Cihan M et al (2007) Chitotriosidase levels in healthy elderly subjects. Ann N Y Acad Sci 1100:185–188CrossRefPubMedGoogle Scholar
  85. Lang R, Patel D, Moms JJ, Rutschman RL, Murray PJ (2002) Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol 169:2253–2263CrossRefPubMedGoogle Scholar
  86. Lavrovsky Y, Chatterjee B, Clark RA, Roy AK (2000) Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol 35:521–532CrossRefPubMedGoogle Scholar
  87. Le Morvan C, Cogne M, Drouet M (2001) HLA-A and HLA-B transcription decrease with ageing in peripheral blood leukocytes. Clin Exp Immunol 125:245–250CrossRefPubMedPubMedCentralGoogle Scholar
  88. Linton PJ, Thoman M (2014) Immunosenescence in monocytes, macrophages, and dendritic cells: lessons learned from the lung and heart. Immunol Lett 162:290–297CrossRefPubMedPubMedCentralGoogle Scholar
  89. Lloberas J, Celada A (2002) Effect of aging on macrophage function. Exp Gerontol 37:1323–1329CrossRefGoogle Scholar
  90. Lu Y, Tan CTY, Nyunt MSZ et al (2016) Inflammatory and immune markers associated with physical frailty syndrome: findings from Singapore longitudinal aging studies. Oncotarget 7:28783–28795PubMedPubMedCentralGoogle Scholar
  91. Ma J, Chen T, Mandelin J et al (2003) Regulation of macrophage activation. Cell Mol Life Sci 40:2334–2346CrossRefGoogle Scholar
  92. Malm C, Sjodin TL, Sjoberg B et al (2004) Leukocytes, cytokines, growth factors and hormones in human skeletal muscle and blood after uphill or downhill running. J Physiol 556:983–1000CrossRefPubMedPubMedCentralGoogle Scholar
  93. Mancuso P, McNish RW, Peters-Golden M, Brock TG (2001) Evaluation of phagocytosis and arachidonate metabolism by alveolar macrophages and recruited neutrophils from F344xBN rats of different ages. Mech Ageing Dev 122:1899–1913CrossRefPubMedGoogle Scholar
  94. Merino A, Buendia P, Martin-Malo A et al (2011) Senescent CD14+CD16+ monocytes exhibit proinflammatory and proatherosclerotic activity. J Immunol 186:1809–1815CrossRefPubMedGoogle Scholar
  95. Meydani SN, Han SN, Wu D (2011) Vitamin E and immune response in the aged: molecular mechanisms and clinical implications. Immunol Rev 205:269–284CrossRefGoogle Scholar
  96. Michaud JP, Hallé M, Lampron A et al (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid a improves Alzheimer’s disease-related pathology. Proc Natl Acad Sci 110:1941–1946CrossRefPubMedPubMedCentralGoogle Scholar
  97. Mills CD, Kincaid K, Alt JM et al (2000) M-1/M-2 macrophages and the Thl/Th2 paradigm. J Immunol 164:6166–6173CrossRefPubMedGoogle Scholar
  98. Min D, Brooks B, Wong J, Salomon R et al (2012) Alterations in monocyte CD16 in association with diabetes complications. Mediators Inflamm 2012:649083. Scholar
  99. Moffatt OD, Devitt A, Bell ED, Simmons DL, Gregory CD (1999) Macrophage recognition of ICAM-3 on apoptotic leukocytes. J Immunol 162:6800–6810PubMedGoogle Scholar
  100. Monti D, Salvioli S, Capri M et al (2000) Decreased susceptibility to ozidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians. Mech Ageing Dev 121:239–250CrossRefPubMedGoogle Scholar
  101. Montoya MC, Sancho D, Bonello G et al (2002) Role of ICAM-3 in the initial interaction of T lymphocytes and APCs. Nat Immunol 3:159–168CrossRefPubMedGoogle Scholar
  102. Mosser DM (2003) Thc many faces of macrophage activation. J Leukoc Biol 73:209–212CrossRefPubMedGoogle Scholar
  103. Naert G, Rivest S (2013) A deficiency in CCR2+ monocytes: the hidden side of Alzheimer’s disease. J Mol Cell Biol 5:284–293CrossRefPubMedGoogle Scholar
  104. Njemini R, Lambert M, Demanet C, Mets T (2006) The effect of aging and inflammation on heat shock protein 27 in human monocytes and lymphocytes. Exp Gerontol 41:312–319CrossRefPubMedGoogle Scholar
  105. Nyugen J, Agrawal S, Gollapudi S, Gupta S (2010) Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol 30:806–813CrossRefPubMedPubMedCentralGoogle Scholar
  106. Ogawa T, Kitagawa M, Hirokawa K et al (2000) Age-related changes of human bone marrow: a histometric estìmation of proliferative cells, apoptotlc cells, T cells, B cells and macrophages. Mech Ageing Dev 117:57–6882CrossRefPubMedGoogle Scholar
  107. Ogden S, Dearman RJ, Kimber I, Griffiths CEM (2011) The effect of ageing on phenotype and function of monocyte-derived Langerhans cells. Br J Dermatol 165:184–188CrossRefPubMedPubMedCentralGoogle Scholar
  108. Ono S, Tsujimoto H, Hiraki S et al (2005) Sex differences in cytokine production and surface antigen expression of peripheral blood mononuclear cells after surgery. Am J Surg 190:439–444CrossRefPubMedGoogle Scholar
  109. Ortega E, Garcia JJ, De la FM (2000) Modulation of adherence and chemotaxis of macrophages by norepinephrine. Influence of ageing. Mol Cell Biochem 203:113–117CrossRefPubMedGoogle Scholar
  110. Paats MS, Bergen IM, Hanselaar WE et al (2013) Local and systemic cytokine profiles in non severe and severe community-acquired pneumonia. Eur Respir J 41:1378–1385CrossRefPubMedGoogle Scholar
  111. Pascual V, Banchereau J, Palucka AK (2003) The central rote of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumatol 15:548–556CrossRefPubMedGoogle Scholar
  112. Pietschmann P, Hahn P, Kudlacek S et al (2000) Surface markers and transendothelial migration of dendritic cells from elderly subjects. Exp Gerontol 35:213–224CrossRefPubMedGoogle Scholar
  113. Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ (2004) Aging and innate immune cells. J Leukoc Biol 76:291–299CrossRefPubMedGoogle Scholar
  114. Plowden J, Renshaw-Hcelscher M, Engleman C et al (2004) Innate immunity in aging: impact on macrophage funclion. Aging Cell 3:161–167CrossRefPubMedGoogle Scholar
  115. Poynter ME, Daynes RA (1998) Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 273:32833–32841CrossRefPubMedGoogle Scholar
  116. Przybyla B, Gurley C, Harvey JF et al (2006) Aging alters macrophage properties in human skeletal muscle both at rest and in response to acute resistance exercise. Exp Gerontol 41:329–370CrossRefGoogle Scholar
  117. Puchta A, Naidoo A, Verschoor CP et al (2016) TNF drives monocyte dysfunction with age and results in impaired anti-pneumococcal immunity. PLoS Pathog 12:e1005368. Scholar
  118. Pulsatelli L, Meliconi R, Mazzetti I et al (2000) Chemokine production by peripheral blood mononuclear cells in elderly subjects. Mech Ageing Dev 20:89–100Google Scholar
  119. Qian BZ, Li J, Zhang H et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225CrossRefPubMedPubMedCentralGoogle Scholar
  120. Rainer TH, Lam N, Cocks RA (1999) Adrenaline upregulates monocyte L-selectin in vitro. Resuscitation 43:47–55CrossRefPubMedGoogle Scholar
  121. Rao KMK (2001) MAP kinase activation in macrophages. J Leukoc Biol 69:3–10PubMedGoogle Scholar
  122. Reiner AP, Lange EM, Jenny NS et al (2013) Soluble CD14: genome-wide association analysis and relationship to cardiovascular risk and mortality in the older adults. Arterioscler Thromb Vasc Biol 33:158. Scholar
  123. Renshaw M, Rockwell J, Engleman C et al (2002) Cutting edge: impaired toll-like receptor expression and function in aging. J Immunol 169:4697–4701CrossRefPubMedGoogle Scholar
  124. Reuben DB, Cheh AL, Harris TB et al (2002) Peripheral blood markers of inflammation predictmortality and functional decline in high-functioning community-dwelling older persons. J Am Geriatr Soc 50:638–644CrossRefPubMedGoogle Scholar
  125. Ricote M, Valledor AF, Glass CK (2004) Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis. Arterioscler Thromb Vasc Biol 24:230–239CrossRefPubMedGoogle Scholar
  126. Rossi M, Young JW (2005) Human dendritic cells: potent antigen presenting cells at the crossroads of innate and adaptive immunity. J Immunol 175:1373–1381CrossRefPubMedGoogle Scholar
  127. Sadeghi HM, Schnelle JF, Thoma JK et al (1999) Phenotypic and functional characteristics of circulating monocytes of elderly persons. Exp Gerontol 34:959–970CrossRefPubMedGoogle Scholar
  128. Saurwein-Teissl M, Blasko I, Zisterer K et al (2000) An imbalance between pro- and anti-inflammatory cytokines, a characteristic feature of old age. Cytokine 12:1160–1161CrossRefPubMedGoogle Scholar
  129. Sebastian C, Espia M, Serra M et al (2005) MacrophAging: a cellular and molecular review. Immunobiology 210:121–126CrossRefPubMedGoogle Scholar
  130. Seidler S, Zimmermann HW, Bartneck M et al (2010) Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol 11:30. Scholar
  131. Shaw AC, Joshi S, Greenwood H et al (2010) Aging of the innate immune system. Curr Opin Immunol 22:507–513CrossRefPubMedPubMedCentralGoogle Scholar
  132. Shortman K, Wu L (2004) Are dendritic cells end cells? Nat Immunol 5:1105–1106CrossRefPubMedGoogle Scholar
  133. Spencer NF, Norton SI, Harrison LL et al (1996) Dysregulation of IL-10 production with aging: possible linkage to the age-associated decline in DHEA and its sulfated derivative. Exp Gerontol 31:393–408CrossRefPubMedGoogle Scholar
  134. Spencer NF, Poynter ME, Im SY, Daynes RA (1997) Constitutive activation of NF-kappa B in an animal model of aging. lnt Immunol 9:1581–1588Google Scholar
  135. Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314CrossRefPubMedGoogle Scholar
  136. Starr R, Willson TA, Viney EM et al (1997) A family of cytokine-inducible inhibitors of signaling. Nature 387:917–921CrossRefPubMedGoogle Scholar
  137. Stout RD, Suttles J (2005) Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev 205:60–71CrossRefPubMedPubMedCentralGoogle Scholar
  138. Stout RD, Jiang C, Matta B et al (2005) Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 175:342–349CrossRefPubMedGoogle Scholar
  139. Swift ME, Bums AL, Gray KL, DiPietro LA (2001) Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 117:1027–1035CrossRefPubMedGoogle Scholar
  140. Swirski FK, Nahrendorf M (2013) Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science 339:161–166CrossRefPubMedPubMedCentralGoogle Scholar
  141. Thériault P, ElAli A, Rivest S (2015) The dynamics of monocytes and microglia in Alzheimer’s disease. Alzheimers Res Ther 41:41. Scholar
  142. Tracy RP (2003) Emerging relationships of inflammation, cardiovascular disease and chronic diseases of aging. Int J Obes Relat Metab Disord 27:29–34CrossRefGoogle Scholar
  143. Uyemura K, Castle SC, Makinodan T (2002) The frail elderly: role of dendritic cells in the susceptibility of infection. Mech Ageing Dev 123:955–962CrossRefPubMedGoogle Scholar
  144. Verschoor CP, Jennie Johnstone J, Jamie Millar J et al (2014) Alterations to the frequency and function of peripheral blood monocytes and associations with chronic disease in the advanced-age, frail elderly. PLoS One 9:e104522CrossRefPubMedPubMedCentralGoogle Scholar
  145. Visser M, Pahor M, Taaffe DR et al (2002) Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the health ABC study. J Gerontol 57:326–332CrossRefGoogle Scholar
  146. Walrand S, Guillet C, Boirie Y, Vasson MP (2006) Insulin differentially regulates monocyte and polymorphonuclear neutrophil functions in healthy young and elderly humans. J Clin Endocrinol Metab 91:2738–2748CrossRefPubMedGoogle Scholar
  147. Weng N (2001) Interplay between telomere length and telomerase in human leukocyte differentiation and aging. J Leukoc Biol 70:861–867PubMedGoogle Scholar
  148. Wichmann MW, Inthorn D, Andress HJ, Schildberg FW (2000) Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intensive Care Med 26:167–172CrossRefPubMedGoogle Scholar
  149. Williams JC, Fotherby MD, Foster LA et al (2000) Mononuclear cell adhesion to collagen ex vivo is related to pulse pressure in elderly subjects. Atherosclerosis 151:463–469CrossRefPubMedGoogle Scholar
  150. Wu D, Meydani SN (2004) Mechanism of age-associated upregulation in macrophage PGE2 synthesis. Brain Behav Immun 18:487–494CrossRefPubMedGoogle Scholar
  151. Wu D, Mura C, Beharka AA et al (1998) Age-associated increase in PGE2 synthesis and COX activity in murine macrophages is reversed by vitamin E. Am J Phys 275:661–668CrossRefGoogle Scholar
  152. Yoon P, Keylock KT, Hartman ME et al (2004) Macrophage hypo-responsiveness to interferon-gamma in aged mice is associated with impaired signaling through Jak-STAT. Mech Ageing Dev 125:137–143CrossRefPubMedGoogle Scholar
  153. Zhang Y, Blattman JN, Kennedy NJ et al (2004a) Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature 430:793–797CrossRefPubMedGoogle Scholar
  154. Zhang M, Tang H, Guo Z et al (2004b) Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nat Immunol 5:1124–1133CrossRefPubMedGoogle Scholar
  155. Ziegler-Heitbrock L, Hofer TP (2013) Toward a refined definition of monocyte subsets. Front Immunol 4:23. Scholar
  156. Zissel G, Schlaak M, Muller-Quemheim J (1999) Age-related decrease in accessory cell function of human alveolar macrophages. J Invest Med 47:51Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Life, Health, & Environmental SciencesUniversity of L’AquilaL’AquilaItaly

Personalised recommendations