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The collective loss of immune protection during aging leads to poor vaccine responses and an increased severity of infection for the elderly. Here, we review our current understanding of effects of aging on the cellular and molecular dysregulation of innate immune cells as well as the relevant tissue milieu which influences their functions. The innate immune system is composed of multiple cell types which provide distinct and essential roles in tissue surveillance and antigen presentation as well as early responses to infection or injury. Functional defects that arise during aging lead to a reduced dynamic range of responsiveness, altered cytokine dynamics, and impaired tissue repair. Heightened inflammation influences both the dysregulation of innate immune responses as well as surrounding tissue microenvironments which have a critical role in development of a functional immune response. In particular, age-related physical and inflammatory changes in the skin, lung, lymph nodes, and adipose tissue reflect disrupted architecture and spatial organization contributing to diminished immune responsiveness. Underlying mechanisms include altered transcriptional programming and dysregulation of critical innate immune signaling cascades. Further, we identify signaling functions of bioactive lipid mediators which address chronic inflammation and may contribute to the resolution of inflammation to improve innate immunity during aging., (© 2020 S. Karger AG, Basel.)

Here, we investigated the relationship of the age-associated expansion of IL-7 receptor alpha low (IL-7Rα low ) effector memory (EM) CD8 + T cells with the global transcriptomic profile of peripheral blood cells in humans. We found 231 aging signature genes of IL-7Rα low EM CD8 + T cells that corresponded to 15% of the age-associated genes (231/1,497) reported by a meta-analysis study on human peripheral whole blood from approximately 15,000 individuals, having high correlation with chronological age. These aging signature genes were the target genes of several transcription factors including MYC, SATB1, and BATF, which also belonged to the 231 genes, supporting the upstream regulatory role of these transcription factors in altering the gene expression profile of peripheral blood cells with aging. We validated the differential expression of these transcription factors between IL-7Rα low and high EM CD8 + T cells as well as in peripheral blood mononuclear cells (PBMCs) of young and older adults. Finally, we found a significant association with influenza vaccine responses in older adults, suggesting the possible biological significance of the aging signature genes of IL-7Rα low EM CD8 + T cells. The results of our study support the relationship of the expansion of IL-7Rα low EM CD8 + T cells with the age-associated changes in the gene expression profile of peripheral blood cells and its possible biological implications., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Both aging and HIV infection are associated with an enhanced pro-inflammatory environment that contributes to impaired immune responses and is mediated in part by innate immune pattern-recognition receptors. MINCLE is a C-type lectin receptor that recognizes trehalose-6,6'-dimycolate or "cord factor," the most abundant glycolipid in Mycobacterium tuberculosis. Here, we evaluated MINCLE function in monocytes in a cohort of HIV-infected and uninfected young (21-35 years) and older adults (≥60 years) via stimulation of peripheral blood mononuclear cells with trehalose-6,6-dibehenate, a synthetic analog of trehalose-6,6'-dimycolate and measurement of cytokine production (interleukin [IL]-10, IL-12, IL-6, tumor necrosis factor-α) by multicolor flow cytometry. Our studies show an age- and HIV-associated increase in cytokine multifunctionality of monocytes both at the population and single cell level that was dominated by IL-12, IL-10, and IL-6. These findings provide insight into the host response to M. tuberculosis and possible sources for the pro-inflammatory environment seen in aging and HIV infection., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We investigated the effect of aging on the multi-dimensional characteristics and heterogeneity of human peripheral CD8 + T cells defined by the expression of a set of molecules at the single cell level using the recently developed mass cytometry or Cytometry by Time-Of-Flight (CyTOF) and computational algorithms. CD8 + T cells of young and older adults had differential expression of molecules, especially those related to cell activation and migration, permitting the clustering of young and older adults through an unbiased approach. The changes in the expression of individual molecules were collectively reflected in the altered high-dimensional profiles of CD8 + T cells in older adults as visualized by the dimensionality reduction analysis tools principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). A combination of PhenoGraph clustering and t-SNE analysis revealed heterogeneous subsets of CD8 + T cells that altered with aging. Furthermore, intermolecular quantitative relationships in CD8 + T cells appeared to change with age as determined by the computational algorithm conditional-Density Resampled Estimate of Mutual Information (DREMI). The results of our study showed that heterogeneity, multidimensional characteristics, and intermolecular quantitative relationships in human CD8 + T cells altered with age, distinctively clustering young and older adults through an unbiased approach., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid-inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors. We found that monocytes from older adults exhibited decreased abundance of the adaptor protein TRAF3 (tumor necrosis factor receptor-associated factor 3) because of its increased proteasomal degradation with age, thereby impairing the primary RIG-I signaling pathway for the induction of type I IFNs. We determined that monocytes from older adults also failed to effectively stimulate the production of the IFN regulatory transcription factor IRF8, which compromised IFN induction through secondary RIG-I signaling. IRF8 played a central role in IFN induction in monocytes, because knocking down IRF8 in monocytes from younger adults was sufficient to replicate the IFN defects observed in monocytes from older adults, whereas restoring IRF8 expression in older adult monocytes was sufficient to restore RIG-I-induced IFN responses. Aging thus compromises both the primary and secondary RIG-I signaling pathways that govern expression of type I IFN genes, thereby impairing antiviral resistance to IAV., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Human immune system aging results in impaired responses to pathogens or vaccines. In the innate immune system, which mediates the earliest pro-inflammatory responses to immunologic challenge, processes ranging from Toll-like Receptor function to Neutrophil Extracellular Trap formation are generally diminished in older adults. Dysregulated, enhanced basal inflammation with age reflecting activation by endogenous damage-associated ligands contributes to impaired innate immune responses. In the adaptive immune system, T and B cell subsets and function alter with age. The control of cytomegalovirus infection, particularly in the T lineage, plays a dominant role in the differentiation and diversity of the T cell compartment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Immunosenescence, describing alterations, including decline of immune responses with age, is comprised of inappropriate elevations, decreases, and dysregulated immune responses, leading to more severe consequences of bacterial and viral infections and reduced responses to vaccination. In adaptive immunity, these changes include increased proportions of antigen-experienced B and T cells at the cost of naïve cell populations. Innate immune changes in aging are complex in spanning multiple cell types, activation states, and tissue context. Innate immune responses are dampened in aging, yet there is also a paradoxical increase in certain signaling pathways and cytokine levels. Here, we review recent progress and highlight novel directions for expected advances that can lead the aging field to a new era of discovery that will embrace the complexity of aging in human populations., (© Society for Leukocyte Biology.)

To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders. The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders). We also identified a mitochondrial signature in young vaccine responders containing genes mediating mitochondrial biogenesis and oxidative phosphorylation that was consistent in two different vaccine seasons and verified by analyses of mitochondrial content and protein expression. These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.

HIV infection is associated with a chronic inflammatory state arising from multiple factors, including innate immune recognition of HIV, increased microbial translocation, and release of endogenous ligands from damaged cells (such as CD4 T cells). In many respects, this heightened pro-inflammatory environment resembles that associated with aging in the absence of HIV infection, and evidence of dysregulated innate immune responses can be found in not only older HIV-negative adults, but also adults with HIV infection. While the study of innate immune aging in HIV infection is still in its early stages, it seems likely that at least additive, or potentially synergistic effects of aging and HIV infection will be found., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

Alterations in T cell immunity occur with aging. Influenza causes significant morbidity and mortality in the elderly. We investigated the relationship of serum IgG responses with hemagglutinin inhibition (HI) antibody titers and the frequency of distinct T cell subsets in young and elderly people who received the inactivated influenza vaccine. Influenza vaccine-specific IgG responses correlated with the increase of HI antibody titers and the frequency of CD4(+) T cells producing IFN-γ and IL-17 in young, but not elderly, people. Also, only in young people, such IgG responses correlated with the frequency of memory T cells, especially central memory cells, CD45RA(-) effector memory CD8(+) T cells and IL-7 receptor alpha high effector memory CD8(+) T cells with potent survival and proliferative capacity. These findings suggest that aging alters the association of influenza-vaccine specific IgG responses with HI antibody titers, cytokine-producing capacity and proportions of memory T cells in humans., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The aging lung is faced with unique challenges. The lungs are the only internal organ with a direct interface with both the internal and the external environments and as a consequence are constantly sampling diverse, potentially injurious, elements. Therefore, the lungs have evolved a sophisticated, multilayered detection system to distinguish low-level, nonharmful signals from those that are toxic. A family of innate immune receptors, Toll-like receptors (TLRs), appears to serve such a function. Initially described as pattern-recognition receptors that recognize and protect against microbes, TLRs can also respond to diverse, nonmicrobial signals. The role of Toll-like receptors in noninfectious, age-related chronic lung disease is poorly understood. This review presents our current understanding of the biology of age-related lung diseases with a focus on the role of Toll-like receptors in idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and late-onset asthma.

Aging is accompanied by a progressive decline in immune function. Studies have shown age-related decreases in the expression and signaling efficiency of Toll-like receptors (TLRs) in monocytes and dendritic cells and dysregulation of macrophage TLR3. Using a multivariable mixed effect model, we report a highly significant increase in TLR5-induced production of IL-8 from monocytes of older individuals (P < 0.0001). Elevated IL-8 is accompanied by increased expression of TLR5, both protein and mRNA, and by increased levels of TLR5-mediated phosphorylation of MAPK p38 and ERK. We noted incomplete activation of NF-κB in response to TLR5 signaling in monocytes of elderly donors, as reflected by the absence of an associated increase in the production of TNF-α. Elevated TLR5 may provide a critical mechanism to enhance immune responsiveness in older individuals., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

Studies addressing immunosenescence in the immune system have expanded to focus on the innate as well as the adaptive responses. In particular, aging results in alterations in the function of Toll-like receptors (TLRs), the first described pattern recognition receptor family of the innate immune system. Recent studies have begun to elucidate the consequences of aging on TLR function in human cohorts and add to existing findings performed in animal models. In general, these studies show that human TLR function is impaired in the context of aging, and in addition there is evidence for inappropriate persistence of TLR activation in specific systems. These findings are consistent with an overarching theme of age-associated dysregulation of TLR signaling that likely contributes to the increased morbidity and mortality from infectious diseases found in geriatric patients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The past decade has seen an explosion in research focusing on innate immunity. Through a wide range of mechanisms including phagocytosis, intracellular killing and activation of proinflammatory or antiviral cytokine production, the cells of the innate immune system initiate and support adaptive immunity. The effects of aging on innate immune responses remain incompletely understood, particularly in humans. Here we review advances in the study of human immunosenescence in the diverse cells of the innate immune system, including neutrophils, monocytes, macrophages, natural killer and natural killer T (NKT) cells and dendritic cells-with a focus on consequences for the response to infection or vaccination in old age.

Toll-like receptors (TLRs) recognize a limited number of conserved elements in pathogens and, by activating antigen-presenting cells such as dendritic cells and monocytes and macrophages, play a crucial role in the immune response to infection and vaccination. Most data on TLR function in the context of human aging focus on responses to lipopolysaccharide, an integral component of gram-negative bacteria, which signals through TLR4. However, such studies have not led to a consensus conclusion and are limited by differences in epidemiological and laboratory methods. A recent comprehensive evaluation of TLR function in monocytes from older adults was conducted using a multivariable mixed statistical model to account for covariates. It was found that cytokine production after TLR1/2 engagement, which is essential for the recognition of triacylated lipopeptides found in a variety of bacteria, is substantially lower in monocytes from older adults. The upregulation of costimulatory proteins such as CD80, essential for optimal activation of T cells, on monocytes from older adults was less for all TLR ligands tested than for cells from young individuals, and the extent of CD80 upregulation predicted subsequent antibody response to influenza immunization. These and other consequences of aging on human TLR function may impair activation of the immune response and contribute to poorer vaccine responses and greater morbidity and mortality from infectious diseases in older adults. Such age-associated alterations have particular relevance in view of the interest in TLR agonists as therapeutic agents not only for infections, but also for allergic, autoimmune, and malignant disease.

Background: Innate immunity, including Toll-like receptor (TLR)-mediated expression of the B7 costimulatory molecules CD80 and CD86, is critical for vaccine immunity. We examined whether CD80 and CD86 expression vary with aging and predict response to the trivalent inactivated influenza vaccine., Methods: One hundred sixty-two subjects between 21 and 30 years of age (the young group) or > or =65 years of age (the older group) enrolled before vaccination. We determined TLR-induced monocyte CD80/CD86 expression by flow cytometry and vaccine antibody responses by hemagglutination inhibition., Results: The mean increase in TLR-induced CD80(+) monocytes was reduced in older, compared with young, adults by 68% (P=.0002), and each decile increase of CD80(+) cells was associated with an 8.5% increase in mean number of vaccine strains with a > or =4-fold titer increase (P=.01) and a 3.8% increase in mean number of strains with a postvaccine titer > or =1 : 64 (P=.037). Each decile decrease of CD86(+) cells was associated with an 11% increase in the mean number of strains with a 4-fold increase (P=.002) and a 3.9% increase in the mean number of strains with a postvaccine titer > or =1 : 64 (P=.07)., Conclusions: CD80 and CD86 expression on activated monocytes is highly associated with influenza vaccine response. This approach prospectively identifies adults unlikely to respond to immunization who may benefit from alternative vaccines or antiviral prophylaxis during influenza outbreaks.

The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-alpha (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-alpha (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.