Abstract
Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.
Similar content being viewed by others
Change history
03 September 2018
In the version of this Review initially published, the type of cell in the final sentence of the legend to Figure 3 (group 2 innate lymphoid cells) was incorrect. The correct type of cell is group 3 innate lymphoid cells. The error has been corrected in the HTML and PDF versions of the article.
References
Albright, J. F. & Albright, J. W. Aging, Immunity, and Infection (Humana Press, Totowa, NJ, 2003).
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).
Sharma, S., Dominguez, A. L., Hoelzinger, D. B. & Lustgarten, J. CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol. Immunother. 57, 549–561 (2008).
Lal, H. et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N. Engl. J. Med. 372, 2087–2096 (2015).
Nikolich-Žugich, J. Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J. Immunol. 193, 2622–2629 (2014).
Hazeldine, J. & Lord, J. M. Innate immunesenescence: underlying mechanisms and clinical relevance. Biogerontology 16, 187–201 (2015).
Montgomery, R. R. & Shaw, A. C. Paradoxical changes in innate immunity in aging: recent progress and new directions. J. Leukoc. Biol. 98, 937–943 (2015).
Zhang, B. et al. Glimpse of natural selection of long-lived T-cell clones in healthy life. Proc. Natl. Acad. Sci. USA 113, 9858–9863 (2016).
Lord, J. M., Butcher, S., Killampali, V., Lascelles, D. & Salmon, M. Neutrophil ageing and immunesenescence. Mech. Ageing Dev. 122, 1521–1535 (2001).
Shaw, A. C., Joshi, S., Greenwood, H., Panda, A. & Lord, J. M. Aging of the innate immune system. Curr. Opin. Immunol. 22, 507–513 (2010).
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).
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).
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).
van Duin, D. et al. Age-associated defect in human TLR-1/2 function. J. Immunol. 178, 970–975 (2007).
Manser, A. R. & Uhrberg, M. Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance. Cancer Immunol. Immunother. 65, 417–426 (2016).
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).
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).
Metcalf, T. U. et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 14, 421–432 (2015).
Metcalf, T. U. et al. Human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists. J. Immunol. 199, 1405–1417 (2017).
Cumberbatch, M., Dearman, R. J. & Kimber, I. Influence of ageing on Langerhans cell migration in mice: identification of a putative deficiency of epidermal interleukin-1beta. Immunology 105, 466–477 (2002).
Desai, A., Grolleau-Julius, A. & Yung, R. Leukocyte function in the aging immune system. J. Leukoc. Biol. 87, 1001–1009 (2010).
Zacca, E. R. et al. Aging impairs the ability of conventional dendritic cells to cross-prime CD8+ T cells upon stimulation with a TLR7 ligand. PLoS One 10, e0140672 (2015).
Chougnet, C. A. et al. Loss of phagocytic and antigen cross-presenting capacity in aging dendritic cells is associated with mitochondrial dysfunction. J. Immunol. 195, 2624–2632 (2015).
Uhrlaub, J. L., Smithey, M. J. & Nikolich-Žugich, J. Cutting edge: the aging immune system reveals the biological impact of direct antigen presentation on CD8 T cell responses. J. Immunol. 199, 403–407 (2017).
Zhao, J., Zhao, J., Legge, K. & Perlman, S. Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J. Clin. Invest. 121, 4921–4930 (2011).
Chinn, I. K., Blackburn, C. C., Manley, N. R. & Sempowski, G. D. Changes in primary lymphoid organs with aging. Semin. Immunol. 24, 309–320 (2012).
Kline, G. H., Hayden, T. A. & Klinman, N. R. B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation. J. Immunol. 162, 3342–3349 (1999).
Stephan, R. P., Lill-Elghanian, D. A. & Witte, P. L. Development of B cells in aged mice: decline in the ability of pro-B cells to respond to IL-7 but not to other growth factors. J. Immunol. 158, 1598–1609 (1997).
Qi, Q. et al. Diversity and clonal selection in the human T-cell repertoire. Proc. Natl. Acad. Sci. USA 111, 13139–13144 (2014).
Thome, J. J. et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016).
Rudd, B. D., Venturi, V., Davenport, M. P. & Nikolich-Zugich, J. Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J. Immunol. 186, 2056–2064 (2011).
Sprent, J. & Surh, C. D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol. 12, 478–484 (2011).
Thompson, H. L., Smithey, M. J., Surh, C. D. & Nikolich-Žugich, J. Functional and homeostatic impact of age-related changes in lymph node stroma. Front. Immunol. 8, 706 (2017).
Cambier, J. Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling. Immunol. Rev. 205, 5–6 (2005).
Wertheimer, A. M. et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192, 2143–2155 (2014).
Rudd, B. D. et al. Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc. Natl. Acad. Sci. USA 108, 13694–13699 (2011).
Kogut, I., Scholz, J. L., Cancro, M. P. & Cambier, J. C. B cell maintenance and function in aging. Semin. Immunol. 24, 342–349 (2012).
Hao, Y., O’Neill, P., Naradikian, M. S., Scholz, J. L. & Cancro, M. P. A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood 118, 1294–1304 (2011).
Becklund, B. R. et al. The aged lymphoid tissue environment fails to support naïve T cell homeostasis. Sci. Rep 6, 30842 (2016).
Decman, V. et al. Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors. J. Immunol. 188, 1933–1941 (2012).
Renkema, K. R., Li, G., Wu, A., Smithey, M. J. & Nikolich-Žugich, J. Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging. J. Immunol. 192, 151–159 (2014).
Chiu, B. C., Martin, B. E., Stolberg, V. R. & Chensue, S. W. Cutting edge: Central memory CD8 T cells in aged mice are virtual memory cells. J. Immunol. 191, 5793–5796 (2013).
Holtappels, R., Pahl-Seibert, M. F., Thomas, D. & Reddehase, M. J. Enrichment of immediate-early 1 (m123/pp89) peptide-specific CD8 T cells in a pulmonary CD62Llo memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. J. Virol. 74, 11495–11503 (2000).
Munks, M. W. et al. Genome-wide analysis reveals a highly diverse CD8 T cell response to murine cytomegalovirus. J. Immunol. 176, 3760–3766 (2006).
Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005).
Souquette, A., Frere, J., Smithey, M., Sauce, D. & Thomas, P. G. A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness. Geroscience 39, 293–303 (2017).
Frasca, D., Van der Put, E., Riley, R. L. & Blomberg, B. B. Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase. J. Immunol. 172, 2155–2162 (2004).
Frasca, D., Diaz, A., Romero, M. & Blomberg, B. B. The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations. Vaccine 34, 2834–2840 (2016).
Richner, J. M. et al. Age-Dependent cell trafficking defects in draining lymph nodes impair adaptive immunity and control of West Nile virus infection. PLoS Pathog. 11, e1005027 (2015).
Sage, P. T., Tan, C. L., Freeman, G. J., Haigis, M. & Sharpe, A. H. Defective TFH cell function and increased TFR cells contribute to defective antibody production in aging. Cell Rep. 12, 163–171 (2015).
Miller, R. A. & Stutman, O. Limiting dilution analysis of IL-2 production: studies of age, genotype, and regulatory interactions. Lymphokine Res. 1, 79–86 (1982).
Effros, R. B. & Walford, R. L. The immune response of aged mice to influenza: diminished T-cell proliferation, interleukin 2 production and cytotoxicity. Cell. Immunol. 81, 298–305 (1983).
Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518–1524 (2012).
Garcia, G. G., Sadighi Akha, A. A. & Miller, R. A. Age-related defects in moesin/ezrin cytoskeletal signals in mouse CD4 T cells. J. Immunol. 179, 6403–6409 (2007).
Garcia, G. G. & Miller, R. A. Differential tyrosine phosphorylation of zeta chain dimers in mouse CD4 T lymphocytes: effect of age. Cell. Immunol. 175, 51–57 (1997).
Garcia, G. G. & Miller, R. A. Age-related defects in the cytoskeleton signaling pathways of CD4 T cells. Ageing Res. Rev. 10, 26–34 (2011).
Haynes, L., Linton, P. J., Eaton, S. M., Tonkonogy, S. L. & Swain, S. L. Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J. Exp. Med. 190, 1013–1024 (1999).
Haynes, L., Linton, P. J. & Swain, S. L. Age-related changes in CD4 T cells of T cell receptor transgenic mice. Mech. Ageing Dev. 93, 95–105 (1997).
Tsukamoto, H. et al. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc. Natl. Acad. Sci. USA 106, 18333–18338 (2009).
Tsukamoto, H., Huston, G. E., Dibble, J., Duso, D. K. & Swain, S. L. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J. Immunol. 185, 4535–4544 (2010).
Brien, J. D., Uhrlaub, J. L., Hirsch, A., Wiley, C. A. & Nikolich-Zugich, J. Key role of T cell defects in age-related vulnerability to West Nile virus. J. Exp. Med. 206, 2735–2745 (2009).
Smithey, M. J., Renkema, K. R., Rudd, B. D. & Nikolich-Žugich, J. Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. Eur. J. Immunol. 41, 1352–1364 (2011).
Uhrlaub, J. L. et al. Dysregulated TGF-β production underlies the age-related vulnerability to chikungunya virus. PLoS Pathog. 12, e1005891 (2016).
Li, G., Smithey, M. J., Rudd, B. D. & Nikolich-Žugich, J. Age-associated alterations in CD8α+ dendritic cells impair CD8 T-cell expansion in response to an intracellular bacterium. Aging Cell 11, 968–977 (2012).
Martinez-Jimenez, C. P. et al. Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355, 1433–1436 (2017).
Moskowitz, D. M. et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2, eaag0192 (2017).
Ucar, D. et al. The chromatin accessibility signature of human immune aging stems from CD8+ T cells. J. Exp. Med. 214, 3123–3144 (2017).
Pulko, V. et al. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat. Immunol. 17, 966–975 (2016).
Di Mitri, D. et al. Reversible senescence in human CD4+CD45RA+CD27– memory T cells. J. Immunol. 187, 2093–2100 (2011).
Lanna, A. et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363 (2017).
Ferrucci, L. et al. The origins of age-related proinflammatory state. Blood 105, 2294–2299 (2005).
De Martinis, M., Franceschi, C., Monti, D. & Ginaldi, L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579, 2035–2039 (2005).
Fagiolo, U. et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J. Immunol. 23, 2375–2378 (1993).
Laudisio, A., Bandinelli, S., Gemma, A., Ferrucci, L. & Incalzi, R. A. Associations of heart rate with inflammatory markers are modulated by gender and obesity in older adults. J. Gerontol. A Biol. Sci. Med. Sci 70, 899–904 (2015).
Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013).
Wick, G. et al. The immunology of fibrosis: innate and adaptive responses. Trends Immunol. 31, 110–119 (2010).
Bhadra, R. et al. Intrinsic TGF-β signaling promotes age-dependent CD8+ T cell polyfunctionality attrition. J. Clin. Invest. 124, 2441–2455 (2014).
Sahin, H. et al. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 55, 1610–1619 (2012).
Notas, G., Kisseleva, T. & Brenner, D. NK and NKT cells in liver injury and fibrosis. Clin. Immunol. 130, 16–26 (2009).
Brown, F. D. & Turley, S. J. Fibroblastic reticular cells: organization and regulation of the T lymphocyte life cycle. J. Immunol. 194, 1389–1394 (2015).
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).
Turner, V. M. & Mabbott, N. A. Structural and functional changes to lymph nodes in ageing mice. Immunology 151, 239–247 (2017).
Davies, J. S., Thompson, H. L., Pulko, V., Torres, J. P. & Nikolich-Žugich, J. Role of cell-intrinsic and environmental age-related changes in altered maintenance of murine T cells in lymphoid organs. J. Gerontol. A Biol. Sci. Med. Sci. http://dx.doi.org/10.1093/gerona/glx102 (2017).
Agius, E. et al. Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging. J. Exp. Med. 206, 1929–1940 (2009).
Cebra, J. J. Influences of microbiota on intestinal immune system development. Am. J. Clin. Nutr. 69, 1046S–1051S (1999).
Kieper, W. C. et al. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol. 174, 3158–3163 (2005).
Claesson, M. J. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 (2012).
Stehle, J. R. Jr. et al. Lipopolysaccharide-binding protein, a surrogate marker of microbial translocation, is associated with physical function in healthy older adults. J. Gerontol. A Biol. Sci. Med. Sci. 67, 1212–1218 (2012).
Jeong, J. H. et al. Microvasculature remodeling in the mouse lower gut during inflammaging. Sci. Rep. 7, 39848 (2017).
Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12, 1365–1371 (2006).
Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).
Woodward, N. C. et al. Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo. J. Neuroinflammation 14, 84 (2017).
Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).
Aiello, A. E., Chiu, Y. L. & Frasca, D. How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms? Geroscience 39, 261–271 (2017).
Bruns, T. et al. CMV infection of human sinusoidal endothelium regulates hepatic T cell recruitment and activation. J. Hepatol. 63, 38–49 (2015).
Cicin-Sain, L. et al. Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging. PLoS Pathog. 8, e1002849 (2012).
Smithey, M. J., Li, G., Venturi, V., Davenport, M. P. & Nikolich-Žugich, J. Lifelong persistent viral infection alters the naive T cell pool, impairing CD8 T cell immunity in late life. J. Immunol. 189, 5356–5366 (2012).
Mekker, A. et al. Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog. 8, e1002850 (2012).
Marandu, T. F. et al. Immune protection against virus challenge in aging mice is not affected by latent herpesviral infections. J. Virol. 89, 11715–11717 (2015).
Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).
Furman, D. et al. Cytomegalovirus infection enhances the immune response to influenza. Sci. Transl. Med. 7, 281ra43 (2015).
Leng, S. X. et al. Recent advances in CMV tropism, latency, and diagnosis during aging. Geroscience 39, 251–259 (2017).
Greene, M. et al. Geriatric syndromes in older HIV-infected adults. J. Acquir. Immune Defic. Syndr. 69, 161–167 (2015).
Pathai, S., Bajillan, H., Landay, A. L. & High, K. P. Is HIV a model of accelerated or accentuated aging? J. Gerontol. A Biol. Sci. Med. Sci 69, 833–842 (2014).
Masoro, E. J. Overview of caloric restriction and ageing. Mech. Ageing Dev. 126, 913–922 (2005).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Chen, J., Astle, C.M. & Harrison, D.E. Delayed immune aging in diet-restricted B6CBAT6 F1 mice is associated with preservation of naive T cells. Exp. Gerontol. 53A, B330–B337 (1998).
Messaoudi, I. et al. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc. Natl. Acad. Sci. USA 103, 19448–19453 (2006).
Youm, Y. H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med 21, 263–269 (2015).
Ventevogel, M. S. & Sempowski, G. D. Thymic rejuvenation and aging. Curr. Opin. Immunol. 25, 516–522 (2013).
Goldberg, E. L. et al. Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell 14, 130–138 (2015).
Goldberg, E. L., Smithey, M. J., Lutes, L. K., Uhrlaub, J. L. & Nikolich-Žugich, J. Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections. J. Immunol. 193, 757–763 (2014).
Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).
Acknowledgements
I thank past and present members of the Nikolich lab and the UA Department of Immunobiology for collaborative work that led to some of the concepts crystallized in this work; E. Goldberg for suggestions; I. Jeftic, M. Jergovic, M. Smithey and H. Thompson for help with illustrations and critical perusal of the manuscript; and M. Kuhns for the suggestion that rules of immune system might change with aging and for critical perusal of the manuscript. Supported by the US Public Health Service (AG020719, AG048021 and AG053259), the US National Institutes of Health (HHSN 272201100017 C and HHSN272200900059C) and the Elizabeth Bowman Endowed Professorship in Medical Science.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Nikolich-Žugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol 19, 10–19 (2018). https://doi.org/10.1038/s41590-017-0006-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41590-017-0006-x
- Springer Nature America, Inc.
This article is cited by
-
Impaired ATP hydrolysis in blood plasma contributes to age-related neutrophil dysfunction
Immunity & Ageing (2024)
-
An aging-related immune landscape in the hematopoietic immune system
Immunity & Ageing (2024)
-
Partial loss of Sorting Nexin 27 resembles age- and Down syndrome-associated T cell dysfunctions
Immunity & Ageing (2024)
-
Prognostic and immunological implications of heterogeneous cell death patterns in prostate cancer
Cancer Cell International (2024)
-
Clinical characteristics of patients hospitalized for COVID-19: comparison between different age groups
BMC Geriatrics (2024)