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Can blocking inflammation enhance immunity during aging?

  • Emma S. Chambers
    Correspondence
    Corresponding author: Emma S. Chambers, PhD, Centre for Immunobiology, Blizard Institute, Queen Mary University of London, 4 Newark St, London E1 2AT, UK.
    Affiliations
    Division of Infection and Immunity, University College London, London, United Kingdom

    Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, United Kingdom
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  • Arne N. Akbar
    Affiliations
    Division of Infection and Immunity, University College London, London, United Kingdom
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      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.

      Key words

      Abbreviations used:

      CMV (Cytomegalovirus), CRP (C-reactive protein), DAMP (Damage-associated molecular pattern), MAP (Mitogen-activated protein), mTOR (Mammalian target of rapamycin), NK (Natural killer), PD-1 (Programmed cell death protein-1), PDL-1 (Programmed death ligand-1), SASP (Senescence-associated secretory phenotype), TLR (Toll-like receptor), TORC (mTOR complex)
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      Inflammaging

      Inflammaging, a term first proposed by Claudio Franceschi, is the state of chronic low-grade sterile inflammation that is observed with age. It is characterized by high serum concentrations of C-reactive protein (CRP) and other inflammatory mediators such as IL-6, IL-8, and TNF-α.
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      Inflammation and immunity

      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.
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      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,
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      Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation.
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      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.
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      Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction.
      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.
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      TNF drives monocyte dysfunction with age and results in impaired anti-pneumococcal immunity.
      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.
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      Instead, these subjects exhibit elevated inflammatory responses induced by the injection itself, the extent of which was negatively correlated with their ability to respond to the antigen.
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      Source of inflammation

      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.
      Figure thumbnail gr1
      Fig 1Potential mechanisms of inflammaging. Schematic representation of the proposed causes of inflammaging observed in the old. Increased visceral fat with associated increased leukocyte infiltration; increased DAMP production that binds to TLRs; increased senescent cell production with production of SASP that also includes DAMPs; increased gut permeability and LPS leakage and subsequent TLR activation; and finally chronic viral infection that leads to chronic immune activation. The SASP secreted from the senescent cells also has the capability to drive senescence in nearby cells, increasing the number of cells overall. All these outcomes result in the production of inflammatory cytokines and the subsequent onset of inflammaging.

       Chronic viral infections

      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,
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      and these cells are highly differentiated and express senescence-associated markers such as CD57 and KLRG1. Furthermore, these cells produce high levels of inflammatory cytokines such as IL-2, IFN-γ, and TNF-α after activation,
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      Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults.
      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.
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      However, the impact of CMV infection on the elevated inflammation in older subjects is controversial.
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      The age-related increase in low-grade systemic inflammation (inflammaging) is not driven by cytomegalovirus infection.

       Increased visceral fat

      Obesity, and in particular accumulation of visceral fat, is highly associated with inflammatory cytokine production.
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      Visceral fat is an inflammatory site that has an infiltration of mononuclear phagocytes, B cells, and T cells, which contribute to the production of inflammatory cytokines such as IL-6, IL-1β, and TNF-α.
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       Gut permeability

      Studies performed from aged mouse models have shown that older mice have more permeable intestines with a breakdown in cell-to-cell contacts, which leads to leakage of gut contents into the bloodstream.
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      Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice.
      This results in an increase in bacterial components such as LPS in the circulation that activate circulating mononuclear phagocytes through pattern recognition receptor expressed by the monocytes and results in production of inflammatory cytokines such as TNFα and IL-6.
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      TNF drives monocyte dysfunction with age and results in impaired anti-pneumococcal immunity.
      In addition, there are alterations in the microbiome of older adults that renders them distinct from younger cohorts.
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      However, whether this dysbiosis is as a result of altered gut permeability rather than causative of increased inflammation still warrants further investigation. Evidence from an aged drosophila model has shown that microbiome dysbiosis precedes the increased gut permeability observed with age and thus microbiome dysbiosis could be a causative factor in the increase gut permeability seen with age.
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       Increase in DAMPs

      DAMPs are endogenous cellular components that are released at times of injury, stress, or cell death. DAMPs can consist of various cellular products including the S100 family of calcium-binding proteins, histones, genomic or mitochondrial DNA, or other secreted factors such as ATP, uric acid, or heparin sulfate. This is not an exhaustive list, and DAMPs have been extensively reviewed previously.
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      When DAMPs bind to their pattern recognition receptor, there is an increase in inflammatory cytokine production from the cell.
      It is proposed that the processes involved in aging result in increased DAMP production, which contributes to inflammaging.
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      There is limited human data to support this hypothesis; however, in aged murine studies, elevated levels of high mobility group box 1 have been observed in old mice.
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       Ineffective immune resolution

      After an acute inflammatory response to an infectious agent or traumatic event such as a wound healing response, there is a period of immune resolution where the tissue is restored back to its original state.
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      A recent study has shown that although the onset of acute inflammation between older and younger adults is similar, the resolution of the inflammation is impaired in the older adults.

      Gilroy D, De Maeyer R, Van De Merwe R, Louie R, Bracken O, Devine O, et al. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat Immunol 2020 Apr 6 [Online ahead of print]. doi: 10.1038/s41590-020-0646-0.

      Indeed, there was reduced efferocytosis and clearance of apoptotic neutrophils by the mononuclear phagocytes during the resolution phase of the inflammatory response, which led to a failure to resolve inflammation. This was due in part to reduced expression of TIM-4, a receptor that recognizes apoptotic cells, on mononuclear phagocytes.

      Gilroy D, De Maeyer R, Van De Merwe R, Louie R, Bracken O, Devine O, et al. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat Immunol 2020 Apr 6 [Online ahead of print]. doi: 10.1038/s41590-020-0646-0.

      This means that acute inflammatory events are not efficiently resolved in older individuals, which could contribute to inflammaging.

       Senescent cell accumulation with age

      Cells entering a state of senescence experience irreversible growth arrest that occurs as a result of the irreparable cell damage, for example, DNA damage, telomere erosion, or oxidative stress.
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      • Victorelli S.
      • Lagnado A.
      • Halim J.
      • Moore W.
      • Talbot D.
      • Barrett K.
      • et al.
      Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction.
      ; however, it is predicted that every cell type in the body has the potential to become senescent. Senescent stromal cells may accumulate because of long-term exposure to DNA-damaging agents such as ultra violet B and exposure to pollutants.
      • Gorgoulis V.
      • Adams P.D.
      • Alimonti A.
      • Bennett D.C.
      • Bischof O.
      • Bishop C.
      • et al.
      Cellular senescence: defining a path forward.
      However, a recent article
      • Karin O.
      • Agrawal A.
      • Porat Z.
      • Krizhanovsky V.
      • Alon U.
      Senescent cell turnover slows with age providing an explanation for the Gompertz law.
      showed that there is reduced elimination of senescent cells during aging, which would also account for their accumulation. This reduced clearance may be due in part to the expression of HLA-E by senescent fibroblasts that bind to the inhibitory receptor NKG2A expressed on natural killer (NK) and CD8+ T cells. Binding of HLA-E to NKG2A results in a negative signal to the NK and CD8+ T cells, which inhibits their cytotoxic activity and prevents killing of the senescent fibroblasts.
      • Pereira B.I.
      • Devine O.P.
      • Vukmanovic-Stejic M.
      • Chambers E.S.
      • Subramanian P.
      • Patel N.
      • et al.
      Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition.
      It is possible that other inhibitory receptor/ligand pairs may also be involved in this evasion strategy that enables senescent cell persistence during aging.
      Senescent cells can secrete a range of inflammatory cytokines (such as IL-1β, IL-6, and TNF-α), chemokines (such as CCL2 and IL-8), growth factors (such as fibroblast growth factor), and matrix metalloproteinase (such as metalloproteinase 1 and metalloproteinase 3). DAMPs such as high mobility group box 1 are also secreted, contributing to the inflammatory phenotype of senescent cells.
      • Davalos A.R.
      • Kawahara M.
      • Malhotra G.K.
      • Schaum N.
      • Huang J.
      • Ved U.
      • et al.
      p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.
      This secretion of proinflammatory mediators is known as the senescence-associated secretory phenotype (SASP). Multiple components of the SASP including CCL2, transforming growth factor beta, and IL-1α have the ability to drive senescence in a paracrine manner in nearby nonsenescent cells, thus overall increasing the number of senescent cells.
      • Acosta J.C.
      • Banito A.
      • Wuestefeld T.
      • Georgilis A.
      • Janich P.
      • Morton J.P.
      • et al.
      A complex secretory program orchestrated by the inflammasome controls paracrine senescence.
      All components of SASP contribute to the local inflammatory environment and may contribute to the inflammaging phenomenon.
      • Lasry A.
      • Ben-Neriah Y.
      Senescence-associated inflammatory responses: aging and cancer perspectives.
      Although most senescence research has focused on stromal cells in tissues, there are also populations of circulating senescent-like leukocytes that accumulate during aging.
      • Liu Y.
      • Sanoff H.K.
      • Cho H.
      • Burd C.E.
      • Torrice C.
      • Ibrahim J.G.
      • et al.
      Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging.
      Examples of senescent-like leukocytes include terminally differentiated CD4+ and CD8+ T effector memory cells that reexpress CD45RA. These cells have low proliferative capacity and secrete inflammatory mediators such as TNF-α, IL-1β, IL-18, and IL-6, which is similar to SASP produced by senescent stromal cells such as fibroblasts.
      • Di Mitri D.
      • Azevedo R.I.
      • Henson S.M.
      • Libri V.
      • Riddell N.E.
      • Macaulay R.
      • et al.
      Reversible senescence in human CD4+CD45RA+CD27− memory T cells.
      • Henson S.M.
      • Franzese O.
      • Macaulay R.
      • Libri V.
      • Azevedo R.I.
      • Kiani-Alikhan S.
      • et al.
      KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells.
      • Tilly G.
      • Doan-Ngoc T.M.
      • Yap M.
      • Caristan A.
      • Jacquemont L.
      • Danger R.
      • et al.
      IL-15 harnesses pro-inflammatory function of TEMRA CD8 in kidney-transplant recipients.
      Terminally differentiated NK cells also accumulate during aging, and these CD16dimKLRG1+ cells have increased inflammatory cytokine production.
      • Muller-Durovic B.
      • Lanna A.
      • Covre L.P.
      • Mills R.S.
      • Henson S.M.
      • Akbar A.N.
      Killer cell lectin-like receptor G1 inhibits NK cell function through activation of adenosine 5'-monophosphate-activated protein kinase.
      The increase in senescent-like leukocytes in older adults that secrete a raft of inflammatory mediators is proposed to contribute to the inflammaging phenomenon.

      How does inflammation inhibit immunity?

      There are direct effects that inflammation has on immunity, such as the suppressive effect of TNF-α on T- cell receptor signalling
      • Cope A.P.
      • Liblau R.S.
      • Yang X.D.
      • Congia M.
      • Laudanna C.
      • Schreiber R.D.
      • et al.
      Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling.
      and monocyte phagocytosis.
      • Puchta 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.
      There are also other mechanisms by which inflammation inhibits immunity, including increasing the expression of inhibitory receptors, increasing the number and function of Foxp3+ regulatory T (Treg) cells, and increasing monocyte infiltration of the tissue.

       Increase of inhibitory ligands and receptors

      There is increasing evidence that inflammaging-associated cytokines can increase the expression of inhibitory ligands on immune cells. An example of this is TNF-α, which increases the expression of programmed death ligand 1 (PDL-1) on antigen-presenting cells such as mononuclear phagocytes.
      • Lim S.O.
      • Li C.W.
      • Xia W.
      • Cha J.H.
      • Chan L.C.
      • Wu Y.
      • et al.
      Deubiquitination and stabilization of PD-L1 by CSN5.
      PDL-1 binds to programmed cell death protein-1 (PD-1), which is expressed on T cells, which leads to apoptosis of the cell. The increase in PDL-1 expression is particularly relevant because increased expression of PD-1 on T cells has been shown in the skin and peripheral blood populations of these cells in older adults, which renders them more susceptible to inhibition.
      • Vukmanovic-Stejic M.
      • Sandhu D.
      • Seidel J.A.
      • Patel N.
      • Sobande T.O.
      • Agius E.
      • et al.
      The characterization of varicella zoster virus-specific T cells in skin and blood during aging.

       Inflammation effects on Foxp3+ Treg cells

      Treg cells are defined by the transcription factor Foxp3, and they play an important role in maintaining immune homeostasis, because in the absence of these cells, there is widespread autoimmune and inflammatory disease that leads to early death.
      • Bennett C.L.
      • Christie J.
      • Ramsdell F.
      • Brunkow M.E.
      • Ferguson P.J.
      • Whitesell L.
      • et al.
      The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.
      ,
      • Brunkow M.E.
      • Jeffery E.W.
      • Hjerrild K.A.
      • Paeper B.
      • Clark L.B.
      • Yasayko S.A.
      • et al.
      Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.
      There are increased number of Foxp3+ Treg cells in the skin of older subjects at baseline and in response to antigens that contribute to decreased cutaneous antigen-specific immune responses during aging.
      • Vukmanovic-Stejic M.
      • Agius E.
      • Booth N.
      • Dunne P.J.
      • Lacy K.E.
      • Reed J.R.
      • et al.
      The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo.
      ,
      • Vukmanovic-Stejic M.
      • Sandhu D.
      • Sobande T.O.
      • Agius E.
      • Lacy K.E.
      • Riddell N.
      • et al.
      Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans.
      It has been proposed that the accumulation of Foxp3+ Treg cells in the skin of older adults may be due to inflammatory processes because Foxp3+ Treg cells are recruited to sites of inflammation.
      • Korn T.
      • Muschaweckh A.
      Stability and maintenance of Foxp3(+) Treg cells in non-lymphoid microenvironments.
      Interestingly, inflammaging-associated cytokines such as TNF-α can increase Foxp3+ Treg-cell number and induce them to become more suppressive.
      • Chen X.
      • Baumel M.
      • Mannel D.N.
      • Howard O.M.
      • Oppenheim J.J.
      Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells.
      As a result, inflammaging may induce increased numbers and function of Foxp3+ Treg cells that can inhibit immunity.

       Senescent cells recruit inflammatory cells via SASP

      One major component of the SASP is monocyte chemoattractant chemokines such as CCL2.
      • Pereira B.I.
      • Devine O.P.
      • Vukmanovic-Stejic M.
      • Chambers E.S.
      • Subramanian P.
      • Patel N.
      • et al.
      Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition.
      When monocytes are recruited into tissues and exposed to inflammatory signals, they upregulate immune resolution pathways such as CD39/CD73 and PDL-1, all of which may have a role in inhibiting immunity.
      • Watanabe R.
      • Shirai T.
      • Namkoong H.
      • Zhang H.
      • Berry G.J.
      • Wallis B.B.
      • et al.
      Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity.
      ,
      • Cohen H.B.
      • Briggs K.T.
      • Marino J.P.
      • Ravid K.
      • Robson S.C.
      • Mosser D.M.
      TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses.
      Indeed, in patients with coronary artery disease, their mononuclear phagocytes from the periphery and atherosclerotic plaques have increased expression of PDL-1, which specifically inhibits antigen-specific T cells in a PD-1–dependent manner.
      • Watanabe R.
      • Shirai T.
      • Namkoong H.
      • Zhang H.
      • Berry G.J.
      • Wallis B.B.
      • et al.
      Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity.
      It has been shown that there is a negative correlation between the number of monocytes recruited to a site of inflammation and cutaneous antigen-specific immunity.
      • Vukmanovic-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.

       Immunoregulatory SASP components

      Not all components of the SASP can be considered directly inflammatory. Indeed, transforming growth factor beta, an early component of SASP,
      • Campisi J.
      • d’Adda di Fagagna F.
      Cellular senescence: when bad things happen to good cells.
      has been shown to have the potential to generate Foxp3+ Treg cells from CD4+ T effector cells.
      • Chen W.
      • Jin W.
      • Hardegen N.
      • Lei K.J.
      • Li L.
      • Marinos N.
      • et al.
      Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.
      Another SASP component is the lipid mediator prostaglandin E2, which is a downstream of cyclooxygenase 2.
      • Dagouassat M.
      • Gagliolo J.M.
      • Chrusciel S.
      • Bourin M.C.
      • Duprez C.
      • Caramelle P.
      • et al.
      The cyclooxygenase-2-prostaglandin E2 pathway maintains senescence of chronic obstructive pulmonary disease fibroblasts.
      ,
      • Kabir T.D.
      • Leigh R.J.
      • Tasena H.
      • Mellone M.
      • Coletta R.D.
      • Parkinson E.K.
      • et al.
      A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts.
      Prostaglandin E2 can promote a more tolerogenic environment by increasing the production of the immunoregulatory cytokine IL-10 from mononuclear phagocytes as well as increasing the number and function of Foxp3+ Treg cells.
      • Baratelli F.
      • Lin Y.
      • Zhu L.
      • Yang S.C.
      • Heuze-Vourc’h N.
      • Zeng G.
      • et al.
      Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells.
      ,
      • Sharma S.
      • Yang S.C.
      • Zhu L.
      • Reckamp K.
      • Gardner B.
      • Baratelli F.
      • et al.
      Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer.
      In addition, prostaglandin E2 has been shown to inhibit the antigen-specific immunity by blocking the proliferation of CD8+ T cells in response to viral antigens.
      • Okano M.
      • Sugata Y.
      • Fujiwara T.
      • Matsumoto R.
      • Nishibori M.
      • Shimizu K.
      • et al.
      E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2.
      ,
      • Chen J.H.
      • Perry C.J.
      • Tsui Y.C.
      • Staron M.M.
      • Parish I.A.
      • Dominguez C.X.
      • et al.
      Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection.

      Therapeutic targets of inflammaging

      Because of the substantial clinical data linking inflammaging with reduced immunity, health, and increased mortality in older adults, it has become a crucial therapeutic target in older adults. The current therapies for reducing inflammation that have been proposed include the removal of senescent cells and the mammalian target of rapamycin (mTOR) and p38-MAP Kinase inhibition (Fig 2).
      Figure thumbnail gr2
      Fig 2Schematic representation of the current therapeutic targets of inflammaging. In humans, the 2 main targets to date have been the use of mTOR blockade to enhance vaccine responses and p38 MAP Kinase blockade to enhance antigen-specific cutaneous immunity. In mouse models, senolytics have been shown to be a very promising target and are as yet untried in humans. The most untested approach is the use of inhibitory ligand blockade to enhance senescent cell clearance via the hosts’ own immune system.

       Senescent cells

      Because senescent cells are a major contributor to the inflammaging process, they are an exciting target for reducing inflammaging. Mouse models have been developed where senescent cells can be specifically removed in vivo, and these studies showed that these animals have increased life span, improved fitness, and reduced fur loss.
      • Baar M.P.
      • Brandt R.M.C.
      • Putavet D.A.
      • Klein J.D.D.
      • Derks K.W.J.
      • Bourgeois B.R.M.
      • et al.
      Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging.
      ,
      • Baker D.J.
      • Childs B.G.
      • Durik M.
      • Wijers M.E.
      • Sieben C.J.
      • Zhong J.
      • et al.
      Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.
      Indeed, removal of senescent cells even after onset of age-related disorders, such as sarcopenia and cataracts, resulted in an attenuation of disease pathology.
      • Baker D.J.
      • Wijshake T.
      • Tchkonia T.
      • LeBrasseur N.K.
      • Childs B.G.
      • van de Sluis B.
      • et al.
      Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.
      As a result of these exciting murine studies, therapies to remove senescent cells with drugs termed senolytics have been an active area of research. Assessments of senescent cell behavior in vitro identified that antiapoptotic/prosurvival pathways such as BCL2, p53, and CDKN1A and also phosphoinositide 3-Kinase δ signaling pathways may represent specific pathways that can be targeted for their elimination.
      • Zhu Y.
      • Tchkonia T.
      • Pirtskhalava T.
      • Gower A.C.
      • Ding H.
      • Giorgadze N.
      • et al.
      The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.
      ,
      • Zhu Y.
      • Doornebal E.J.
      • Pirtskhalava T.
      • Giorgadze N.
      • Wentworth M.
      • Fuhrmann-Stroissnigg H.
      • et al.
      New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.
      Senolytics that have been tested in aged mouse models include the combination of dasatinib and quercetin that significantly reduced vascular pathologies.
      • Roos C.M.
      • Zhang B.
      • Palmer A.K.
      • Ogrodnik M.B.
      • Pirtskhalava T.
      • Thalji N.M.
      • et al.
      Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.
      ABT263, a specific inhibitor for BCL2 and BCL-x, was used in an aged mouse model and has resulted in a rejuvenation of hematopoietic stem cells.
      • Chang J.
      • Wang Y.
      • Shao L.
      • Laberge R.M.
      • Demaria M.
      • Campisi J.
      • et al.
      Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.
      Inhibitors of heat shock protein 90 have prevented the onset of age-related pathologies in mice.
      • Fuhrmann-Stroissnigg H.
      • Ling Y.Y.
      • Zhao J.
      • McGowan S.J.
      • Zhu Y.
      • Brooks R.W.
      • et al.
      Identification of HSP90 inhibitors as a novel class of senolytics.
      Although all these senolytic agents have been shown to significantly reduce the senescent cells in mouse models, they have yet to be translated to humans and this is an area of intense investigation.
      Another potential therapeutic area is to unleash the activity of the individuals’ own immune system against senescent cells. Because there are strategies that enable the evasion of senescent cells from immune surveillance, preventing this inhibitory axis would facilitate the recognition and removal of senescent cells in older adults. Because the expression of the inhibitory receptor HLA-E by the senescent fibroblasts binds to its cognate ligand, NKG2A expressed on NK and CD8+ T cells, and provides a negative signal to the leukocytes that prevents killing and clearance of senescent cells,
      • Pereira B.I.
      • Devine O.P.
      • Vukmanovic-Stejic M.
      • Chambers E.S.
      • Subramanian P.
      • Patel N.
      • et al.
      Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition.
      strategies that block the interaction between HLA-E and NKG2A would enable the NK and CD8+ T cells to recognize the senescent cells and to enhance senescent cell clearance in vivo. An anti-NKG2A mAb, monalizumab, has been developed as a check point inhibitor, and has been shown to enhance antitumour immunity via preventing the negative signaling through NKG2A, and thus enabling the NK and CD8+ T cells to kill tumor cells that also express HLA-E.
      • Andre P.
      • Denis C.
      • Soulas C.
      • Bourbon-Caillet C.
      • Lopez J.
      • Arnoux T.
      • et al.
      Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells.
      ,
      • van Montfoort N.
      • Borst L.
      • Korrer M.J.
      • Sluijter M.
      • Marijt K.A.
      • Santegoets S.J.
      • et al.
      NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines.
      It is possible that monalizumab could be used as a senolytic agent to facilitate removal of senescent cells from older adults using their own NK cells and CD8+ T cells; however, this requires further investigation. However, it will be important to assess the capability of older adults’ NK cells to kill senescent fibroblasts, because NK cells from older adults have reduced killing capacity.
      • 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.

       The mammalian target of rapamycin

      mTOR is composed of 2 distinct protein complexes— mTOR complex (TORC)1 and TORC2—that are involved with numerous cellular processes including inflammation. mTOR is involved in many inflammatory processes; in particular, mTOR signaling is downstream of a number of innate immune cell receptors such as TLRs including TLR4, cytokine receptors such as IL-15, and lipid receptors such as prostaglandin receptors, all of which can increase inflammatory mediator production from cells.
      • Weichhart T.
      • Hengstschlager M.
      • Linke M.
      Regulation of innate immune cell function by mTOR.
      In addition, mTOR has been shown to be a regulator of the SASP in senescent cells via promoting IL-1α production.
      • Laberge R.M.
      • Sun Y.
      • Orjalo A.V.
      • Patil C.K.
      • Freund A.
      • Zhou L.
      • et al.
      MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.
      mTOR inhibition, via rapamycin, has been shown to increase life expectancy.
      • Harrison D.E.
      • Strong R.
      • Sharp Z.D.
      • Nelson J.F.
      • Astle C.M.
      • Flurkey K.
      • et al.
      Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.
      However, more recently it has been used to improve vaccine responses in older adults in vivo.
      • Mannick J.B.
      • Del Giudice G.
      • Lattanzi M.
      • Valiante N.M.
      • Praestgaard J.
      • Huang B.
      • et al.
      mTOR inhibition improves immune function in the elderly.
      Mannick et al
      • Mannick J.B.
      • Del Giudice G.
      • Lattanzi M.
      • Valiante N.M.
      • Praestgaard J.
      • Huang B.
      • et al.
      mTOR inhibition improves immune function in the elderly.
      treated older subjects with a specific TORC1 inhibitor called RAD001 before influenza vaccination. They found that there was an enhanced response to vaccination as determined by circulating antibody titers. This improvement in vaccine response was proposed to be due to reduced expression of the inhibitory receptor PD-1 on circulating CD4+ and CD8+ T cells.
      • Mannick J.B.
      • Del Giudice G.
      • Lattanzi M.
      • Valiante N.M.
      • Praestgaard J.
      • Huang B.
      • et al.
      mTOR inhibition improves immune function in the elderly.
      A subsequent study by the same group demonstrated that TORC1 inhibitor treatment before vaccination also significantly reduced influenza infections in older subjects.
      • Mannick J.B.
      • Morris M.
      • Hockey H.P.
      • Roma G.
      • Beibel M.
      • Kulmatycki K.
      • et al.
      TORC1 inhibition enhances immune function and reduces infections in the elderly.
      However, it is not clear whether rapamycin is acting directly on the inflammation in these subjects or some other process to enhance vaccine efficacy.

       p38 MAP Kinase

      p38 MAP Kinase has been shown to be a major signaling molecule upstream of SASP production from senescent fibroblasts and from CD8+ T effector memory cells that reexpress CD45 cells.
      • Alimbetov D.
      • Davis T.
      • Brook A.J.
      • Cox L.S.
      • Faragher R.G.
      • Nurgozhin T.
      • et al.
      Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2.
      • Callender L.A.
      • Carroll E.C.
      • Beal R.W.J.
      • Chambers E.S.
      • Nourshargh S.
      • Akbar A.N.
      • et al.
      Human CD8(+) EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK.
      • Freund A.
      • Patil C.K.
      • Campisi J.
      p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.
      It was shown that a nonspecific inflammatory response occurs after mild tissue injury after saline injection in the skin of older but not young adults and that this was associated with p38 MAP Kinase signaling.
      • Vukmanovic-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.
      The older subjects also have increased numbers of senescent cells in the skin compared with younger individuals. The observed inflammatory response was reminiscent of inflammaging and correlated negatively with their response to recall antigen challenge (varicella zoster virus antigens) in the skin.
      • Vukmanovic-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.
      To test directly whether the inflammation observed was responsible for decreasing the immune response, old subjects were pretreated with an oral p38 MAP Kinase inhibitor (losmapimod) for 4 days before injection of the antigen.
      • Akbar A.N.
      • Reed J.R.
      • Lacy K.E.
      • Jackson S.E.
      • Vukmanovic-Stejic M.
      • Rustin M.H.
      Investigation of the cutaneous response to recall antigen in humans in vivo.
      It was found that blocking p38 in vivo significantly increased cutaneous immunity, which was associated with an increase in T-cell recruitment to the site of antigen challenge.
      • Vukmanovic-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.
      Therefore, in addition to senescent cell elimination as a strategy to reduce inflammation, the inflammatory response itself can be manipulated in older individuals with benefit to immunity. It remains to be determined whether the inhibition of inflammation may also alleviate other facets of frailty during aging. However, although short-term inhibition would be acceptable, longer-term inhibition, especially with p38 MAP Kinase inhibitors, is associated with hepatotoxicity.
      • Sweeney S.E.
      The as-yet unfulfilled promise of p38 MAPK inhibitors.

      Future perspectives

      Inflammaging is caused by a combination of age-related defects including increased DAMP production, increased gut permeability, increased visceral fat, chronic infections, and increase in senescent cell numbers. Senescent cells contribute to inflammaging because of their SASP production, which includes a wide range of inflammatory cytokines and DAMPs. Therefore, strategies to remove the senescent cells from the body are a promising therapeutic target. There has been extensive research in mouse models to show that removal of senescent cells from an old mouse renders the mouse young again. However, what the long-term implications are for removing senescent structural cells, such as fibroblasts, from tissues when they make up a major proportion of the tissue structure needs further investigation. An exciting potential drug candidate to targeting inflammaging is metformin, which activates the AMP-activated protein kinase signaling pathway, and thus blocking inflammatory cytokine signaling has been successfully used as a long-term therapy in older adults as a first-line therapy for type 2 diabetes. It has been shown to improve cardiovascular health in these individuals.
      • Valencia W.M.
      • Palacio A.
      • Tamariz L.
      • Florez H.
      Metformin and ageing: improving ageing outcomes beyond glycaemic control.
      However, strategies that target inflammatory signaling pathways using rapamycin and metformin have been used with some success, but the effect of longer-term inhibition and potential side effects are not clear at present.
      Current therapies that have been developed use a short-term inhibition of inflammation to boost immunity without side effects in older individuals and may be of benefit as an adjunct to vaccination and/or antitumor therapy. A combination of approaches including 1 or more of senolytic drug, checkpoint inhibitors (anti-NKG2A), and anti-inflammatory agents may be required for optimal blocking of inflammaging to reduce frailty and enhance immunity in older adults.

       DAMAGE-ASSOCIATED MOLECULAR PATTERNS

      Molecules that are released from host cells during episodes of cellular stress or cell death to induce inflammatory or cell-death signaling.

       HOMEOSTASIS

      The steady-state condition that exists in the absence of damage, inflammation, or infection.

       INFLAMMAGING

      The state of chronic low-grade inflammation that progressively increases with age in the absence of overt inflammatory disease or infection.

       INFLAMMASOME

      A multiprotein intracellular complex that secretes certain proinflammatory innate cytokines on activation.

       MEMORY T CELLS

      Long-term antigen-specific T cells that have previously encountered and responded to their cognate antigen.

       MICROBIOME

      The totality of the microbes and their genetic material present within a particular environment.

       PATHOBIONTS

      A potentially pathological organism that lives as a nonharming symbiont under normal conditions.

       PATTERN RECOGNITION RECEPTOR

      Receptor expressed by host cells that activate innate immune responses on detection of damage-associated molecular patterns or molecular motifs conserved within a class of microbes.

       RECALL ANTIGENS

      Antigens to which an individual has developed specific memory T cells after a previous exposure.

       REGULATORY T (TREG) CELLS

      A subset of CD4+ T cells that express the transcription factor Foxp3 and suppress immune responses.

       SENESCENCE

      A cellular state characterized by irreversible cessation of cell division among other phenotypic changes.

       SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE

      A phenotype associated with senescent cells that is characterized by secretion of high levels of inflammatory cytokines, growth factors, and proteases.

       SENOLYTIC

      Therapeutic agents that selectively induce the death of senescent cells.
      The editors acknowledge Jared Travers, MD, PhD, for preparing the glossary.

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      Linked Article

      • Nonpharmacologic therapeutic possibilities for immunosenescence
        Journal of Allergy and Clinical ImmunologyVol. 146Issue 4
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          We read the article “Can blocking inflammation enhance immunity during aging?” by Chambers and Akbar1 with great anticipation that modalities commonly used in integrative medicine might be discussed as mediators of immunity. We were disappointed to see that only pharmaceutical interventions were presented when reviewing “therapeutic targets of inflammaging.” Although pharmaceuticals provide great hope and promise in targeting these pathways, both mind-body medicine and nutritional interventions have already shown great potential to dampen the process of aging in the immune system.
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