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The immune system plays a crucial role in the ageing process. As individuals age, significant alterations in the immune system experiences occur, marked by a decline in immune cell count, compromised immune function, and decreased immune regulation across various immune organs. These changes collectively weaken the capacity to combat diseases and infections, highlighting the vulnerability that accompanies ageing. Exercise is a potent intervention that profoundly influences holistic well-being and disease mitigation, with a notable emphasis on immune modulation. In general, regular moderate exercise holds significant potential to enhance immune defense mechanisms and metabolic well-being by augmenting the circulation and activation of immune cells. However, some exercise modalities would trigger detrimental effects on the immune system. It can be seen that the regulatory responses of various immune organs to diverse exercise patterns are different. This review aims to examine the immunological responses elicited by exercise across various immune organs, including the lymph nodes, spleen, bone marrow, and thymus, to underscore the nuanced interplay between exercise patterns and the immune organ. This underscores the importance of customizing exercise interventions to optimize immune function across the lifespan., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The stability and variability of older adults' late-differentiated peripheral blood T and natural killer (NK) cells over time remains incompletely quantified or understood. We examined the variability and change over time in T and NK cell subsets in a longitudinal sample of older adults; the effects of sex, cytomegalovirus (CMV) serostatus, and chronic disease severity on immune levels and trajectories; and interdependencies among T and NK cell subsets. Older adults (N = 149, age 64-94 years, 42% male) provided blood every 6 months for 2.5 years (up to 5 waves) to evaluate late-differentiated CD8 T cells (CD28-, CD57+) and CD56 dim NK cells (CD57+, NKG2C+, FcɛRIγ-). In multilevel models, most of the variance in immune subsets reflected stable differences between people. However, CD56 dim NK cell subsets (CD57+ and FcɛRIγ-) also increased with age, whereas T cell subsets did not. Independent of age, all subsets examined were higher in CMV-positive older adults. Men had higher levels of CD56 dim CD57+ than women. Chronic disease was not associated with any immune subset investigated. T and NK cell subsets correlated within each cell type, but interdependencies differed by CMV serostatus. Our results suggest the accumulation of these stable cell populations may be driven less by chronological aging, even less by chronic disease severity, and more by CMV, which may differentially skew T and NK cell differentiation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The human ageing process encompasses mechanisms that effect a decline in homeostasis with increased susceptibility to disease and the development of chronic life-threatening illness. Increasing age affects the immune system which undergoes a progressive loss of efficiency, termed immunosenescence (ISC), to impact on quantitative and functional aspects of innate and adaptive immunity. The human demyelinating disease multiple sclerosis (MS) and the corresponding animal model experimental autoimmune encephalomyelitis (EAE) are strongly governed by immunological events that primarily involve the adaptive arm of the immune response. MS and EAE are frequently characterised by a chronic pathology and a protracted disease course which thereby creates the potential for exposure to the inherent, on-going effects and consequences of ISC. Collective evidence is presented to confirm the occurrence of established and unendorsed biological markers of ISC during the development of both diseases. Moreover, results are discussed from studies during the course of MS and EAE that reveal a premature upregulation of ISC-related biomarkers which indicates untimely alterations to the adaptive immune system. The effects of ISC and a prematurely aged immune system on autoimmune-associated neurodegenerative conditions such as MS and EAE are largely unknown but current evaluation of data justifies and encourages further investigation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recent published findings have shown that many proteins discovered in the immune system and residing on immune cells with well established immune-related functions are also found in neurons of the central nervous system. These studies have uncovered a rich variety of neuronal functions attributed to these immune proteins. This review will focus on two key interacting protein complexes that previously were known for adaptive immune reactions, the major histocompatability complex and the T-cell receptor complex. We will review where these immune proteins are expressed in the CNS and their neuronal function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The vertebrate adaptive immune system is remarkable for its possession of a very broad range of antigen receptors imbuing the system with exquisite specificity, in addition to the phagocytic and inflammatory cells of the innate system shared with invertebrates. This system requires strict control both at the level of the generation the cells carrying these receptors and at the level of their activation and effector function mediation in order to avoid autoimmunity and mitigate immune pathology. Thus, quality control checkpoints are built into the system at multiple nodes in the response, relying on clonal selection and regulatory networks to maximize pathogen-directed effects and minimize collateral tissue damage. However, these checkpoints are compromised with age, resulting in poorer immune control manifesting as tissue-damaging autoimmune and inflammatory phenomena which can cause widespread systemic disease, paradoxically compounding the problems associated with increased susceptibility to infectious disease and possibly cancer in the elderly. Better understanding the reasons for slippage of immune control will pave the way for developing rational strategies for interventions to maintain appropriate immunity while reducing immunopathology., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: To describe the immune alterations associated with age-related macular degeneration (AMD); and, based on these findings, to offer an approach to possibly prevent the expression of late disease., Design: Perspective., Methods: Review of the existing literature dealing with epidemiology, models, and immunologic findings in patients., Results: Significant genetic associations have been identified and reported, but environmentally induced (including epigenetic) changes are also an important consideration. Immune alterations include a strong interleukin 17 family signature as well as marked expression of these molecules in the eye. Oxidative stress as well as other homeostatic altering mechanisms occur throughout life. With this immune dysregulation there is a rationale for considering immunotherapy. Indeed, immunotherapy has been shown to affect the late stages of AMD., Conclusion: Immune dysregulation appears to be an underlying alteration in AMD, as in other diseases thought to be degenerative and attributable to aging. Para-inflammation and immunosenescence may importantly contribute to the development of disease. The role of complement factor H still needs to be better defined, but in light of its association with ocular inflammatory conditions such as sarcoidosis, it does not appear to be unique to AMD but rather may be a marker for retinal pigment epithelium function. With the strong interleukin 17 family signature and the need to treat early on in the disease process, oral tolerance may be considered to prevent disease progression., (Published by Elsevier Inc.)

The elderly usually suffer from increased morbidity and mortality due to infectious diseases, and this process may be attributed to diminishing immune protection with age. This phenomenon is commonly referred to as immunosenescence. However, this theory is still not well defined. Non-human primates serve as a favorable model to facilitate the study in aging of the immune system. Here, we investigated the phenotypic features of T- and B-cell aging in peripheral blood from Chinese rhesus macaques, which included (1) a decrease of CD4/CD8 ratio; (2) a loss of naïve T cells accompanied with elevated proliferation and expansion of effector memory subset; (3) a reduction in B cell numbers and a shift from naïve B cells towards memory phenotype; and (4) increased levels of PD-1 expression in T cells and CD95 expression in B cells. Moreover, an accelerated decline in CD4(+) T cells and naïve T cells was found in male macaques, giving them a more severe immune risk profile. These data indicated that Chinese rhesus macaques share a significant homology with humans in phenotypic aging of adaptive immunity, and may be an appropriate animal model for human aging research., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are the best example of healthy aging in humans as most of them have escaped or substantially delayed the onset of major age-related diseases. Within this scenario, the purpose of the present work was to understand if immune status is associated with survival and health status in centenarians. To this aim, 116 centenarians were concomitantly characterized for their immunological, health and functional status, and followed-up for five-year survival. On the basis of previous knowledge we focused on a core of fundamental and basic immune parameters (number of leukocytes, monocytes, total lymphocytes, CD3(+) T lymphocytes, CD4(+) helper T lymphocytes, CD8(+) cytotoxic T lymphocytes, CD19(+) B lymphocytes and plasma levels of IgM), and the most important findings can be summarized as follows: i. a hierarchical cluster analysis was able to define Cluster1 (88 centenarians) and Cluster2 (28 centenarians) characterized by low and high values of all these immune parameters, respectively; ii. centenarians of Cluster2 showed a statistically longer five-year survival and more favorable values of other important immune (naïve, activated/memory and effector/memory T cells) and metabolic (glycemia, insulin and HOMA-IR) parameters, in accord with previous observations that centenarians have a peculiar immune profile, a preserved insulin pathway and a lower incidence of type 2 diabetes; and iii. unexpectedly, parameters related to frailty, as well as functional and cognitive status, did not show any significant correlation with the immune clustering, despite being capable per se of predicting survival. In conclusion, high values of basic immunological parameters and important T cell subsets correlate with five-year survival in centenarians, independent of other phenotypic characteristics. This unexpected biological scenario is compatible with the general hypothesis that in centenarians a progressive disconnection and loss of biological coherence among the different functions of the body occur, where survival/mortality result from the failure of any of these domains which apparently follow an independent age-related trajectory., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aging leads to reduced immunity, especially adaptive responses. A key deficiency is the poor ability to mount robust antibody response. Although intrinsic alterations in B cells with age are in part responsible, impaired CD4 T cell help makes a major contribution to the poor antibody response. Other CD4 effector responses and memory generation are also impaired. We find delayed and reduced development of CD4 T follicular help (Tfh) cells in aged mice in response to influenza infection with reduction of long-lived plasma cells. When we examine CD4 subsets we also find a shift towards Th1 and cytotoxic CD4 (ThCTL) responses. We summarize strategies to circumvent the CD4 T cell defect in aged, including adjuvants and proinflammatory cytokines. We find that we can strongly enhance responses of aged naïve CD4 T cells by using Toll-like receptor (TLR) activated dendritic cells (DC) as APC in vivo and that this leads to improved germinal center B cells and IgG antibody responses. The enhanced response of aged naïve CD4 T cells is dependent on IL-6 produced by the DC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Research into marsupial adaptive immunity during ontogeny has been hampered by the lack of antibodies that react to marsupial immunological cell populations. In this study, newly synthesised polyclonal antibodies to the T cell marker, CD8, have been developed and used to investigate the ontogeny and distribution of this T cell population in the tammar wallaby. Immunohistochemical analysis indicated that the distribution of the CD8 lymphocytes in the lymphoid tissues of tammar neonates during the first 144 days of pouch life was similar to that of the eutherian mammals. However, CD8α(+) lymphocytes were observed in the intestines of tammar neonates prior to their first appearance in the cervical thymus, an observation that has not been found in eutherians. A dual labelling immunohistochemical approach was used for the indirect demonstration of CD4 and enabled the simultaneous detection in the tammar wallaby tissues of the two major T-lymphocyte populations, CD4 and CD8 that are associated with adaptive immunity. As in eutherian mammals, CD4(+) cells were the predominant T cell lymphocyte subset observed in the spleen while in the nodal tissues, an age-related decrease in the CD4(+)/CD8(+) ratio was noted. These antibodies provide a new immunological tool to study the role of T cell subsets in marsupial immunity and disease pathogenesis studies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Inflammatory bowel disease (IBD) has unclear pathogenesis and it is related to the increasing risk of developing colorectal cancer (CRC). Recent studies have uncovered the molecular mechanism of intracellular signaling pathways of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6. The major transcription factors including STAT3 have been shown to play a major role in transmitting inflammatory cytokine signals to the nucleus. The suppressors of cytokine signaling (SOCS) 3 protein is the key physiological regulators of cytokine-mediated STAT3 signaling. As such it influences the development of inflammatory and malignant disorders like this associated with IBD. Here we review the complex function of SOCS3 in innate and adaptive immunity, different cell types (macrophages, neutrophils, dendritic cells, B cells, T cells and intestinal epithelial cells) and the role of SOCS3 on the pathogenesis of inflammatory bowel disease (IBD) and IBD-related cancer. Finally, we explore how this knowledge may open novel avenues for the rational treatment of IBD and IBD-related cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A better knowledge of the process by which inflammatory extracellular signals are relayed from the plasma membrane to specific intracellular sites is a key step to understand how inflammation develops and how it is regulated. This review focuses on Lnk (SH2B3) a member, with SH2B1 and SH2B2, of the SH2B family of adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase and receptor tyrosine kinases. SH2B adaptor proteins contain conserved dimerization, pleckstrin homology, and SH2 domains. Initially described as a regulator of hematopoiesis and lymphocyte differentiation, Lnk now emerges as a key regulator in hematopoeitic and non hematopoeitic cells such as endothelial cells (EC) moderating growth factor and cytokine receptor-mediated signaling. In EC, Lnk is a negative regulator of TNF signaling that reduce proinflammatory phenotype and prevent EC from apoptosis. Lnk is a modulator in integrin signaling and actin cytoskeleton organization in both platelets and EC with an impact on cell adhesion, migration and thrombosis. In this review, we discuss some recent insights proposing Lnk as a key regulator of bone marrow-endothelial progenitor cell kinetics, including the ability to cell growth, endothelial commitment, mobilization, and recruitment for vascular regeneration. Finally, novel findings also provided evidences that mutations in Lnk gene are strongly linked to myeloproliferative disorders but also autoimmune and inflammatory syndromes where both immune and vascular cells display a role. Overall, these studies emphasize the importance of the Lnk adaptor molecule not only as prognostic marker but also as potential therapeutic target., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Vaccination policies in most high-income countries attempt to reduce the adverse impact of influenza targeting people aged at least 60 years. However, while it is widely believed that the current immunization strategy saves many lives, influenza infection still remains a severe burden in aged individuals leading to a wide debate on the exact magnitude of the benefit of vaccination in this population. The first aim of the present review is to examine how effective current influenza-vaccine strategies are in aged adults, by analysing which are the most important factors modulating the interpretation of study results in this population. Furthermore, consideration will be given to how immune factors influence the measurement of vaccine efficacy/effectiveness, where advancing age leads to deleterious changes in the adaptive immune system, resulting in less than optimal responses to infectious agents and vaccination. Finally this review concludes with possible strategies to improve the ability of the senescent immune system to respond to vaccination., (Copyright © 2010 Elsevier B.V. All rights reserved.)

As the repertoire of αβT cell receptors (TCR) contracts with advancing age, there is an associated age-dependent accumulation of oligoclonal T cells expressing of a variety of receptors (NKR), normally expressed on natural killer (NK) cells. Evidences for differential regulation of expression of particular NKRs between T cells and NK cells suggest that NKR expression on T cells is physiologically programmed rather than a random event of the aging process. Experimental studies show NKRs on aged αβT cells may function either as independent receptors, and/or as costimulatory receptors to the TCR. Considering the reported deficits of conventional αβTCR-driven activation and also functional deficits of classical NK cells, NKR(+) αβT cells likely represent novel immune effectors that are capable of combining innate and adaptive functions. Inasmuch as immunity is a determinant of individual fitness, the type and density of NKRs could be important contributing factors to the wide heterogeneity of health characteristics of older adults, ranging from institutionalized frail elders who are unable to mount immune responses to functionally independent community-dwelling elders who exhibit protective immunity. Understanding the biology of NKR(+) αβT cells could lead to new avenues for age-specific intervention to improve protective immunity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The most profound consequences of immune senescence with respect to public health are the increased susceptibility to influenza and loss of efficacy of the current split-virus influenza vaccines in older adults, which are otherwise very effective in younger populations. Influenza infection is associated with high rates of complicated illness including pneumonia, heart attacks and strokes in the 65+ population. Changes in both innate and adaptive immune function not only converge in the reduced response to vaccination and protection against influenza, but present significant challenges to new vaccine development. In older adults, the goal of vaccination is more realistically targeted to providing clinical protection against disease rather sterilizing immunity. Correlates of clinical protection may not be measured using standard techniques such as antibody titres to predict vaccine efficacy. Further, antibody responses to vaccination as a correlate of protection may fail to detect important changes in cellular immunity and enhanced vaccine-mediated protection against influenza illness in older people. This article will discuss the impact of influenza in older adults, immunologic targets for improved efficacy of the vaccines, and alternative correlates of clinical protection against influenza that are needed for more effective translation of novel vaccination strategies to improved protection against influenza in older adults., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Census reports of many countries indicate continuing trends for the graying of their populations. For the United States alone, persons aged ≥65 years are projected to comprise over 20% of the population by the year 2050. In view of the special medical needs of elders, scientific investigation into the biological aspects of ageing is key towards the improvement of geriatric care for the coming decades. This special issue of Ageing Research Reviews focuses on advances in research on the immunology of human ageing. Herein are nine articles about the age-related alterations in both the innate and adaptive arms of the immune system, and about continuing hurdles in vaccinology. These articles point to a common theme that the immunological milieu in old age is substantially different from that seen in the young. This suggests that new development and/or innovation of immune-based clinical interventions for the elderly may need to be customized for their age group, rather than the mere adoption of therapies that have been designed for and/or tested for younger persons., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Introduction: Population aging has become a global phenomenon, and HIV infection among older individuals is also increasing. Because age can affect the progression of HIV infection, we aimed to evaluate the present knowledge on HIV infection in older patients., Methods: Literature review of the last 20 years., Results: Older HIV-infected patients have lower CD4(+) T cell counts, higher viral load and are more frequently symptomatic at diagnosis. The infection progresses more rapidly, with higher morbidity and lethality rates. However, older patients are more compliant to antiretroviral treatment; they experience a better virologic response, and treatment represents a positive clinical impact. Aging affects the complex interaction between HIV infection and the immune system. Both conditions contribute to the dysfunction of immune cells, including a decrease in the phagocytes' microbicidal capability, natural killer cells' cytolytic function, expression of toll-like receptors and production of interleukin-12. Chronic immune activation responsible for the depletion of CD4(+) and CD8(+) T cells in HIV infection appears to worsen with senescence. Older patients also exhibit a less robust humoral response, with the production of less avid and specific antibodies., Conclusion: Both HIV and aging contribute to immune dysfunction, morbidity and mortality. However, highly active antiretroviral therapy (HAART) is beneficial for older patients, and treatment of older patients should not be discouraged., (Copyright © 2010 Elsevier B.V. All rights reserved.)