The twilight of immunity: emerging concepts in aging of the immune system

Abstract

Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Defective activation of naive CD8+ T cell responses with aging.
Fig. 2: Fibrotic changes as a consequence of tissue damage and aging.
Fig. 3: Age-associated changes in LNs.
Fig. 4: Systemic and tissue-specific consequences of CMV latency, micro-reactivation and full reactivation.

Change history

  • 03 September 2018

    In the version of this Review initially published, the type of cell in the final sentence of the legend to Figure 3 (group 2 innate lymphoid cells) was incorrect. The correct type of cell is group 3 innate lymphoid cells. The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1.

    Albright, J. F. & Albright, J. W. Aging, Immunity, and Infection (Humana Press, Totowa, NJ, 2003).

    Google Scholar 

  2. 2.

    Haynes, L., Eaton, S. M., Burns, E. M., Rincon, M. & Swain, S. L. Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo. J. Immunol. 172, 5194–5199 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. 3.

    Sharma, S., Dominguez, A. L., Hoelzinger, D. B. & Lustgarten, J. CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol. Immunother. 57, 549–561 (2008).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Lal, H. et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N. Engl. J. Med. 372, 2087–2096 (2015).

    PubMed  Article  Google Scholar 

  5. 5.

    Nikolich-Žugich, J. Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J. Immunol. 193, 2622–2629 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Hazeldine, J. & Lord, J. M. Innate immunesenescence: underlying mechanisms and clinical relevance. Biogerontology 16, 187–201 (2015).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Montgomery, R. R. & Shaw, A. C. Paradoxical changes in innate immunity in aging: recent progress and new directions. J. Leukoc. Biol. 98, 937–943 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Zhang, B. et al. Glimpse of natural selection of long-lived T-cell clones in healthy life. Proc. Natl. Acad. Sci. USA 113, 9858–9863 (2016).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Lord, J. M., Butcher, S., Killampali, V., Lascelles, D. & Salmon, M. Neutrophil ageing and immunesenescence. Mech. Ageing Dev. 122, 1521–1535 (2001).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Shaw, A. C., Joshi, S., Greenwood, H., Panda, A. & Lord, J. M. Aging of the innate immune system. Curr. Opin. Immunol. 22, 507–513 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Solana, R. et al. Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin. Immunol. 24, 331–341 (2012).

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Simell, B. et al. Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis. Vaccine 29, 1929–1934 (2011).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Tseng, C. W. et al. Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus. PLoS One 7, e41454 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    van Duin, D. et al. Age-associated defect in human TLR-1/2 function. J. Immunol. 178, 970–975 (2007).

    PubMed  Article  Google Scholar 

  15. 15.

    Manser, A. R. & Uhrberg, M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol. Immunother. 65, 417–426 (2016).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Fang, M., Roscoe, F. & Sigal, L. J. Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking. J. Exp. Med. 207, 2369–2381 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Aprahamian, T., Takemura, Y., Goukassian, D. & Walsh, K. Ageing is associated with diminished apoptotic cell clearance in vivo. Clin. Exp. Immunol. 152, 448–455 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Metcalf, T. U. et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 14, 421–432 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Metcalf, T. U. et al. Human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists. J. Immunol. 199, 1405–1417 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Cumberbatch, M., Dearman, R. J. & Kimber, I. Influence of ageing on Langerhans cell migration in mice: identification of a putative deficiency of epidermal interleukin-1beta. Immunology 105, 466–477 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Desai, A., Grolleau-Julius, A. & Yung, R. Leukocyte function in the aging immune system. J. Leukoc. Biol. 87, 1001–1009 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Zacca, E. R. et al. Aging impairs the ability of conventional dendritic cells to cross-prime CD8+ T cells upon stimulation with a TLR7 ligand. PLoS One 10, e0140672 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Chougnet, C. A. et al. Loss of phagocytic and antigen cross-presenting capacity in aging dendritic cells is associated with mitochondrial dysfunction. J. Immunol. 195, 2624–2632 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Uhrlaub, J. L., Smithey, M. J. & Nikolich-Žugich, J. Cutting edge: the aging immune system reveals the biological impact of direct antigen presentation on CD8 T cell responses. J. Immunol. 199, 403–407 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Zhao, J., Zhao, J., Legge, K. & Perlman, S. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Invest. 121, 4921–4930 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Chinn, I. K., Blackburn, C. C., Manley, N. R. & Sempowski, G. D. Changes in primary lymphoid organs with aging. Semin. Immunol. 24, 309–320 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Kline, G. H., Hayden, T. A. & Klinman, N. R. B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation. J. Immunol. 162, 3342–3349 (1999).

    PubMed  CAS  Google Scholar 

  28. 28.

    Stephan, R. P., Lill-Elghanian, D. A. & Witte, P. L. Development of B cells in aged mice: decline in the ability of pro-B cells to respond to IL-7 but not to other growth factors. J. Immunol. 158, 1598–1609 (1997).

    PubMed  CAS  Google Scholar 

  29. 29.

    Qi, Q. et al. Diversity and clonal selection in the human T-cell repertoire. Proc. Natl. Acad. Sci. USA 111, 13139–13144 (2014).

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Thome, J. J. et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016).

  31. 31.

    Rudd, B. D., Venturi, V., Davenport, M. P. & Nikolich-Zugich, J. Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J. Immunol. 186, 2056–2064 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Sprent, J. & Surh, C. D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol. 12, 478–484 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

    Thompson, H. L., Smithey, M. J., Surh, C. D. & Nikolich-Žugich, J. Functional and homeostatic impact of age-related changes in lymph node stroma. Front. Immunol. 8, 706 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Cambier, J. Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling. Immunol. Rev. 205, 5–6 (2005).

    PubMed  Article  Google Scholar 

  35. 35.

    Wertheimer, A. M. et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192, 2143–2155 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Rudd, B. D. et al. Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc. Natl. Acad. Sci. USA 108, 13694–13699 (2011).

    PubMed  Article  Google Scholar 

  37. 37.

    Kogut, I., Scholz, J. L., Cancro, M. P. & Cambier, J. C. B cell maintenance and function in aging. Semin. Immunol. 24, 342–349 (2012).

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Hao, Y., O’Neill, P., Naradikian, M. S., Scholz, J. L. & Cancro, M. P. A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood 118, 1294–1304 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Becklund, B. R. et al. The aged lymphoid tissue environment fails to support naïve T cell homeostasis. Sci. Rep 6, 30842 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Decman, V. et al. Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors. J. Immunol. 188, 1933–1941 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Renkema, K. R., Li, G., Wu, A., Smithey, M. J. & Nikolich-Žugich, J. Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging. J. Immunol. 192, 151–159 (2014).

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Chiu, B. C., Martin, B. E., Stolberg, V. R. & Chensue, S. W. Cutting edge: Central memory CD8 T cells in aged mice are virtual memory cells. J. Immunol. 191, 5793–5796 (2013).

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Holtappels, R., Pahl-Seibert, M. F., Thomas, D. & Reddehase, M. J. Enrichment of immediate-early 1 (m123/pp89) peptide-specific CD8 T cells in a pulmonary CD62Llo memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. J. Virol. 74, 11495–11503 (2000).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Munks, M. W. et al. Genome-wide analysis reveals a highly diverse CD8 T cell response to murine cytomegalovirus. J. Immunol. 176, 3760–3766 (2006).

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Souquette, A., Frere, J., Smithey, M., Sauce, D. & Thomas, P. G. A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness. Geroscience 39, 293–303 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Frasca, D., Van der Put, E., Riley, R. L. & Blomberg, B. B. Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase. J. Immunol. 172, 2155–2162 (2004).

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Frasca, D., Diaz, A., Romero, M. & Blomberg, B. B. The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations. Vaccine 34, 2834–2840 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Richner, J. M. et al. Age-Dependent cell trafficking defects in draining lymph nodes impair adaptive immunity and control of West Nile virus infection. PLoS Pathog. 11, e1005027 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Sage, P. T., Tan, C. L., Freeman, G. J., Haigis, M. & Sharpe, A. H. Defective TFH cell function and increased TFR cells contribute to defective antibody production in aging. Cell Rep. 12, 163–171 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51.

    Miller, R. A. & Stutman, O. Limiting dilution analysis of IL-2 production: studies of age, genotype, and regulatory interactions. Lymphokine Res. 1, 79–86 (1982).

    PubMed  CAS  Google Scholar 

  52. 52.

    Effros, R. B. & Walford, R. L. The immune response of aged mice to influenza: diminished T-cell proliferation, interleukin 2 production and cytotoxicity. Cell. Immunol. 81, 298–305 (1983).

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518–1524 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    Garcia, G. G., Sadighi Akha, A. A. & Miller, R. A. Age-related defects in moesin/ezrin cytoskeletal signals in mouse CD4 T cells. J. Immunol. 179, 6403–6409 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Garcia, G. G. & Miller, R. A. Differential tyrosine phosphorylation of zeta chain dimers in mouse CD4 T lymphocytes: effect of age. Cell. Immunol. 175, 51–57 (1997).

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Garcia, G. G. & Miller, R. A. Age-related defects in the cytoskeleton signaling pathways of CD4 T cells. Ageing Res. Rev. 10, 26–34 (2011).

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Haynes, L., Linton, P. J., Eaton, S. M., Tonkonogy, S. L. & Swain, S. L. Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J. Exp. Med. 190, 1013–1024 (1999).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Haynes, L., Linton, P. J. & Swain, S. L. Age-related changes in CD4 T cells of T cell receptor transgenic mice. Mech. Ageing Dev. 93, 95–105 (1997).

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Tsukamoto, H. et al. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc. Natl. Acad. Sci. USA 106, 18333–18338 (2009).

    PubMed  Article  Google Scholar 

  60. 60.

    Tsukamoto, H., Huston, G. E., Dibble, J., Duso, D. K. & Swain, S. L. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J. Immunol. 185, 4535–4544 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Brien, J. D., Uhrlaub, J. L., Hirsch, A., Wiley, C. A. & Nikolich-Zugich, J. Key role of T cell defects in age-related vulnerability to West Nile virus. J. Exp. Med. 206, 2735–2745 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Smithey, M. J., Renkema, K. R., Rudd, B. D. & Nikolich-Žugich, J. Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. Eur. J. Immunol. 41, 1352–1364 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Uhrlaub, J. L. et al. Dysregulated TGF-β production underlies the age-related vulnerability to chikungunya virus. PLoS Pathog. 12, e1005891 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Li, G., Smithey, M. J., Rudd, B. D. & Nikolich-Žugich, J. Age-associated alterations in CD8α+ dendritic cells impair CD8 T-cell expansion in response to an intracellular bacterium. Aging Cell 11, 968–977 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Martinez-Jimenez, C. P. et al. Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355, 1433–1436 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Moskowitz, D. M. et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2, eaag0192 (2017).

  67. 67.

    Ucar, D. et al. The chromatin accessibility signature of human immune aging stems from CD8+ T cells. J. Exp. Med. 214, 3123–3144 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Pulko, V. et al. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat. Immunol. 17, 966–975 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Di Mitri, D. et al. Reversible senescence in human CD4+CD45RA+CD27 memory T cells. J. Immunol. 187, 2093–2100 (2011).

    PubMed  Article  Google Scholar 

  70. 70.

    Lanna, A. et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Ferrucci, L. et al. The origins of age-related proinflammatory state. Blood 105, 2294–2299 (2005).

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    De Martinis, M., Franceschi, C., Monti, D. & Ginaldi, L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579, 2035–2039 (2005).

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Fagiolo, U. et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J. Immunol. 23, 2375–2378 (1993).

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Laudisio, A., Bandinelli, S., Gemma, A., Ferrucci, L. & Incalzi, R. A. Associations of heart rate with inflammatory markers are modulated by gender and obesity in older adults. J. Gerontol. A Biol. Sci. Med. Sci 70, 899–904 (2015).

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Wick, G. et al. The immunology of fibrosis: innate and adaptive responses. Trends Immunol. 31, 110–119 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Bhadra, R. et al. Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition. J. Clin. Invest. 124, 2441–2455 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79.

    Sahin, H. et al. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 55, 1610–1619 (2012).

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Notas, G., Kisseleva, T. & Brenner, D. NK and NKT cells in liver injury and fibrosis. Clin. Immunol. 130, 16–26 (2009).

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Brown, F. D. & Turley, S. J. Fibroblastic reticular cells: organization and regulation of the T lymphocyte life cycle. J. Immunol. 194, 1389–1394 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    Turner, V. M. & Mabbott, N. A. Structural and functional changes to lymph nodes in ageing mice. Immunology 151, 239–247 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Davies, J. S., Thompson, H. L., Pulko, V., Torres, J. P. & Nikolich-Žugich, J. Role of cell-intrinsic and environmental age-related changes in altered maintenance of murine T cells in lymphoid organs. J. Gerontol. A Biol. Sci. Med. Scihttp://dx.doi.org/10.1093/gerona/glx102 (2017).

  85. 85.

    Agius, E. et al. Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J. Exp. Med. 206, 1929–1940 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Cebra, J. J. Influences of microbiota on intestinal immune system development. Am. J. Clin. Nutr. 69, 1046S–1051S (1999).

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Kieper, W. C. et al. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol. 174, 3158–3163 (2005).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Claesson, M. J. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 (2012).

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Stehle, J. R. Jr. et al. Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J. Gerontol. A Biol. Sci. Med. Sci. 67, 1212–1218 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90.

    Jeong, J. H. et al. Microvasculature remodeling in the mouse lower gut during inflammaging. Sci. Rep. 7, 39848 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12, 1365–1371 (2006).

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Woodward, N. C. et al. Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo. J. Neuroinflammation 14, 84 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Aiello, A. E., Chiu, Y. L. & Frasca, D. How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms? Geroscience 39, 261–271 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Bruns, T. et al. CMV infection of human sinusoidal endothelium regulates hepatic T cell recruitment and activation. J. Hepatol. 63, 38–49 (2015).

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Cicin-Sain, L. et al. Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging. PLoS Pathog. 8, e1002849 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Smithey, M. J., Li, G., Venturi, V., Davenport, M. P. & Nikolich-Žugich, J. Lifelong persistent viral infection alters the naive T cell pool, impairing CD8 T cell immunity in late life. J. Immunol. 189, 5356–5366 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. 99.

    Mekker, A. et al. Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog. 8, e1002850 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 100.

    Marandu, T. F. et al. Immune protection against virus challenge in aging mice is not affected by latent herpesviral infections. J. Virol. 89, 11715–11717 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. 101.

    Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Furman, D. et al. Cytomegalovirus infection enhances the immune response to influenza. Sci. Transl. Med. 7, 281ra43 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Leng, S. X. et al. Recent advances in CMV tropism, latency, and diagnosis during aging. Geroscience 39, 251–259 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Greene, M. et al. Geriatric syndromes in older HIV-infected adults. J. Acquir. Immune Defic. Syndr. 69, 161–167 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Pathai, S., Bajillan, H., Landay, A. L. & High, K. P. Is HIV a model of accelerated or accentuated aging? J. Gerontol. A Biol. Sci. Med. Sci 69, 833–842 (2014).

    PubMed  Article  Google Scholar 

  106. 106.

    Masoro, E. J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005).

    PubMed  Article  CAS  Google Scholar 

  107. 107.

    Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Chen, J., Astle, C.M. & Harrison, D.E. Delayed immune aging in diet-restricted B6CBAT6 F1 mice is associated with preservation of naive T cells. Exp. Gerontol. 53A, B330–B337 (1998).

  109. 109.

    Messaoudi, I. et al. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc. Natl. Acad. Sci. USA 103, 19448–19453 (2006).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Youm, Y. H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med 21, 263–269 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. 111.

    Ventevogel, M. S. & Sempowski, G. D. Thymic rejuvenation and aging. Curr. Opin. Immunol. 25, 516–522 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Goldberg, E. L. et al. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14, 130–138 (2015).

    PubMed  Article  CAS  Google Scholar 

  113. 113.

    Goldberg, E. L., Smithey, M. J., Lutes, L. K., Uhrlaub, J. L. & Nikolich-Žugich, J. Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J. Immunol. 193, 757–763 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

I thank past and present members of the Nikolich lab and the UA Department of Immunobiology for collaborative work that led to some of the concepts crystallized in this work; E. Goldberg for suggestions; I. Jeftic, M. Jergovic, M. Smithey and H. Thompson for help with illustrations and critical perusal of the manuscript; and M. Kuhns for the suggestion that rules of immune system might change with aging and for critical perusal of the manuscript. Supported by the US Public Health Service (AG020719, AG048021 and AG053259), the US National Institutes of Health (HHSN 272201100017 C and HHSN272200900059C) and the Elizabeth Bowman Endowed Professorship in Medical Science.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Janko Nikolich-Žugich.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nikolich-Žugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol 19, 10–19 (2018). https://doi.org/10.1038/s41590-017-0006-x

Download citation

Further reading