Review Article | Published:

Age-dependent dysregulation of innate immunity

Nature Reviews Immunology volume 13, pages 875887 (2013) | Download Citation

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.

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

    , , , & 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).

  5. 5.

    , , , & Age effects on B cells and humoral immunity in humans. Ageing Res. Rev. 10, 330–335 (2011).

  6. 6.

    , , , & Age-related changes in CD8 T cell homeostasis and immunity to infection. Semin. Immunol. 24, 356–364 (2012).

  7. 7.

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

  8. 8.

    , , & B cell maintenance and function in aging. Semin. Immunol. 24, 342–349 (2012).

  9. 9.

    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).

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 13.

    , & Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am. J. Med. 114, 180–187 (2003).

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

    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).

  18. 18.

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

  19. 19.

    , & 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).

  20. 20.

    , , , & Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J. Exp. Med. 208, 2691–2703 (2011).

  21. 21.

    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.

  22. 22.

    , & The ageing haematopoietic stem cell compartment. Nature Rev. Immunol. 13, 376–389 (2013).

  23. 23.

    , & Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119, 2500–2509 (2012).

  24. 24.

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

  25. 25.

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

  26. 26.

    & The relationship of patient age to the pathobiology of clonal myeloid diseases. Semin. Oncol. 31, 185–197 (2004).

  27. 27.

    , , & Aging and marrow neutrophil reserves. J. Am. Geriatr. Soc. 42, 77–81 (1994).

  28. 28.

    , & Phenotypic and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol. Cell Biol. 82, 415–420 (2004).

  29. 29.

    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).

  30. 30.

    & Homeostasis of lymphocytes and monocytes in frequent blood donors. Front. Immunol. 3, 271 (2012).

  31. 31.

    , , , & Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol. 11, 30 (2010).

  32. 32.

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

  33. 33.

    , , & Impaired functions of peripheral blood monocyte subpopulations in aged humans. J. Clin. Immunol. 30, 806–813 (2010).

  34. 34.

    , , , & Plasmacytoid dendritic cells and their Toll-like receptor 9 expression selectively decrease with age. Hum. Immunol. 73, 493–497 (2012).

  35. 35.

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

  36. 36.

    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.

  37. 37.

    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).

  38. 38.

    , , , & Effect of age on human neutrophil function. J. Leukoc. Biol. 67, 40–45 (2000).

  39. 39.

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

  40. 40.

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

  41. 41.

    , , , & Influence of aging on murine neutrophil and macrophage function against Candida albicans. FEMS Immunol. Med. Microbiol. 53, 214–221 (2008).

  42. 42.

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

  43. 43.

    & Impaired immune responses in the lungs of aged mice following influenza infection. Respir. Res. 10, 112 (2009).

  44. 44.

    , , , & Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J. Immunol. 190, 1746–1757 (2013).

  45. 45.

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

  46. 46.

    , , , & 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.

  47. 47.

    , & Differential ability of exogenous chemotactic agents to disrupt transendothelial migration of flowing neutrophils. J. Immunol. 164, 5961–5969 (2000).

  48. 48.

    , , & 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.

  49. 49.

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

  50. 50.

    , , & Aging and neutrophils: there is still much to do. Rejuven. Res. 11, 873–882 (2008).

  51. 51.

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

  52. 52.

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

  53. 53.

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

  54. 54.

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

  55. 55.

    , , , & 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).

  56. 56.

    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).

  57. 57.

    , & Effects of aging on triggering receptor expressed on myeloid cells (TREM)-1-induced PMN functions. FEBS Lett. 581, 1173–1178 (2007).

  58. 58.

    , , , & 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).

  59. 59.

    , & 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).

  60. 60.

    & Influence of aging and protein deficiency on neutrophil function. J. Gerontol. 41, 690–694 (1986).

  61. 61.

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

  62. 62.

    , , , & Characterization of age-related changes in natural killer cells during primary influenza infection in mice. Mech. Ageing Dev. 129, 223–230 (2008).

  63. 63.

    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).

  64. 64.

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

  65. 65.

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

  66. 66.

    , & 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).

  67. 67.

    Human natural killer cells. Blood 112, 461–469 (2008).

  68. 68.

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

  69. 69.

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

  70. 70.

    , , , & Ageing is associated with a decline in peripheral blood CD56bright NK cells. Immun. Ageing 3, 10 (2006).

  71. 71.

    , , & Variation of human natural killer cell phenotypes with age: identification of a unique KLRG1-negative subset. Hum. Immunol. 71, 676–681 (2010).

  72. 72.

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

  73. 73.

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

  74. 74.

    , & 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.

  75. 75.

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

  76. 76.

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

  77. 77.

    , , , & CD1d-restricted NKT cells contribute to the age-associated decline of T cell immunity. J. Immunol. 175, 3102–3109 (2005).

  78. 78.

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

  79. 79.

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

  80. 80.

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

  81. 81.

    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).

  82. 82.

    , , , & Age-related decline in murine macrophage production of nitric oxide. J. Infect. Dis. 175, 1004–1007 (1997).

  83. 83.

    , , , & 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).

  84. 84.

    , , & Age-dependent change in reactive oxygen species and nitric oxide generation by rat alveolar macrophages. Aging Cell 2, 159–164 (2003).

  85. 85.

    , , & Alterations in marginal zone macrophages and marginal zone B cells in old mice. J. Immunol. 186, 3441–3451 (2011).

  86. 86.

    , , , & 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).

  87. 87.

    , , & Ageing is associated with diminished apoptotic cell clearance in vivo. Clin. Exp. Immunol. 152, 448–455 (2008).

  88. 88.

    , , & 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).

  89. 89.

    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).

  90. 90.

    & Impact of aging on antigen presentation cell function of dendritic cells. Curr. Opin. Immunol. 25, 535–541 (2013).

  91. 91.

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

  92. 92.

    , , & Impaired dendritic cell function in aging leads to defective antitumor immunity. Cancer Res. 68, 6341–6349 (2008).

  93. 93.

    , , & 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.

  94. 94.

    , & Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen. J. Immunol. 181, 7977–7984 (2008).

  95. 95.

    , , & 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).

  96. 96.

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

  97. 97.

    , & Peripheral blood dendritic cells reinduce proliferation in in vitro aged T cell populations. Mech. Ageing Dev. 93, 125–130 (1997).

  98. 98.

    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.

  99. 99.

    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.

  100. 100.

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

  101. 101.

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

  102. 102.

    , , & 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).

  103. 103.

    , , & 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).

  104. 104.

    , , , & Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia. Exp. Gerontol. 47, 507–518 (2012).

  105. 105.

    , & Immune response of macrophages from young and aged mice to the oral pathogenic bacterium Porphyromonas gingivalis. Immun. Ageing 7, 15 (2010).

  106. 106.

    et al. Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta). Pathobiol. Aging Age Relat. Dis. 2, (2012).

  107. 107.

    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).

  108. 108.

    & Flagellin as an adjuvant: cellular mechanisms and potential. J. Immunol. 185, 5677–5682 (2010).

  109. 109.

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

  110. 110.

    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.

  111. 111.

    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.

  112. 112.

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

  113. 113.

    , , , & 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.

  114. 114.

    , , & 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).

  115. 115.

    , & Prostaglandin E2-dependent IL-23 production in aged murine dendritic cells. Exp. Gerontol. 45, 834–841 (2010).

  116. 116.

    , , , & Nuclear factor-κB-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J. 22, 2142–2150 (2008).

  117. 117.

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

  118. 118.

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

  119. 119.

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

  120. 120.

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

  121. 121.

    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.

  122. 122.

    , , , & Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA. J. Immunol. 182, 1138–1145 (2009).

  123. 123.

    & Immunobiology of the TAM receptors. Nature Rev. Immunol. 8, 327–336 (2008).

  124. 124.

    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.

  125. 125.

    , , , & 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.

  126. 126.

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

  127. 127.

    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).

  128. 128.

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

  129. 129.

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

  130. 130.

    , , & A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

  131. 131.

    , & Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (Albany NY) 4, 166–175 (2012).

  132. 132.

    , & Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells. Cytokine 16, 178–186 (2001).

  133. 133.

    , , , & 17 β-estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J. Clin. Invest. 93, 944–950 (1994).

  134. 134.

    , & 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).

  135. 135.

    , , & Exogenous dehydroepiandrosterone modified the expression of T helper-related cytokines in NZB/NZW F1 mice. Immunol. Invest. 27, 291–302 (1998).

  136. 136.

    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).

  137. 137.

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

  138. 138.

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

  139. 139.

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

  140. 140.

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

  141. 141.

    , & Obesity and inflammation: the effects of weight loss. Nutr. Res. Rev. 21, 117–133 (2008).

  142. 142.

    , , & Adipose tissue-derived tumor necrosis factor-α activity is elevated in older rats. J. Gerontol. A Biol. Sci. Med. Sci. 52, B190–B195 (1997).

  143. 143.

    , & 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).

  144. 144.

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

  145. 145.

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

  146. 146.

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

  147. 147.

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

  148. 148.

    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.

  149. 149.

    , , & The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

  150. 150.

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

  151. 151.

    , , , & 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).

  152. 152.

    , , , & Circulating cell-free DNA is associated with mortality and inflammatory markers in nonagenarians: the Vitality 90+ Study. Exp. Gerontol. 47, 372–378 (2012).

  153. 153.

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

  154. 154.

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

  155. 155.

    , & Cutting edge: Necrosis activates the NLRP3 inflammasome. J. Immunol. 183, 1528–1532 (2009).

  156. 156.

    , , & The impact of CMV infection on survival in older humans. Curr. Opin. Immunol. 24, 507–511 (2012).

  157. 157.

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

  158. 158.

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

  159. 159.

    , , & Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am. J. Epidemiol. 172, 363–371 (2010).

  160. 160.

    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).

  161. 161.

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

  162. 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. 163.

    , & Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

  164. 164.

    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).

  165. 165.

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

  166. 166.

    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).

  167. 167.

    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).

  168. 168.

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

  169. 169.

    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).

  170. 170.

    , , & CD14 and Toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J. Neurosci. 29, 11982–11992 (2009).

  171. 171.

    , , & 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).

  172. 172.

    , & Hematopoietic MyD88-adaptor protein acts as a natural defense mechanism for cognitive deficits in Alzheimer's disease. Stem Cell Rev. 8, 898–904 (2012).

  173. 173.

    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).

  174. 174.

    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).

  175. 175.

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

  176. 176.

    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).

  177. 177.

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

  178. 178.

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

  179. 179.

    et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

  180. 180.

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

  181. 181.

    , & A role for immature myeloid cells in immune senescence. J. Immunol. 186, 697–707 (2011).

  182. 182.

    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).

  183. 183.

    & Aging and cancer in America. Demographic and epidemiologic perspectives. Hematol. Oncol. Clin. North Am. 14, 17–23 (2000).

  184. 184.

    , & Neutrophils confer T cell resistance to myeloid-derived suppressor cell-mediated suppression to promote chronic inflammation. J. Immunol. 190, 5037–5047 (2013).

  185. 185.

    , & Frailty, inflammation, and immunity. Aging Dis. 2, 466–473 (2011).

  186. 186.

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

  187. 187.

    , & Should the human microbiome be considered when developing vaccines? PLoS Pathog. 6, e1001190 (2010).

  188. 188.

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

  189. 189.

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

  190. 190.

    , , , & Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo. J. Immunol. 172, 5194–5199 (2004).

  191. 191.

    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).

  192. 192.

    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).

  193. 193.

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

  194. 194.

    , , & A novel adjuvant for vaccine development in the aged. Vaccine 28, 8275–8279 (2010).

  195. 195.

    , & 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).

  196. 196.

    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).

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

Affiliations

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

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

    • Daniel R. Goldstein
  3. Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.

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

    • Ruth R. Montgomery

Authors

  1. Search for Albert C. Shaw in:

  2. Search for Daniel R. Goldstein in:

  3. Search for Ruth R. Montgomery in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Albert C. Shaw.

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.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nri3547

Further reading

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