[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Age-dependent dysregulation of innate immunity

Nature Reviews Immunology volume 13, pages 875–887 (2013)Cite this article

Subjects

Key Points

  • The diverse cell lineages that mediate innate immunity show heterogeneous ageing phenotypes that reflect their different developmental, tissue and activation contexts.

  • In general, ageing of the innate immune system is characterized by dysregulated inflammatory responses that may contribute to a heightened pro-inflammatory milieu, particularly in humans. In the context of such persistent inflammation, failure in innate immune activation may occur in response to pathogens or vaccines.

  • Neutrophils in aged humans show decreased functions, as assessed by intracellular killing, chemotaxis and phagocytosis, and these defects may be due to reduced signalling induced by granulocyte/macrophage colony-stimulating factor, triggering receptor expressed on myeloid cells 1, and alterations in membrane lipid raft domains. Intracellular killing and phagocytosis by neutrophils from aged mice are generally preserved, although deficits in neutrophil extracellular trap formation, chemokine production and recruitment are seen.

  • Toll-like receptor (TLR) function in monocytes, macrophages and dendritic cell (DC) populations is generally decreased with age in humans and in mice. Both transcriptional and post-transcriptional mechanisms contribute to alterations in TLR expression. Furthermore, examples of increased TLR function in monocyte-derived DCs and West Nile virus-infected macrophages, together with evidence for increased basal cytokine production by DCs, reflect innate immune dysregulation.

  • Systemic factors, such as age-associated alterations in sex steroids, chronic viral infections (for example, with cytomegalovirus), lipotoxicity arising from metabolic syndrome and DNA damage, could contribute ligands for pattern recognition receptors, such as TLRs and NLRP3 (NOD-, LRR- and pyrin domain-containing 3), thereby potentiating an age-associated inflammatory environment.

  • The consequences of innate immune ageing are reflected in diverse tissues and organs, and this has potential implications for age-associated chronic inflammatory conditions, including Alzheimer's disease, atherosclerosis and metabolic syndrome.

Abstract

As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses that involve multiple immune and non-immune cell types and that vary depending on the cell activation state and tissue context. This ageing-associated basal inflammation, particularly in humans, is thought to be induced by several factors, including the reactivation of latent viral infections and the release of endogenous damage-associated ligands of pattern recognition receptors (PRRs). Innate immune cell functions that are required to respond to pathogens or vaccines, such as cell migration and PRR signalling, are also impaired in aged individuals. This immune dysregulation may affect conditions associated with chronic inflammation, such as atherosclerosis and Alzheimer's disease.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Organ-specific changes of the innate immune system associated with ageing and disease.
Figure 2: Effects of ageing on innate immune PRR signalling.

Similar content being viewed by others

References

  1. Population Division, Department of Economic and Social Affairs, United Nations. World Population Ageing: 1950–2050 (United Nations, 2001).

  2. Centers for Disease Control and Prevention. National Ambulatory Medical Survey (National Center for Health Statistics, 2005).

  3. Yoshikawa, T. T. Epidemiology and unique aspects of aging and infectious diseases. Clin. Infect. Dis. 30, 931–933 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Arnold, C. R., Wolf, J., Brunner, S., Herndler-Brandstetter, D. & Grubeck-Loebenstein, B. Gain and loss of T cell subsets in old age—age-related reshaping of the T cell repertoire. J. Clin. Immunol. 31, 137–146 (2011).

    Article  PubMed  Google Scholar 

  5. Frasca, D., Diaz, A., Romero, M., Landin, A. M. & Blomberg, B. B. Age effects on B cells and humoral immunity in humans. Ageing Res. Rev. 10, 330–335 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Nikolich-Zugich, J., Li, G., Uhrlaub, J. L., Renkema, K. R. & Smithey, M. J. Age-related changes in CD8 T cell homeostasis and immunity to infection. Semin. Immunol. 24, 356–364 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Haynes, L. & Lefebvre, J. S. Age-related deficiencies in antigen-specific CD4 T cell responses: lessons from mouse models. Aging Dis. 2, 374–381 (2011).

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Bruunsgaard, H. et al. A high plasma concentration of TNF-α is associated with dementia in centenarians. J. Gerontol. A Biol. Sci. Med. Sci. 54, M357–M364 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Mari, D. et al. Hypercoagulability in centenarians: the paradox of successful aging. Blood 85, 3144–3149 (1995).

    CAS  PubMed  Google Scholar 

  12. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908, 244–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Cohen, H. J., Harris, T. & Pieper, C. F. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am. J. Med. 114, 180–187 (2003).

    Article  PubMed  Google Scholar 

  14. Ferrucci, L. et al. Serum IL-6 level and the development of disability in older persons. J. Am. Geriatr. Soc. 47, 639–646 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Beharka, A. A. et al. Interleukin-6 production does not increase with age. J. Gerontol. A Biol. Sci. Med. Sci. 56, B81–B88 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Beerman, I. et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl Acad. Sci. USA 107, 5465–5470 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl. Acad. Sci. USA 102, 9194–9199 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cho, R. H., Sieburg, H. B. & Muller-Sieburg, C. E. A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood 111, 5553–5561 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dykstra, B., Olthof, S., Schreuder, J., Ritsema, M. & de Haan, G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J. Exp. Med. 208, 2691–2703 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pang, W. W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011). This report shows that human HSCs from aged adults show a bias towards myeloid differentiation, at the expense of lymphoid differentiation, as was also observed in mice.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Geiger, H., de Haan, G. & Florian, M. C. The ageing haematopoietic stem cell compartment. Nature Rev. Immunol. 13, 376–389 (2013).

    Article  CAS  Google Scholar 

  23. Ergen, A. V., Boles, N. C. & Goodell, M. A. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119, 2500–2509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Esplin, B. L. et al. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J. Immunol. 186, 5367–5375 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Rube, C. E. et al. Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging. PLoS ONE 6, e17487 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lichtman, M. A. & Rowe, J. M. The relationship of patient age to the pathobiology of clonal myeloid diseases. Semin. Oncol. 31, 185–197 (2004).

    Article  PubMed  Google Scholar 

  27. Chatta, G. S., Price, T. H., Stratton, J. R. & Dale, D. C. Aging and marrow neutrophil reserves. J. Am. Geriatr. Soc. 42, 77–81 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. De Martinis, M., Modesti, M. & Ginaldi, L. Phenotypic and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol. Cell Biol. 82, 415–420 (2004).

    Article  PubMed  Google Scholar 

  29. Ferrando-Martinez, S. et al. Thymic function failure and C-reactive protein levels are independent predictors of all-cause mortality in healthy elderly humans. Age (Dordr.) 35, 251–259 (2013).

    Article  CAS  Google Scholar 

  30. Ratts, R. B. & Weng, N. P. Homeostasis of lymphocytes and monocytes in frequent blood donors. Front. Immunol. 3, 271 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Seidler, S., Zimmermann, H. W., Bartneck, M., Trautwein, C. & Tacke, F. Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol. 11, 30 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hearps, A. C. et al. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11, 867–875 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Nyugen, J., Agrawal, S., Gollapudi, S. & Gupta, S. Impaired functions of peripheral blood monocyte subpopulations in aged humans. J. Clin. Immunol. 30, 806–813 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Garbe, K., Bratke, K., Wagner, S., Virchow, J. C. & Lommatzsch, M. Plasmacytoid dendritic cells and their Toll-like receptor 9 expression selectively decrease with age. Hum. Immunol. 73, 493–497 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Orsini, G. et al. Enumeration of human peripheral blood dendritic cells throughout the life. Int. Immunol. 24, 347–356 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Agrawal, A. et al. Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J. Immunol. 178, 6912–6922 (2007). This study shows an age-associated increase in TLR4- and TLR8-dependent cytokine production by human MDDCs, which occurs together with impaired phagocytosis and chemotaxis that is associated with decreased PI3K activation.

    Article  CAS  PubMed  Google Scholar 

  37. Jing, Y. 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. 70, 777–784 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wenisch, C., Patruta, S., Daxbock, F., Krause, R. & Horl, W. Effect of age on human neutrophil function. J. Leukoc. Biol. 67, 40–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Nomellini, V. et al. Dysregulation of neutrophil CXCR2 and pulmonary endothelial ICAM-1 promotes age-related pulmonary inflammation. Aging Dis. 3, 234–247 (2012).

    PubMed  PubMed Central  Google Scholar 

  40. Niwa, Y., Kasama, T., Miyachi, Y. & Kanoh, T. Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: cross-sectional and longitudinal studies. Life Sci. 44, 1655–1664 (1989).

    Article  CAS  PubMed  Google Scholar 

  41. Murciano, C., Yanez, A., O'Connor, J. E., Gozalbo, D. & Gil, M. L. Influence of aging on murine neutrophil and macrophage function against Candida albicans. FEMS Immunol. Med. Microbiol. 53, 214–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Ren, Z. et al. Effect of age on susceptibility to Salmonella typhimurium infection in C57BL/6 mice. J. Med. Microbiol. 58, 1559–1567 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Toapanta, F. R. & Ross, T. M. Impaired immune responses in the lungs of aged mice following influenza infection. Respir. Res. 10, 112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brubaker, A. L., Rendon, J. L., Ramirez, L., Choudhry, M. A. & Kovacs, E. J. Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J. Immunol. 190, 1746–1757 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Gomez, C. R. et al. Advanced age exacerbates the pulmonary inflammatory response after lipopolysaccharide exposure. Crit. Care Med. 35, 246–251 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Stout-Delgado, H. W., Du, W., Shirali, A. C., Booth, C. J. & Goldstein, D. R. Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host Microbe 6, 446–456 (2009). This paper uses an HSV-infection model to show that the increased mortality of aged mice following HSV infection results from increased IL-17 production by NKT cells, together with increased neutrophil recruitment and activation in the liver and resultant liver failure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Luu, N. T., Rainger, G. E. & Nash, G. B. Differential ability of exogenous chemotactic agents to disrupt transendothelial migration of flowing neutrophils. J. Immunol. 164, 5961–5969 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Zhao, J., Zhao, J., Legge, K. & Perlman, S. Age-related increases in PGD2 expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Invest. 121, 4921–4930 (2011). This study uses mouse models of infection with several respiratory viruses (including influenza virus, severe acute respiratory syndrome coronavirus and respiratory syncytial virus) to show an age-associated decrease in respiratory DC migration to the draining lymph nodes that is associated with increased PGD2 levels in the lungs, and that the defect improved with pharmacological inhibition of PGD2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Butcher, S. K. et al. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J. Leukoc. Biol. 70, 881–886 (2001).

    CAS  PubMed  Google Scholar 

  50. Fortin, C. F., McDonald, P. P., Lesur, O. & Fulop, T. Jr. Aging and neutrophils: there is still much to do. Rejuven. Res. 11, 873–882 (2008).

    Article  CAS  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. Fulop, T. et al. Signal transduction and functional changes in neutrophils with aging. Aging Cell 3, 217–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Radford, D. J. et al. Dehdyroepiandrosterone sulfate directly activates protein kinase C-β to increase human neutrophil superoxide generation. Mol. Endocrinol. 24, 813–821 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fortin, C. F., Larbi, A., Dupuis, G., Lesur, O. & Fulop, T. Jr. GM-CSF activates the Jak/STAT pathway to rescue polymorphonuclear neutrophils from spontaneous apoptosis in young but not elderly individuals. Biogerontology 8, 173–187 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Tortorella, C. et al. Role of phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways in granulocyte macrophage-colony-stimulating factor failure to delay fas-induced neutrophil apoptosis in elderly humans. J. Gerontol. A Biol. Sci. Med. Sci. 61, 1111–1118 (2006).

    Article  PubMed  Google Scholar 

  57. Fortin, C. F., Lesur, O. & Fulop, T. Jr. Effects of aging on triggering receptor expressed on myeloid cells (TREM)-1-induced PMN functions. FEBS Lett. 581, 1173–1178 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Fortin, C. F., Larbi, A., Lesur, O., Douziech, N. & Fulop, T. Jr. Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J. Leukoc. Biol. 79, 1061–1072 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Esposito, A. L., Poirier, W. J. & Clark, C. A. In vitro assessment of chemotaxis by peripheral blood neutrophils from adult and senescent C57BL/6 mice: correlation with in vivo responses to pulmonary infection with type 3 Streptococcus pneumoniae. Gerontology 36, 2–11 (1990).

    Article  CAS  PubMed  Google Scholar 

  60. Lipschitz, D. A. & Udupa, K. B. Influence of aging and protein deficiency on neutrophil function. J. Gerontol. 41, 690–694 (1986).

    Article  CAS  PubMed  Google Scholar 

  61. Kaplan, M. J. & Radic, M. Neutrophil extracellular traps: double-edged swords of innate immunity. J. Immunol. 189, 2689–2695 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Nogusa, S., Ritz, B. W., Kassim, S. H., Jennings, S. R. & Gardner, E. M. Characterization of age-related changes in natural killer cells during primary influenza infection in mice. Mech. Ageing Dev. 129, 223–230 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Beli, E. et al. Natural killer cell function is altered during the primary response of aged mice to influenza infection. Mech. Ageing Dev. 132, 503–510 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Plett, A. & Murasko, D. M. Genetic differences in the age-associated decrease in inducibility of natural killer cells by interferon-α/β. Mech. Ageing Dev. 112, 197–215 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Nogusa, S., Murasko, D. M. & Gardner, E. M. Differential effects of stimulatory factors on natural killer cell activities of young and aged mice. J. Gerontol. A Biol. Sci. Med. Sci. 67, 947–954 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Caligiuri, M. A. Human natural killer cells. Blood 112, 461–469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Almeida-Oliveira, A. et al. Age-related changes in natural killer cell receptors from childhood through old age. Hum. Immunol. 72, 319–329 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Borrego, F. et al. NK phenotypic markers and IL2 response in NK cells from elderly people. Exp. Gerontol. 34, 253–265 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Chidrawar, S. M., Khan, N., Chan, Y. L., Nayak, L. & Moss, P. A. Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun. Ageing 3, 10 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hayhoe, R. P., Henson, S. M., Akbar, A. N. & Palmer, D. B. Variation of human natural killer cell phenotypes with age: identification of a unique KLRG1-negative subset. Hum. Immunol. 71, 676–681 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Le Garff-Tavernier, M. et al. Human NK cells display major phenotypic and functional changes over the life span. Aging Cell 9, 527–535 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. Hazeldine, J., Hampson, P. & Lord, J. M. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell 11, 751–759 (2012). This is the first study to implicate defective perforin mobilization to the immunological synapse in age-associated impairment of NK cell cytotoxicity.

    Article  CAS  PubMed  Google Scholar 

  75. Ogata, K. et al. Association between natural killer cell activity and infection in immunologically normal elderly people. Clin. Exp. Immunol. 124, 392–397 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Peralbo, E., Alonso, C. & Solana, R. Invariant NKT and NKT-like lymphocytes: two different T cell subsets that are differentially affected by ageing. Exp. Gerontol. 42, 703–708 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Faunce, D. E., Palmer, J. L., Paskowicz, K. K., Witte, P. L. & Kovacs, E. J. CD1d-restricted NKT cells contribute to the age-associated decline of T cell immunity. J. Immunol. 175, 3102–3109 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. DelaRosa, O. et al. Vα24+ NKT cells are decreased in elderly humans. Exp. Gerontol. 37, 213–217 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Peralbo, E. et al. Decreased frequency and proliferative response of invariant Vα24Vβ11 natural killer T (iNKT) cells in healthy elderly. Biogerontology 7, 483–492 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Kawabata, T. et al. Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide. Hepatology 48, 1586–1597 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Inui, T. et al. Age-associated augmentation of the synthetic ligand-mediated function of mouse NK1.1 Ag+ T cells: their cytokine production and hepatotoxicity in vivo and in vitro. J. Immunol. 169, 6127–6132 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Kissin, E., Tomasi, M., McCartney-Francis, N., Gibbs, C. L. & Smith, P. D. Age-related decline in murine macrophage production of nitric oxide. J. Infect. Dis. 175, 1004–1007 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Wu, D., Marko, M., Claycombe, K., Paulson, K. E. & Meydani, S. N. Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through upregulation of NF-κB activity. J. Biol. Chem. 278, 10983–10992 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Tasat, D. R., Mancuso, R., O'Connor, S. & Molinari, B. Age-dependent change in reactive oxygen species and nitric oxide generation by rat alveolar macrophages. Aging Cell 2, 159–164 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Birjandi, S. Z., Ippolito, J. A., Ramadorai, A. K. & Witte, P. L. Alterations in marginal zone macrophages and marginal zone B cells in old mice. J. Immunol. 186, 3441–3451 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Liang, S., Domon, H., Hosur, K. B., Wang, M. & Hajishengallis, G. Age-related alterations in innate immune receptor expression and ability of macrophages to respond to pathogen challenge in vitro. Mech. Ageing Dev. 130, 538–546 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pereira, L. F., de Souza, A. P., Borges, T. J. & Bonorino, C. Impaired in vivo CD4+ T cell expansion and differentiation in aged mice is not solely due to T cell defects: decreased stimulation by aged dendritic cells. Mech. Ageing Dev. 132, 187–194 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Plowden, J. et al. Impaired antigen-induced CD8+ T cell clonal expansion in aging is due to defects in antigen presenting cell function. Cell. Immunol. 229, 86–92 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Wong, C. & Goldstein, D. R. Impact of aging on antigen presentation cell function of dendritic cells. Curr. Opin. Immunol. 25, 535–541 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tan, S. Y. et al. Phenotype and functions of conventional dendritic cells are not compromised in aged mice. Immunol. Cell Biol. 90, 722–732 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Grolleau-Julius, A., Harning, E. K., Abernathy, L. M. & Yung, R. L. Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res. 68, 6341–6349 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li, G., Smithey, M. J., Rudd, B. D. & Nikolich-Zugich, 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). This study indicates that ageing mouse CD8α+ DCs have impaired migration and upregulation of co-stimulatory molecules, and that this also impairs in vivo T cell responses in a model of bacterial infection.

    Article  CAS  PubMed  Google Scholar 

  94. Moretto, M. M., Lawlor, E. M. & Khan, I. A. Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen. J. Immunol. 181, 7977–7984 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Brown, K. L., Gossner, A., Mok, S. & Mabbott, N. A. The effects of host age on the transport of complement-bound complexes to the spleen and the pathogenesis of intravenous scrapie infection. J. Virol. 86, 25–35 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Clark, H. L. et al. Characterization of MHC-II antigen presentation by B cells and monocytes from older individuals. Clin. Immunol. 144, 172–177 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Steger, M. M., Maczek, C. & Grubeck-Loebenstein, B. Peripheral blood dendritic cells reinduce proliferation in in vitro aged T cell populations. Mech. Ageing Dev. 93, 125–130 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. van Duin, D. et al. Age-associated defect in human TLR-1/2 function. J. Immunol. 178, 970–975 (2007). This study uses multivariable mixed effects modelling to show an age-related decrease in TLR1–TLR2-mediated cytokine production and TLR1 expression by monocytes from 159 human volunteers.

    Article  CAS  PubMed  Google Scholar 

  99. Panda, A. et al. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J. Immunol. 184, 2518–2527 (2010). This paper shows an extensive, age-associated decrease in TLR-dependent cytokine production by primary human mDCs and pDCs that reflects elevated basal levels of cytokine production in aged adults and that is strongly associated with antibody responses to influenza virus vaccination.

    Article  CAS  PubMed  Google Scholar 

  100. Renshaw, M. et al. Cutting edge: impaired Toll-like receptor expression and function in aging. J. Immunol. 169, 4697–4701 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Qian, F. et al. Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell 11, 104–110 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Boehmer, E. D., Goral, J., Faunce, D. E. & Kovacs, E. J. Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J. Leukoc. Biol. 75, 342–349 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Boehmer, E. D., Meehan, M. J., Cutro, B. T. & Kovacs, E. J. Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway. Mech. Ageing Dev. 126, 1305–1313 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Boyd, A. R., Shivshankar, P., Jiang, S., Berton, M. T. & Orihuela, C. J. Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia. Exp. Gerontol. 47, 507–518 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shaik-Dasthagirisaheb, Y. B., Kantarci, A. & Gibson, F. C. Immune response of macrophages from young and aged mice to the oral pathogenic bacterium Porphyromonas gingivalis. Immun. Ageing 7, 15 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Asquith, M. et al. Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta). Pathobiol. Aging Age Relat. Dis. 2, http://dx.doi.org/10.3402%2Fpba.v2i0.18052 (2012).

  107. van Duin, D. et al. Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J. Infect. Dis. 195, 1590–1597 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Mizel, S. B. & Bates, J. T. Flagellin as an adjuvant: cellular mechanisms and potential. J. Immunol. 185, 5677–5682 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Nakaya, H. I. et al. Systems biology of vaccination for seasonal influenza in humans. Nature Immunol. 12, 786–795 (2011).

    Article  CAS  Google Scholar 

  110. Kong, K. F. et al. Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly. J. Virol. 82, 7613–7623 (2008). This paper shows a DC-SIGN-dependent interaction with WNV, which results in a STAT1-dependent downregulation of TLR3 expression by human macrophages that is impaired in cells from aged adults.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Agius, E. et al. Decreased TNF-α synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J. Exp. Med. 206, 1929–1940 (2009). Using skin biopsy and suction blister samples, this study shows an age-associated impairment in human delayed-type hypersensitivity responses, reduced TNF production by dermal macrophages and an associated increase in regulatory T cell infiltration of the skin of older individuals, compared with that of young individuals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tesar, B. M. et al. Murine myeloid dendritic cell-dependent toll-like receptor immunity is preserved with aging. Aging Cell 5, 473–486 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Stout-Delgado, H. W., Yang, X., Walker, W. E., Tesar, B. M. & Goldstein, D. R. Aging impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during TLR9 activation. J. Immunol. 181, 6747–6756 (2008). This study shows that pDCs from aged mice have a TLR9-dependent defect in type I IFN production that is associated with impaired IRF7 upregulation. The defect in type I IFN production could be rescued by antioxidants or caloric restriction.

    Article  CAS  PubMed  Google Scholar 

  114. El Mezayen, R., El Gazzar, M., Myer, R. & High, K. P. Aging-dependent upregulation of IL-23p19 gene expression in dendritic cells is associated with differential transcription factor binding and histone modifications. Aging Cell 8, 553–565 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Myer, R. G., El Mezayen, R. & High, K. P. Prostaglandin E2-dependent IL-23 production in aged murine dendritic cells. Exp. Gerontol. 45, 834–841 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Huang, M. C., Liao, J. J., Bonasera, S., Longo, D. L. & Goetzl, E. J. Nuclear factor-κB-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J. 22, 2142–2150 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Lee, J. S. et al. Age-associated alteration in naive and memory TH17 cell response in humans. Clin. Immunol. 140, 84–91 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Della Bella, S. et al. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin. Immunol. 122, 220–228 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Canaday, D. H. et al. Influenza-induced production of interferon-alpha is defective in geriatric individuals. J. Clin. Immunol. 30, 373–383 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sridharan, A. et al. Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age (Dordr.) 33, 363–376 (2011).

    Article  CAS  Google Scholar 

  121. Qian, F. et al. Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J . Infect. Dis. 203, 1415–1424 (2011). This study shows that MDDCs from aged adults have reduced expression of co-stimulatory molecules and cytokines following WNV infection and TLR3 and TLR8 stimulation because of impaired STAT1 phosphorylation and IRF7 upregulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Agrawal, A., Tay, J., Ton, S., Agrawal, S. & Gupta, S. Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA. J. Immunol. 182, 1138–1145 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Lemke, G. & Rothlin, C. V. Immunobiology of the TAM receptors. Nature Rev. Immunol. 8, 327–336 (2008).

    Article  CAS  Google Scholar 

  124. Youm, Y. H. et al. Canonical NLRP3 inflammasome links systemic low grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013). This manuscript shows that age-associated inflammation in adipose tissue and the brain is decreased in aged Nlrp3 -knockout mice, and that this leads to improvements in glucose tolerance and in tests of learning and memory.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Stout-Delgado, H. W., Vaughan, S. E., Shirali, A. C., Jaramillo, R. J. & Harrod, K. S. Impaired NLRP3 inflammasome function in elderly mice during influenza infection is rescued by treatment with nigericin. J. Immunol. 188, 2815–2824 (2012). This paper is the first to show an age-associated impairment in induced NLRP3 function in mice.

    Article  CAS  PubMed  Google Scholar 

  126. Cuervo, A. M. Autophagy and aging: keeping that old broom working. Trends Genet. 24, 604–612 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunol. 12, 222–230 (2011).

    Article  CAS  Google Scholar 

  128. Tal, M. C. et al. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl Acad. Sci. USA 106, 2770–2775 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature Immunol. 12, 408–415 (2011).

    Article  CAS  Google Scholar 

  130. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. Salminen, A., Kaarniranta, K. & Kauppinen, A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (Albany NY) 4, 166–175 (2012).

    Article  CAS  Google Scholar 

  132. Gordon, C. M., LeBoff, M. S. & Glowacki, J. Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells. Cytokine 16, 178–186 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Pottratz, S. T., Bellido, T., Mocharla, H., Crabb, D. & Manolagas, S. C. 17 β-estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J. Clin. Invest. 93, 944–950 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ray, A., Prefontaine, K. E. & Ray, P. Down-modulation of interleukin-6 gene expression by 17 β-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J. Biol. Chem. 269, 12940–12946 (1994).

    CAS  PubMed  Google Scholar 

  135. Yang, B. C., Liu, C. W., Chen, Y. C. & Yu, C. K. Exogenous dehydroepiandrosterone modified the expression of T helper-related cytokines in NZB/NZW F1 mice. Immunol. Invest. 27, 291–302 (1998).

    Article  PubMed  Google Scholar 

  136. Abu-Taha, M. et al. Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan. J. Immunol. 183, 1393–1402 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Maggio, M. et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J. Clin. Endocrinol. Metab. 91, 345–347 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Matarese, G. et al. Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses. Proc. Natl Acad. Sci. USA 110, 6193–6198 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Zhang, G. et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497, 211–216 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tchkonia, T. et al. Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Forsythe, L. K., Wallace, J. M. & Livingstone, M. B. Obesity and inflammation: the effects of weight loss. Nutr. Res. Rev. 21, 117–133 (2008).

    Article  CAS  PubMed  Google Scholar 

  142. Morin, C. L., Pagliassotti, M. J., Windmiller, D. & Eckel, R. H. Adipose tissue-derived tumor necrosis factor-α activity is elevated in older rats. J. Gerontol. A Biol. Sci. Med. Sci. 52, B190–B195 (1997).

    Article  CAS  PubMed  Google Scholar 

  143. Starr, M. E., Evers, B. M. & Saito, H. Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. J. Gerontol. A Biol. Sci. Med. Sci. 64, 723–730 (2009).

    Article  CAS  PubMed  Google Scholar 

  144. Wu, D. et al. Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J. Immunol. 179, 4829–4839 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Lumeng, C. N. et al. Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J. Immunol. 187, 6208–6216 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature Med. 17, 179–188 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Mori, M. A. et al. Role of microRNA processing in adipose tissue in stress defense and longevity. Cell. Metab. 16, 336–347 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature Cell Biol. 11, 973–979 (2009). This paper shows that DNA damage associated with senescence induces the secretion of pro-inflammatory cytokines, such as IL-6, and this suggests that endogenous DNA could contribute to an age-associated increase in inflammation.

    Article  CAS  PubMed  Google Scholar 

  149. Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Freund, A., Patil, C. K. & Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Orjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K. & Campisi, J. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc. Natl Acad. Sci. USA 106, 17031–17036 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Jylhava, J., Jylha, M., Lehtimaki, T., Hervonen, A. & Hurme, M. Circulating cell-free DNA is associated with mortality and inflammatory markers in nonagenarians: the Vitality 90+ Study. Exp. Gerontol. 47, 372–378 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Imaeda, A. B. et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J. Clin. Invest. 119, 305–314 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the NLRP3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Li, H., Ambade, A. & Re, F. Cutting edge: Necrosis activates the NLRP3 inflammasome. J. Immunol. 183, 1528–1532 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Pawelec, G., McElhaney, J. E., Aiello, A. E. & Derhovanessian, E. The impact of CMV infection on survival in older humans. Curr. Opin. Immunol. 24, 507–511 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Limaye, A. P. et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 300, 413–422 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Stowe, R. P. et al. Chronic herpesvirus reactivation occurs in aging. Exp. Gerontol. 42, 563–570 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Roberts, E. T., Haan, M. N., Dowd, J. B. & Aiello, A. E. Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am. J. Epidemiol. 172, 363–371 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Trzonkowski, P. et al. Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination—an impact of immunosenescence. Vaccine 21, 3826–3836 (2003).

    Article  CAS  PubMed  Google Scholar 

  161. Bartlett, D. B. et al. The age-related increase in low-grade systemic inflammation (inflammaging) is not driven by cytomegalovirus infection. Aging Cell 11, 912–915 (2012).

    Article  CAS  PubMed  Google Scholar 

  162. Asia Pacific Cohort Studies Collaboration. The impact of cardiovascular risk factors on the age-related excess risk of coronary heart disease. Int. J. Epidemiol. 35, 1025–1033 (2006).

  163. Libby, P., Ridker, P. M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Bjorkbacka, H. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Med. 10, 416–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  165. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Song, Y. et al. Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 32, 103–109 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Csiszar, A. et al. Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J. Gerontol. A Biol. Sci. Med. Sci. 67, 811–820 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Carty, M. & Bowie, A. G. Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem. Pharmacol. 81, 825–837 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Cribbs, D. H. et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J. Neuroinflammation 9, 179 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Reed-Geaghan, E. G., Savage, J. C., Hise, A. G. & Landreth, G. E. CD14 and Toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J. Neurosci. 29, 11982–11992 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Richard, K. L., Filali, M., Prefontaine, P. & Rivest, S. Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid β1–42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J. Neurosci. 28, 5784–5793 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Michaud, J. P., Richard, K. L. & Rivest, S. Hematopoietic MyD88-adaptor protein acts as a natural defense mechanism for cognitive deficits in Alzheimer's disease. Stem Cell Rev. 8, 898–904 (2012).

    Article  CAS  Google Scholar 

  173. Doi, Y. et al. Microglia activated with the Toll-like receptor 9 ligand CpG attenuate oligomeric amyloid-β neurotoxicity in in vitro and in vivo models of Alzheimer's disease. Am. J. Pathol. 175, 2121–2132 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Scholtzova, H. et al. Induction of Toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. J. Neurosci. 29, 1846–1854 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lee, J. W. et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J. Neuroinflammation 5, 37 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Sheng, J. G. et al. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid-β peptide in APPswe transgenic mice. Neurobiol. Dis. 14, 133–145 (2003).

    Article  CAS  PubMed  Google Scholar 

  177. Holmes, C. et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768–774 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008).

    Article  CAS  Google Scholar 

  179. Heneka, M. T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  181. Enioutina, E. Y., Bareyan, D. & Daynes, R. A. A role for immature myeloid cells in immune senescence. J. Immunol. 186, 697–707 (2011).

    Article  CAS  PubMed  Google Scholar 

  182. Verschoor, C. P. et al. Blood CD33+HLA-DR− myeloid-derived suppressor cells are increased with age and a history of cancer. J. Leukoc. Biol. 93, 633–637 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Yancik, R. & Ries, L. A. Aging and cancer in America. Demographic and epidemiologic perspectives. Hematol. Oncol. Clin. North Am. 14, 17–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  184. Ryan, S. O., Johnson, J. L. & Cobb, B. A. Neutrophils confer T cell resistance to myeloid-derived suppressor cell-mediated suppression to promote chronic inflammation. J. Immunol. 190, 5037–5047 (2013).

    Article  CAS  PubMed  Google Scholar 

  185. Li, H., Manwani, B. & Leng, S. X. Frailty, inflammation, and immunity. Aging Dis. 2, 466–473 (2011).

    PubMed  PubMed Central  Google Scholar 

  186. Furman, D. et al. Apoptosis and other immune biomarkers predict influenza vaccine responsiveness. Mol. Syst. Biol. 9, 659 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Ferreira, R. B., Antunes, L. C. & Finlay, B. B. Should the human microbiome be considered when developing vaccines? PLoS Pathog. 6, e1001190 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Biagi, E. et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE 5, e10667 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  190. 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).

    Article  CAS  PubMed  Google Scholar 

  191. Leng, J. et al. Efficacy of a vaccine that links viral epitopes to flagellin in protecting aged mice from influenza viral infection. Vaccine 29, 8147–8155 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Taylor, D. N. et al. Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI). Vaccine 29, 4897–4902 (2011).

    Article  CAS  PubMed  Google Scholar 

  193. Asanuma, H. et al. A novel combined adjuvant for nasal delivery elicits mucosal immunity to influenza in aging. Vaccine 30, 803–812 (2012).

    Article  CAS  PubMed  Google Scholar 

  194. Morgan, E. L., Thoman, M. L., Sanderson, S. D. & Phillips, J. A. A novel adjuvant for vaccine development in the aged. Vaccine 28, 8275–8279 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Sen, G., Chen, Q. & Snapper, C. M. Immunization of aged mice with a pneumococcal conjugate vaccine combined with an unmethylated CpG-containing oligodeoxynucleotide restores defective immunoglobulin G antipolysaccharide responses and specific CD4+-T-cell priming to young adult levels. Infect. Immun. 74, 2177–2186 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Behzad, H. et al. GLA-SE, a synthetic toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. J. Infect. Dis. 205, 466–473 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to colleagues whose work we were unable to discuss due to space limitations. Work in this Review was supported by the US National Institutes of Health grants N01 272201100019C-3-0-1 and U19 AI089992 (to A.C.S. and R.R.M.), AG042489 (to A.C.S.), and AG028082 and AG033049 (to D.R.G.). D.R.G. is also supported by an Established Investigator Award from the American Heart Association (grant 094006N).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Albert C. Shaw

  2. Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Daniel R. Goldstein

  3. Department of Immunobiology, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Daniel R. Goldstein

  4. Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, 06520, Connecticut, USA

    Ruth R. Montgomery

Authors
  1. Albert C. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel R. Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruth R. Montgomery
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Albert C. Shaw.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Plasmacytoid dendritic cells

(pDCs). Immature DCs with morphology that resembles that of a plasma cell. Mouse pDCs express markers such as B220, which is usually associated with the B cell lineage. In humans, pDCs express CD123 and blood DC antigen 2 (BDCA2; also known as CLEC4C and CD303), and are CD11c−. These DCs are the main producers of type I interferons in response to viral infection.

Conventional DCs

Specialized phagocytic antigen-presenting cells that have the classic stellate dendritic cell (DC) morphology. Mouse conventional DCs generally express CD11c, but are highly heterogeneous and are divided into subsets: CD8α+ and CD4+ subsets in secondary lymphoid organs, and CD8α+CD103+ and CD4+CD11b+ subsets in the periphery. Human conventional DCs are generally termed myeloid DCs and are lineage-negative MHC class II+CD11c+ DCs. Human equivalents to the mouse CD8α+ and CD4+ subsets can be distinguished by expression of blood DC antigen 3 (BDCA3; also known as CD141) and BDCA1 (also known as CD1c), respectively.

Monocyte-derived DCs

(MDDCs). MDDCs can be generated in vitro from peripheral blood mononuclear cells in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor. MDDCs resemble myeloid dendritic cells (DCs) and may model the differentiation of DCs from monocytes that enter sites of inflammation.

NOD-like receptors

(NLRs). A family of more than 20 nucleotide-binding oligomerization domain (NOD)-like cytoplasmic pattern recognition receptors that sense pathogens, toxins, endogenous danger signals (such as uric acid) and exogenous crystalline substances (such as alum, silica and asbestos) and induce inflammatory responses.

RIG-I-like receptors

(RLRs). A family of cytoplasmic pattern recognition receptors that are related to the RNA helicase retinoic acid-inducible gene I (RIG-I). They recognize single- and double-stranded viral RNA and mediate antiviral responses, such as type I interferon production.

Inflammasome

A multiprotein complex that consists of a NOD-like receptor, an adaptor protein and pro-caspase 1. On assembly, the complex facilitates the caspase 1-mediated cleavage and production of mature cytokines, such as interleukin-1β and interleukin-18.

Macroautophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and, through fusion to secondary lysosomes, target them for degradation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shaw, A., Goldstein, D. & Montgomery, R. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13, 875–887 (2013). https://doi.org/10.1038/nri3547

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3547

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing