Can blocking inflammation enhance immunity during aging?

Aging is a global burden, and the increase in life span does not increase in parallel with health span. Therefore, older adults are currently living longer with chronic diseases, increased infections, and cancer. A characteristic of aging is the presence of chronic low-grade inflammation that is characterized by elevated concentrations of IL-6, TNF-α, and C-reactive protein, which has been termed inflammaging. Previous studies have demonstrated that chronic inflammation interferes with T-cell response and macrophage function and is also detrimental for vaccine responses. This raises the question of whether therapeutic strategies that reduce inflammation may be useful for improving immunity in older adults. In this review we discuss the potential causes of inflammaging, the cellular source of the inflammatory mediators, and the mechanisms by which inflammation may inhibit immunity. Finally, we describe existing interventions that target inflammation that have been used to enhance immunity during aging. Aging is a global burden, and the increase in life span does not increase in parallel with health span. Therefore, older adults are currently living longer with chronic diseases, increased infections, and cancer. A characteristic of aging is the presence of chronic low-grade inflammation that is characterized by elevated concentrations of IL-6, TNF-α, and C-reactive protein, which has been termed inflammaging. Previous studies have demonstrated that chronic inflammation interferes with T-cell response and macrophage function and is also detrimental for vaccine responses. This raises the question of whether therapeutic strategies that reduce inflammation may be useful for improving immunity in older adults. In this review we discuss the potential causes of inflammaging, the cellular source of the inflammatory mediators, and the mechanisms by which inflammation may inhibit immunity. Finally, we describe existing interventions that target inflammation that have been used to enhance immunity during aging. Aging results in increased susceptibility to infections, reduced vaccine responses, and increased susceptibility to cancers.1Gavazzi G. Krause K.H. Ageing and infection.Lancet Infect Dis. 2002; 2: 659-666Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar, 2Diffey B.L. Langtry J.A. Skin cancer incidence and the ageing population.Br J Dermatol. 2005; 153: 679-680Crossref PubMed Scopus (75) Google Scholar, 3Ciabattini A. Nardini C. Santoro F. Garagnani P. Franceschi C. Medaglini D. 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Acute inflammation is necessary to initiate an immune response against an invading pathogen. After the initial inflammatory response there is a period of resolution that occurs to prevent unnecessary tissue damage and to restore tissue homeostasis.19Gilroy D. De Maeyer R. New insights into the resolution of inflammation.Semin Immunol. 2015; 27: 161-168Crossref PubMed Scopus (87) Google Scholar However, there is accumulating data showing that chronic inflammation can inhibit immunity in vivo, as elevated inflammatory responses are detrimental for vaccine efficacy against influenza,20Parmigiani A. Alcaide M.L. Freguja R. Pallikkuth S. Frasca D. Fischl M.A. et al.Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation.PLoS One. 2013; 8e79816Crossref Scopus (83) Google Scholar yellow fever,21Muyanja E. Ssemaganda A. Ngauv P. Cubas R. Perrin H. Srinivasan D. et al.Immune activation alters cellular and humoral responses to yellow fever 17D vaccine.J Clin Invest. 2014; 124: 3147-3158Crossref PubMed Scopus (112) Google Scholar and hepatitis B. In addition, excessive inflammation, in particular TNF-α production, is linked to decreased killing and clearance of Streptococcus pneumonia in macrophages in an aged mouse model of infection.22Thevaranjan N. Puchta A. Schulz C. Naidoo A. Szamosi J.C. Verschoor C.P. et al.Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction.Cell Host Microbe. 2017; 21: 455-466.e4Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar This may occur in part by the induction of premature monocyte egress from the bone marrow by TNF-α that impairs their function. Interestingly, blockade of TNF-α restores monocyte function in old animals, showing that the effect of chronic inflammation can be reversed.23Puchta A. Naidoo A. Verschoor C.P. Loukov D. Thevaranjan N. Mandur T.S. et al.TNF drives monocyte dysfunction with age and results in impaired anti-pneumococcal immunity.PLoS Pathog. 2016; 12e1005368Crossref Scopus (81) Google Scholar Elevated inflammation can also inhibit the response to cutaneous recall antigens in vivo. Older humans have decreased response to challenge with antigens such as tuberculin purified protein derivative, candida albicans antigens, and varicella zoster virus antigens in the skin compared with young individuals.24Agius E. Lacy K.E. Vukmanovic-Stejic M. Jagger A.L. Papageorgiou A.P. Hall S. et al.Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging.J Exp Med. 2009; 206: 1929-1940Crossref PubMed Scopus (130) Google Scholar However, this was not due to a decrease in the number of circulating or resident memory T cells.24Agius E. Lacy K.E. Vukmanovic-Stejic M. Jagger A.L. Papageorgiou A.P. 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Gava A.L. et al.Increased ROS production and DNA damage in monocytes are biomarkers of aging and atherosclerosis.Biol Res. 2018; 51: 33Crossref PubMed Scopus (38) Google Scholar The temporary inhibition of systemic inflammation with an oral p38 mitogen-activated protein (MAP) (p38-MAP Kinase) kinase inhibitor enhances the response to antigen in older subjects, indicating the direct association between excessive inflammation and immune inhibition.27Vukmanovic-Stejic M. Chambers E.S. Suarez-Farinas M. Sandhu D. Fuentes-Duculan J. Patel N. et al.Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation.J Allergy Clin Immunol. 2018; 142: 844-856Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar The exact source of elevated inflammation during aging may be due to a combination of the following mechanisms that are accentuated in older adults. These include chronic viral infection leading to immune activation, increased inflammatory mediator secretion from visceral fat, increased gut permeability resulting in leakage of bacterial components into the circulation, increase in damage-associated molecular patterns (DAMPs), altered immune resolution, and accumulation of senescent cells, as shown in Fig 1. Chronic infections, which cause a lifelong latent infection, are believed to lead to long-term activation of the immune system over time, contributing to inflammaging. The most studied example is cytomegalovirus (CMV) infection, which induces a lifelong latent infection after the primary infection, and the virus reactivates periodically and initiates a subclinical immune response. A large proportion of T cells in seropositive older subjects are CMV-specific,28Khan N. Shariff N. Cobbold M. Bruton R. Ainsworth J.A. 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Henson S.M. et al.Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults.Immunology. 2015; 144: 549-560Crossref PubMed Scopus (0) Google Scholar which may contribute to inflammaging. Individuals who are CMV seropositive and exhibit elevated CRP levels have increased all-cause mortality as compared with CMV-seropositive subjects with low CRP levels.31Simanek A.M. Dowd J.B. Pawelec G. Melzer D. Dutta A. Aiello A.E. Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States.PLoS One. 2011; 6e16103Crossref Scopus (272) Google Scholar However, the impact of CMV infection on the elevated inflammation in older subjects is controversial.32Bartlett D.B. Firth C.M. Phillips A.C. Moss P. Baylis D. 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Aging, obesity, and inflammatory age-related diseases.Front Immunol. 2017; 8: 1745Crossref PubMed Scopus (157) Google Scholar In young obese individuals, there is an alteration in their circulating leukocyte populations that resemble the cells found in older adults. There is an increase in circulating end-stage senescent-like CD4+ and CD8+ cells that secrete high levels of inflammatory cytokines after activation and decreased naive T cells.35Spielmann G. Johnston C.A. O'Connor D.P. Foreyt J.P. Simpson R.J. Excess body mass is associated with T cell differentiation indicative of immune ageing in children.Clin Exp Immunol. 2014; 176: 246-254Crossref PubMed Scopus (0) Google Scholar Apart from changes in immune cells resident in fat tissue, there is an increase in visceral adiposity during aging, due in part to the age-related decrease in muscle.36Hunter G.R. Gower B.A. Kane B.L. 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