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Since associations between lifespan and certain simple immune parameters such as T cell proliferative responses to mitogens were reported in the 1970´s, efforts to dissect out immune parameters correlating with morbidity and mortality have sought to define factors predicting individual longevity. Such "immune signatures" associating with defined clinical outcomes would represent biomarkers of "immunosenescence" that might also provide mechanistic insights into the ageing process. Because appropriate immune function is necessary for a healthy old age, a better understanding of immunosenescence contributing to frailty and death might allow interventions to improve personal and public health. Here, we discuss data from our studies in several different European countries and document significant differences between overtly similar populations. These findings draw attention to the marked variation even between presumably quite homogeneous populations, which may be due to the different birth cohorts studied in addition to numerous other variables. Thus, immunological parameters, and presumably many other factors, are sensitive to context-dependent variation, making it currently difficult to extrapolate biomarkers of longevity from any one human population to another.

Seasonal influenza remains a major public health problem, responsible for hundreds of thousands of deaths every year, mostly of elderly people. Despite the wide availability of vaccines, there are multiple problems decreasing the effectiveness of vaccination programs. These include viral variability and hence the requirement to match strains by estimating which will become prevalent each season, problems associated with vaccine and adjuvant production, and the route of administration as well as the perceived lower vaccine efficiency in older adults. Clinical protection is still suboptimal for all of these reasons, and vaccine uptake remains too low in most countries. Efforts to improve the effectiveness of influenza vaccines include developing universal vaccines independent of the circulating strains in any particular season and stimulating cellular as well as humoral responses, especially in the elderly. This commentary assesses progress over the last 3 years towards achieving these aims. Since the beginning of 2020, an unprecedented international academic and industrial effort to develop effective vaccines against the new coronavirus SARS-CoV-2 has diverted attention away from influenza, but many of the lessons learned for the one will synergize with the other to mutual advantage. And, unlike the SARS-1 epidemic and, we hope, the SARS-CoV-2 pandemic, influenza will not be eliminated and thus efforts to improve influenza vaccines will remain of crucial importance.

Influenza can lead to serious illness, particularly for older adults. In addition to short-term morbidity and mortality during the acute infection, recovery can be prolonged and often incomplete. This may lead to persistent declines in health and function, including catastrophic disability, which has dramatic implications for the well-being and support needs of older adults and their caregivers. All of this means that prevention of infection and effective treatment when illness has occurred are of paramount importance. In this narrative review, we discuss the effectiveness of influenza vaccines for the prevention of influenza illness and serious outcomes in older adults. We review evidence of vaccine effectiveness for older adults in comparison with younger age groups, and also highlight the importance of frailty as a determinant of vaccine effectiveness. We then turn our attention to the question of why older and frailer individuals have poorer vaccine responses, and consider changes in immune function and inflammatory responses. This sets the stage for a discussion of newer influenza vaccine products that have been developed with the aim of enhancing vaccine effectiveness in older adults. We review the available evidence on vaccine efficacy, effectiveness and cost benefits, consider the potential place of these innovations in clinical geriatric practice, and discuss international advisory committee recommendations on influenza vaccination in older adults. Finally, we highlight the importance of influenza prevention to support healthy aging, along with the need to improve vaccine coverage rates using available vaccine products, and to spur development of better influenza vaccines for older adults in the near future.

Increasing numbers of trials employing anti-PD-1 immunotherapy emphasize the requirement for predictive biomarkers of clinical response. Many studies examine the cell surface expression of PD-1 and other key regulators of T-cell activation and inhibition. Here, we compared common commercially available anti-PD-1 diagnostic antibodies and tested whether they can bind the PD-1 receptor in the presence of the therapeutic antagonists pembrolizumab and nivolumab. We observed that currently no antibodies are available that can reliably stain all PD-1 receptors on T-cells from patients treated with anti-PD-1 antibodies. Furthermore, none of the diagnostic antibodies detected the entire population of PD-1+ T-cells relative to indirect staining using the therapeutic antibodies themselves. To overcome this problem, here we present a reliable method for quantifying PD-1 expression on immune cells from treated patients which can be included in any conventional flow or mass cytometry antibody panel used for patient monitoring.

Alzheimer's disease is one of the most devastating neurodegenerative diseases. The exact cause of the disease is still not known although many scientists believe in the beta amyloid hypothesis which states that the accumulation of the amyloid peptide beta (Aβ) in brain is the initial cause which consequently leads to pathological neuroinflammation. However, it was recently shown that Aβ may have an important role in defending the brain against infections. Thus, the balance between positive and negative impact of Aβ may determine disease progression. Microglia in the brain are innate immune cells, and brain-initiated inflammatory responses reflected in the periphery suggests that Alzheimer's disease is to some extent also a systemic inflammatory disease. Greater permeability of the blood brain barrier facilitates the transport of peripheral immune cells to the brain and vice versa so that a vicious circle originating on the periphery may contribute to the development of overt clinical AD. Persistent inflammatory challenges by pathogens in the periphery, increasing with age, may also contribute to the central propagation of the pathological changes seen clinically. Therefore, the activation status of peripheral innate immune cells may represent an early biomarker of the upcoming impact on the brain. The modulation of these cells may thus become a useful mechanism for modifying disease progression.

BACKGROUND: Little is known about associations between dietary inflammation, age and anthropometric measurements. OBJECTIVE: In this regard, we examine how DII is related to age, anthropometrics [weight, Body mass index (BMI), waist to hip ratio (WHR)] and other parameters of nutrition (energy, protein, fats and cholesterol intake, Net Endogenous Acid Production (NEAP) and Phytochemical Index (PI)) in a cross-sectional study in Pakistan. DESIGN: Only men (n = 651, age 54–95 years) participated in the study. Anthropometric data were collected using standard methods. DII was calculated from nutrients derived from 24-hr Dietary Recall questionnaires. NEAP and PI were calculated by established algorithms using information on nutrient intake. RESULTS: The results show that with increasing age, there was a significant increase in the DII score (p 0.05). Similarly, a significant positive correlation with NEAP (p

Metastatic melanoma is the most dangerous form of skin cancer, with an ever-increasing incidence worldwide. Despite encouraging results with immunotherapeutic approaches, long-term survival is still poor. This is likely partly due to tumour-induced immune suppression mediated by myeloid-derived suppressor cells (MDSCs), which were shown to be associated with response to therapy and survival. Thus, identifying pathways responsible for MDSC differentiation may provide new therapeutic targets and improve efficacy of existing immunotherapies. Therefore, we've analysed mechanisms by which tumour cells contribute to the induction of MDSCs. Established melanoma cell lines were pre-treated with inhibitors of different pathways and tested for their capacity to alleviate T cell suppression via MDSC differentiation in vitro. Targeting HSP70/90 in melanoma cells resulted in reduced induction of immune suppressive cells on a phenotypic and functional basis, for which a more potent effect was observed when HSP90 was inhibited under hypoxic conditions. This initial study suggests a novel mechanism in tumour cells responsible for the induction of MDSC in melanoma.

As is apparent from the many contributions to this Special Issue of the Journal, the impact of age on immunity is nefarious, with all manner of dysregulated responses attributed to "immunosenescence". These range from poorer responses to vaccination, lower capacity to mediate anti-cancer responses, more inflammation and tissue damage, along with autoimmunity and loss of control of persistent infections. Given the grave clinical implications of altered immune status in aged people, it is of paramount importance to understand the nature of and mechanisms responsible for "immunosenescence". As in any rapidly developing research area, certain paradigms establish themselves early on, by necessity based on earlier and fewer data, and have a disproportionate influence on how investigators think about the subject, especially investigators from other disciplines. It may therefore be appropriate to reconsider our basic knowledge at this juncture, asking exactly what do we mean by the term "immunosenescence"? This is attempted in this contribution to the Special Issue.

Since the first immunomodulatory antibody was licensed by the FDA in 2011 for treating melanoma it has remained the case that only a certain proportion of cancer patients respond favourably to a particular therapy. Recent results from combining two or more different antibodies each targeting a different immune checkpoint indicate that the proportion of responding patients can be increased, but thus far there are no such therapies routinely yielding clinical benefit in 100% of patients in any cancer type. Therefore, predicting which patients will respond to a particular therapy remains of the utmost importance in order to maximise treatment efficacy and minimise side-effects and costs. Moreover, determining biomarkers predicting responses may provide insight into the mechanisms responsible for success or failure of that therapy. This article reviews seminal papers mostly from the past two years of progress in this area of intense investigation, and mostly in melanoma, the tumour type for which the largest body of data exists thus far.

It is our pleasure to inaugurate the new open access journal, the Journal of Ageing and Longevity (JAL, ISSN 2673-9259) [...]

Melanoma has long been recognized as a potentially immunogenic tumour, but only recently has it become clear that the reason for this resides in its many ultraviolet (UV)‐induced mutations and expression of multiple autoantigens which can be targeted by the immune system. The first successful applications of immune‐based treatments included passive immunotherapy using high‐dose interleukin (IL)‐2 and/or adoptive transfer of natural killer (NK)‐cells, as well as active immunotherapy using whole cell‐derived or peptide vaccines. In the intervening decades, it has become clear that these approaches can lead to durable responses in stage III/IV melanoma, and even to functional cures – but only in a vanishingly small fraction of patients. With the advent of immune checkpoint blockade first with anti‐cytotoxic T‐lymphocyte 4 (CTLA‐4), then with anti‐programmed cell death 1 (PD‐1) antibodies, and combinations thereof, the small percentage of responding patients may be increased to half, a major accomplishment in this refractory disease. Improved techniques for identifying mutation‐derived neoantigens and thus more sophisticated active immunotherapies, probably combined with checkpoint blockade, currently hold great promise for further increasing the fraction of responding patients. As additional immunomodulatory antibodies and therapies become available, it will be increasingly important to develop diagnostic tools to determine which particular therapy is likely to elicit the best response for the individual patient. Practically speaking, therapy selection and efficacy monitoring on the basis of the results of a blood test would be most desirable. The purpose of this review is to consider the feasibility of identifying ‘immune signatures’ for predicting responses and determining mechanisms responsible for success or failure of these immunotherapies.

The pioneering Swedish OCTO/NONA-Immune longitudinal studies led by Anders Wikby in Jönköping in the 1990s established a cluster of simple baseline immune parameters associated with excess mortality in 85 year-old non-institutionalized individuals over 2, 4 and 6-year follow-up. We dubbed this cluster the "Immune Risk Profile" (IRP) consisting of poor proliferative responses of peripheral blood mononuclear cells to T cell mitogens, accumulations of CD8+ CD28- T-cells resulting in an inverted CD4:8 ratio, decreased amounts of B-cells, and seropositivity for Cytomegalovirus (CMV). The concept of the IRP has since been applied by others to many different populations in different circumstances and at different ages, but in general without specifically establishing whether the same risk factors were relevant in the tested subjects. However, our own later studies showed that risk factors in aged populations from The Netherlands and Belgium were markedly different, indicating that the IRP cannot simply be transferred between populations. Moreover, there was a striking sex difference in the Belgian study, which was the only one large enough to include sufficient numbers of old men. The reasons for these marked differences between populations which one might have assumed a priori to be quite similar to one another are not clear, and many candidates can be speculated upon, but the important lesson is that there is a marked context-dependency of immune biomarkers of ageing, suggesting that IRPs cannot be assumed to be identical in different populations.

The mechanisms of neurodegeneration in Alzheimer's disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n = 13), patients with mild AD (mAD, n = 15), and healthy elderly controls (n = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1β, IL-12p70) and chemokine (MIP-1α, MIP-1β, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development.

It is widely accepted that the brain and the immune system continuously interact during normal as well as pathological functioning. Human aging is commonly accompanied by low-grade inflammation in both the immune and central nervous systems, thought to contribute to many age-related diseases. This review of the current literature focuses first on the normal neuroimmune interactions occurring in the brain, which promote learning, memory and neuroplasticity. Further, we discuss the protective and dynamic role of barriers to neuroimmune interactions, which have become clearer with the recent discovery of the meningeal lymphatic system. Next, we consider age-related changes of the immune system and possible deleterious influences of immunosenescence and low-grade inflammation (inflammaging) on neurodegenerative processes in the normally aging brain. We survey the major immunomodulators and neuroregulators in the aging brain and their highly tuned dynamic and reciprocal interactions. Finally, we consider our current understanding of how physical activity, as well as a combination of physical and cognitive interventions, may mediate anti-inflammatory effects and thus positively impact brain aging.

Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

Purpose: Wild-type isocitrate dehydrogenase–expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of Experimental Design: (i) Clinical data: GBM patient datasets from The Cancer Genome Atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating ICB were stratified by age and compared for OS. (ii) Animal models: young, middle-aged, and older adult wild-type and indoleamine 2,3 dioxygenase (IDO)-knockout syngeneic mice were intracranially engrafted with CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti–PD-1 mAb, and/or a pharmacologic IDO enzyme inhibitor. Results: Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age–associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment. Conclusions: Immunosuppression increases in the brain during advanced age and inhibits antiglioma immunity in older adults. Going forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older patients with GBM during treatment with ICB.

Globally, citizens exist for sustained periods in states of aging-related disease and multimorbidity. Given the urgent and unmet clinical, health care, workforce, and economic needs of aging populations, we need interventions and programs that regenerate tissues and organs and prevent and reverse aging-related damage, disease, and frailty (1). In response to these challenges, the World Health Organization (WHO) has called for a comprehensive public-health response within an international legal framework based on human rights law (1). Yet for a clinical trial to be conducted, a disease to be diagnosed, intervention prescribed, and treatment administered; a corresponding disease classification code is needed, adopted nationally from the WHO International Classification of Diseases (ICD). Such classifications and staging are fundamental for health care governance among governments and intergovernmental bodies. We describe a systematic and comprehensive approach to the classification and staging of organismal senescence and aging-related diseases at the organ and tissue levels in order to guide policy and practice and enable appropriate interventions and clinical guidance, systems, resources, and infrastructure.

With advancing age, many organs exhibit functional deterioration. The age-associated accumulation of senescent cells is believed to represent one factor contributing to this phenomenon. While senescent cells are found in several different organ systems, it is not known whether they arise independently in each organ system or whether their prevalence within an individual reflects that individual's intrinsic aging process. To address this question, we studied senescence in two different organ systems in humans, namely skin and T cells in 80 middle-aged and older individuals from the Leiden Longevity Study. Epidermal p16INK4a positivity was associated with neither CD4(+) nor CD8(+) T-cell immunosenescence phenotype composites (i.e., end-stage differentiated/senescent T cells, including CD45RA(+)CCR7(-)CD28(-)CD27(-)CD57(+)KLRG1(+) T cells). Dermal p16INK4a positivity was significantly associated with the CD4(+), but not with the CD8(+) immunosenescence composite. We therefore conclude that there is limited evidence for a link between skin senescence and immunosenescence within individuals.

Cancer treatment remains unsatisfactory with high rates of recurrence and metastasis. Immunomodulatory agents capable of promoting cellular antitumor immunity while inhibiting the local immunosuppressive tumor microenvironment could greatly improve cancer treatment. We have developed a multi-targeted mannosylated cationic liposome delivery system containing muramyl dipeptide (DS) and low doses of the chemotherapeutic agent cytarabine (Ara-C). Immunomodulation of primary immune cells and immortalized cancer cell lines by Ara-C/DS was assessed by measuring cytokine levels and surface marker expression. As a proof of concept, the generation of targeted cellular immunity was investigated in the context of responses to viral antigens. This report is the first demonstrating that Ara-C combined with DS can modulate immune responses and revert immunosuppression as evidenced by increased IFN-γ and IL-12p40 without changes in IL-10 in peripheral blood mononuclear cells, and increased CD80 and decreased CD163 on immunosuppressive macrophages. Furthermore, Ara-C/DS increased MHC class I expression on cancer cells while increasing the production of antigen-specific IFN-γ+ CD8+ T cells in viral peptide-challenged lymphocytes from both humans and vaccinated mice. Taken together, these results are the first to document immunomodulatory properties of Ara-C linked with recognition of antigens and potentially the generation of antitumor immune memory.

The existence of CD4+ cytotoxic T cells (CTLs) at relatively high levels under different pathological conditions in vivo suggests their role in protective and/or pathogenic immune functions. CD4+ CTLs utilize the fundamental cytotoxic effector mechanisms also utilized by CD8+ CTLs and natural killer cells. During long-term cultivation, CD4+ T cells were also shown to acquire cytotoxic functions. In this study, CD4+ human T-cell clones derived from activated peripheral blood lymphocytes of healthy young adults were examined for the expression of cytotoxic machinery components. Cystatin F is a protein inhibitor of cysteine cathepsins, synthesized by CD8+ CTLs and natural killer cells. Cystatin F affects the cytotoxic efficacy of these cells by inhibiting the major progranzyme convertases cathepsins C and H as well as cathepsin L, which is involved in perforin activation. Here, we show that human CD4+ T-cell clones express the cysteine cathepsins that are involved in the activation of granzymes and perforin. CD4+ T-cell clones contained both the inactive, dimeric form as well as the active, monomeric form of cystatin F. As in CD8+ CTLs, cysteine cathepsins C and H were the major targets of cystatin F in CD4+ T-cell clones. Furthermore, CD4+ T-cell clones expressed the active forms of perforin and granzymes A and B. The levels of the cystatin F decreased with time in culture concomitantly with an increase in the activities of granzymes A and B. Therefore, our results suggest that cystatin F plays a role in regulating CD4+ T cell cytotoxicity. Since cystatin F can be secreted and taken up by bystander cells, our results suggest that CD4+ CTLs may also be involved in regulating immune responses through cystatin F secretion.

The challenge of distinguishing between changes attributable to ageing and those attributable to pathology is even greater for the immune system than for many other organs, and this is especially true for myeloid-derived suppressor cells (MDSCs). Hematopoiesis is different in older adults with a bias towards myelopoiesis, and older adults also manifest "inflammageing" exacerbated by disease and contributing to MDSC induction. Hence, at least in humans, one can only investigate MDSCs in the context of ageing and disease states, and not in the context of ageing processes per se. This contribution provides a brief overview of the literature on MDSCs and ageing in humans.

International audience; The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naïve and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio = 1.5, p = 0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p = 0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted.

The identification of blood-borne biomarkers correlating with melanoma patient survival remains elusive. Novel techniques such as mass cytometry could help to identify melanoma biomarkers, allowing simultaneous detection of up to 100 parameters. However, the evaluation of multiparametric data generated via time-of-flight mass cytometry requires novel analytical techniques because the application of conventional gating strategies currently used in polychromatic flow cytometry is not feasible. In this study, we have employed 38-channel time-of-flight mass cytometry analysis to generate comprehensive immune cell signatures using matrix boolean analysis in a cohort of 28 stage IV melanoma patients and 17 controls. Clusters of parameters were constructed from the abundance of cellular phenotypes significantly different between patients and controls. This approach identified patient-specific combinatorial immune signatures consisting of high-resolution subsets of the T cell, NK cell, B cell, and myeloid compartments. An association with superior survival was characterized by a balanced distribution of myeloid-derived suppressor cell-like and APC-like myeloid phenotypes and differentiated NK cells. The results of this study in a discovery cohort of melanoma patients suggest that multifactorial immune signatures have the potential to allow more accurate prediction of individual patient outcome. Further investigation of the identified immune signatures in a validation cohort is now warranted.

In addition to measures already used in clinical practice, molecular measures have been proposed to assess health status, but these have not yet been introduced into clinical practice. We aimed to test the association of functional capacity measures used in current practice and molecular measures with age and health status. The cohort consisted of 178 middle-aged to old participants of the Leiden Longevity Study (range 42-82years). We tested associations between functional capacity measures (physical tests: grip strength, 4-meter walk, chair stand test; cognitive tests: Stroop test, digit symbol substitution test and 15-picture learning test) with age and with cardiovascular or metabolic disease as a measure of the health status. These associations with age and health status were also tested for molecular measures (C reactive protein (CRP), numbers of senescent p16INK4a positive cells in the epidermis and dermis and putative immunosenescence (presence of CD57+ T cells)). All functional capacity measures were associated with age. CRP and epidermal p16INK4a positivity were also associated with age, but with smaller estimates. Grip strength and the Stroop test were associated with cardiovascular or metabolic disease, as was epidermal p16INK4a positivity. All associations with cardiovascular or metabolic disease attenuated when adjusting for age. In conclusion, in middle-aged to old persons, the molecular measures tested here were more weakly associated with age and health status than functional capacity measures. Whether these molecular measures associate more closely with health status in the elderly or in specific groups of patients needs to be explored further.

Socioeconomic disadvantage may contribute to poor health through immune-related biological mechanisms. We examined the associations between socioeconomic status, as measured by annual household income, and T-cell markers of aging, including the ratios of CD4 and CD8 effector cells to naïve cells (E/N ratio) and the CD4/CD8 T-cell ratio. We hypothesized that participants with a lower income would have higher E/N ratios and lower CD4/CD8 ratios compared with participants with a higher income, and that these associations would be partially mediated by elevated cytomegalovirus (CMV) IgG antibody levels, a virus implicated in aging and clonal expansion of T cells.Data were from 79 individuals who participated in the population-based Detroit Neighborhood Health Study. We used linear regression to quantify the association between a $10,000 decrease in income and each ratio outcome.After adjustment for age, sex, race, smoking, medication use, and lifetime history of mental health conditions, lower income was associated with a 0.41 (95% confidence interval = 0.09-0.72) log-unit increase in the CD4 E/N ratio and a 0.20 (95% confidence interval = 0.02-0.39) log-unit increase in the CD8 E/N ratio. CMV immunoglobulin G antibody level partially mediated these associations.Our study suggests that low socioeconomic status is associated with immunological aging as measured by the E/N ratio and that impaired immune control of CMV may partially mediate these associations.

// Crystal Tze Ying Tan 1 , Kilian Wistuba-Hamprecht 2,3 , Weili Xu 1,4 , Ma Schwe Zin Nyunt 5 , Anusha Vasudev 1 , Bernett Teck Kwong Lee 1 , Graham Pawelec 2 , Kia Joo Puan 1 , Olaf Rotzschke 1 , Tze Pin Ng 5 and Anis Larbi 1,4,6 1 Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Biopolis, Singapore 2 Department of Internal Medicine II, Centre for Medical Research, University Medical Center, Tubingen, Germany 3 Department of Dermatology, University Medical Center, Tubingen, Germany 4 School of Biological Sciences, Nanyang Technological University, Singapore 5 Gerontology Research Programme, Department of Psychological Medicine, National University Health System, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 6 Department of Microbiology, National University of Singapore, Singapore Correspondence to: Anis Larbi, email: // Keywords : unconventional T cells, immunosenescence, phenotype, aging, Gerotarget Received : December 11, 2015 Accepted : May 29, 2016 Published : June 15, 2016 Abstract Chronological aging and a variety of stressors are driving forces towards immunosenescence. While much attention was paid to the main T cell component, α/β T cells, few studies concentrate on the impact of age on γ/δ T cells’ characteristics. The latter are important players of adaptive immunity but also have features associated with innate immunity. Vδ2+ are the main component of γ/δ while Vδ1+ T cells expand upon Cytomegalovirus (CMV) infection and with age. The Vδ2+ T cells are not influenced by persistent infections but do contribute to immunosurveillance against bacterial pathogens. Here, we focus on Vδ2+ T cells and report that their composition and functionality is not altered in older adults. We have performed a side-by-side comparison of α/β and Vδ2 cells by using two robust markers of T cell replicative history and cell differentiation (CD28 and CD27), and cytokine secretion (IFN-γ and TNF-α). Significant differences in Vδ2 versus α/β homeostasis, as well as phenotypic and functional changes emerged. However, the data strongly suggest a sustained functionality of the Vδ2 population with age, independently of the challenge. This suggests differential trajectories towards immunosenescence in α/β and Vδ2+ T cells, most likely explained by their intrinsic functions.

Considering the large number of studies focused on myeloid-derived suppressor cells (MDSCs) to date, only a handful of well-defined relationships in human cancer have been established. The difficulty of assessing the impact of MDSCs in human cancer is partly due to the relatively small number of studies performed in humans. This is compounded in the literature by a common lack of clear indication of which species is being referred to for each characteristic described. These aspects may result in inappropriate extrapolation of animal studies to those in the human setting. This is especially the case for studies focused on investigating therapies which can be used to target MDSCs or those aimed at understanding their mechanism. Here, we attempt to rectify this by reviewing only studies on MDSC performed in humans. We survey studies which explore (1) whether MDSC levels are altered in cancer patients and if this is correlated with patient survival, (2) the so far identified mechanisms employed by MDSC to exert immune suppression, and (3) whether therapeutic agents can be used to target MDSCs by either altering their level, influencing their differentiation or inhibiting their suppressive function. Despite the fact that these studies clearly show that MDSCs are important in human cancer, the clinical employment of agents intended to target them has not yet been accomplished. We identify factors which have contributed to this and propose steps which may facilitate the translation of these therapies to the clinic in future.

According to the current paradigm, the main cause of AD is the accumulation of neurotoxic amyloid beta (Aβ) peptide aggregates resulting from the cleavage of the amyloid precursor protein into peptides of different length, with the 42 amino acid long Aβ42 being the most toxic form. Aβ can aggregate and form plaques in the brain. It further promotes the hyperphosphorylation of the tau protein which forms characteristic neurofibrillary tangles and thereby loses its important role in axonal transport and contributes to neurodegeneration. Therefore, treatments have targeted Aβ, but clinical trials of immunotherapies caused severe side effects and showed that Aβ clearance alone did not result in any cognitive improvement. This leads to the question: what else promotes AD pathology? Here, we review data on systemic inflammation and the possible roles that the immune system might play in AD. Microglia and astrocytes are activated and secrete inflammatory cytokines and chemokines. Via a disturbed blood-brain barrier, peripheral immune cells are activated and recruited towards inflamed brain lesions and amyloid plaques, but due to the chronic nature of the amyloid burden and their reduced function, these cells are not able to control inflammation and the associated detrimental immune responses. In addition, age-related inflammation and chronic infection with herpes viruses might contribute to the systemic inflammation and exacerbate attempts to restore the balance of inflammation.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic was first reported in Wuhan, China in December 2019, moved across the globe at an unprecedented speed, and is having a profound and yet still unfolding health and socioeconomic impacts. SARS-CoV-2, a β-coronavirus, is a highly contagious respiratory pathogen that causes a disease that has been termed the 2019 coronavirus disease (COVID-19). Clinical experience thus far indicates that COVID-19 is highly heterogeneous, ranging from being asymptomatic and mild to severe and causing death. Host factors including age, sex, and comorbid conditions are key determinants of disease severity and progression. Aging itself is a prominent risk factor for severe disease and death from COVID-19. We hypothesize that age-related decline and dysregulation of immune function, i.e., immunosenescence and inflammaging play a major role in contributing to heightened vulnerability to severe COVID-19 outcomes in older adults. Much remains to be learned about the immune responses to SARS-CoV-2 infection. We need to begin partitioning all immunological outcome data by age to better understand disease heterogeneity and aging. Such knowledge is critical not only for understanding of COVID-19 pathogenesis but also for COVID-19 vaccine development.

Highlights • Biomarkers of human immunosenescence are discussed. • Longitudinal studies are essential. • Associations of immune markers in older adults with clinical outcome are context-dependent. • There are no universal biomarkers of human immunosenescence. • There are common age-associated changes to peripheral immune markers in humans., There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as “immunosenescence”. But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.

Aging leads to numerous changes that affect all physiological systems of the body including the immune system, causing greater susceptibility to infectious disease and contributing to the cardiovascular, metabolic, autoimmune, and neurodegenerative diseases of aging. The immune system is itself also influenced by age-associated changes occurring in such physiological systems as the endocrine, nervous, digestive, cardio-vascular and muscle-skeletal systems. This chapter describes the multidimensional effects of aging on the most important components of the immune system. It considers the age-related changes in immune cells and molecules of innate and adaptive immunity and consequent impairments in their ability to communicate with each other and with their aged environment. The contribution of age-related dysregulation of hematopoiesis, required for continuous replenishment of immune cells throughout life, is discussed in this context, as is the developmentally-programmed phenomenon of thymic involution that limits the output of naïve T cells and markedly contributes to differences between younger and older people in the distribution of peripheral blood T-cell types. How all these changes may contribute to low-grade inflammation, sometimes dubbed "inflammaging", is considered. Due to findings implicating elevated inflammatory immuno-mediators in age-associated chronic autoimmune and neurodegenerative processes, evidence for their possible contribution to neuroinflammation is reviewed.

The detection of antigen-reactive T cells has shown great utility for patient clinical monitoring. However, many of the methods commonly used to detect these cells face major limitations, like the predetermination of the given HLA type. The herein described protocol provides a means of overcoming many of the obstacles associated with the use of multimers and other common approaches in this field. In order to be able to detect rare cells which are below the detection limit of direct ex vivo measurement, in the present protocol, antigen-reactive T cells are first expanded in vitro using libraries of overlapping peptides which span the entire protein of interest and consist of 15 amino acid-long peptides that share a 12-amino-acid overlap. This theoretically allows the detection of T cells to any epitope within a protein of interest and consequently does not require the patient's HLA type to be characterized. Furthermore, this method simultaneously detects CD4+ and CD8+ T cells that produce cytokines upon encounter with antigen and thereby provides a functional insight into the behavior of the responding T cells. In our case, we have investigated the pro- or anti-inflammatory cytokines IL-2, IL-5, IL-10, IL-17, TNF-α, and IFN-γ.

Background The frequency of circulating leukocytes has been shown to be a prognostic factor in patients being treated for different types of cancer. In breast cancer, tumor-infiltrating leukocytes may predict patient outcome, but few studies have investigated such associations for circulating leukocytes. Patients and Methods Multiparametric flow cytometry was used to examine the immunophenotypes of circulating peripheral blood mononuclear cells for 88 patients with metastatic breast cancer, which was then correlated to breast cancer–specific survival. Patients had been treated either with high-dose cyclophosphamide-containing regimens (group 1, n = 51 patients) or high-dose paclitaxel-containing regimens (group 2, n = 37 patients). Results The frequency of peripheral blood CD14+ monocytes indicated prognosis for patients in group 1 (but not group 2), while higher levels of CD11c+ dendritic cells indicated a better prognosis for patients in group 2 (but not group 1). The frequency of a number of different CD4+ or CD8+ T cell subtypes also predicted prognosis for patients in group 2. For example, patients in group 2 with a higher frequency of circulating CD4+ or CD8+ naive T cells (CD45RA+CD95−CD27+CD28+) showed a poorer prognosis. In contrast, T cells were not associated with prognosis for patients in group 1. Conclusion Circulating leukocytes can predict clinical outcome for patients with breast cancer. Prediction of clinical outcome in this cohort of metastatic breast cancer patients was specific to the type of chemotherapy, and this finding is likely to apply to other therapies.

The detection of antigen-reactive T cells has shown great utility for patient clinical monitoring. However, many of the methods commonly used to detect these cells face major limitations, like the predetermination of the given HLA type. The herein described protocol provides a means of overcoming many of the obstacles associated with the use of multimers and other common approaches in this field. In order to be able to detect rare cells which are below the detection limit of direct ex vivo measurement, in the present protocol, antigen-reactive T cells are first expanded in vitro using libraries of overlapping peptides which span the entire protein of interest and consist of 15 amino acid-long peptides that share a 12-amino-acid overlap. This theoretically allows the detection of T cells to any epitope within a protein of interest and consequently does not require the patient's HLA type to be characterized. Furthermore, this method simultaneously detects CD4+ and CD8+ T cells that produce cytokines upon encounter with antigen and thereby provides a functional insight into the behavior of the responding T cells. In our case, we have investigated the pro- or anti-inflammatory cytokines IL-2, IL-5, IL-10, IL-17, TNF-α, and IFN-γ.

Aging leads to numerous changes that affect all physiological systems of the body including the immune system, causing greater susceptibility to infectious disease and contributing to the cardiovascular, metabolic, autoimmune, and neurodegenerative diseases of aging. The immune system is itself also influenced by age-associated changes occurring in such physiological systems as the endocrine, nervous, digestive, cardio-vascular and muscle-skeletal systems. This chapter describes the multidimensional effects of aging on the most important components of the immune system. It considers the age-related changes in immune cells and molecules of innate and adaptive immunity and consequent impairments in their ability to communicate with each other and with their aged environment. The contribution of age-related dysregulation of hematopoiesis, required for continuous replenishment of immune cells throughout life, is discussed in this context, as is the developmentally-programmed phenomenon of thymic involution that limits the output of naive T cells and markedly contributes to differences between younger and older people in the distribution of peripheral blood T-cell types. How all these changes may contribute to low-grade inflammation, sometimes dubbed "inflammaging", is considered. Due to findings implicating elevated inflammatory immuno-mediators in age-associated chronic autoimmune and neurodegenerative processes, evidence for their possible contribution to neuroinflammation is reviewed.

Background Cytokines are signaling molecules operating within complex cascade patterns and having exceptional modulatory functions. They impact various physiological processes such as neuroendocrine and metabolic interactions, neurotrophins’ metabolism, neuroplasticity, and may affect behavior and cognition. In our previous study, we found that sex and Cytomegalovirus (CMV)-serostatus may modulate levels of circulating pro- and anti-inflammatory cytokines, metabolic factors, immune cells, and cognitive performance, as well as associations between them. Results In the present study, we used a graph-theoretical approach to investigate the network topology dynamics of 22 circulating biomarkers and 11 measures of cognitive performance in 161 older participants recruited to undergo a six-months training intervention. For network construction, we applied coefficient of determination (R2) that was calculated for all possible pairs of variables (N = 33) in four groups (CMV− men and women; CMV+ men and women). Network topology has been evaluated by clustering coefficient (CC) and characteristic path length (CPL) as well as local (Elocal) and global (Eglobal) efficiency, showing the degree of network segregation (CC and Elocal) and integration (CPL and Eglobal). We found that networks under consideration showed small-world networks properties with more random characteristics. Mean CC, as well as local and global efficiency were highest and CPL shortest in CMV− males (having lowest inflammatory status and highest cognitive performance). CMV− and CMV+ females did not show any significant differences. Modularity analyses showed that the networks exhibit in all cases highly differentiated modular organization (with Q-value ranged between 0.397 and 0.453). Conclusions In this work, we found that segregation and integration properties of the network were notably stronger in the group with balanced inflammatory status. We were also able to confirm our previous findings that CMV-infection and sex modulate multiple circulating biomarkers and cognitive performance and that balanced inflammatory and metabolic status in elderly contributes to better cognitive functioning. Thus, network analyses provide a useful strategy for visualization and quantitative description of multiple interactions between various circulating pro- and anti-inflammatory biomarkers, hormones, neurotrophic and metabolic factors, immune cells, and measures of cognitive performance and can be in general applied for analyzing interactions between different physiological systems.

While challenging, only longitudinal studies can pinpoint biomarkers dynamically associated with a selected outcome. In human studies of ageing, this challenge is particularly onerous, both in terms of the time required and the outcome selected. While recognizing the limitations of our approach, taking the most robust and unequivocal outcome (all-cause mortality), and taking a very old population as the starting point, we have sought to define peripheral blood “immune signatures” predicting incipient mortality. Studies in overtly similar populations in Sweden, Belgium and The Netherlands reveal certain constellations of immune biomarkers associated with all-cause mortality in people >80 years of age. Unexpectedly, however, these “immune risk profiles” are different in the different populations. Thus, it is unlikely that it will be possible to identify “one-size-fits-all” biomarkers of ageing in different populations, at least when solely focusing on parameters of immunity.

Shingles and its most common disabling complication, post-herpetic neuralgia, represent a serious public health challenge in the older population. The decline in the T-cell-mediated immune response to varicella zoster virus after age 50 is clearly associated with increased risk of viral reactivation, causing an acutely painful zoster rash, which may have a severe prodrome of dermatomal pain and persist as seriously debilitating post-herpetic neuralgia well beyond the resolution of the rash. However, new vaccines and adjuvants are being developed and trialed and are now more effective in preventing shingles and the sequelae of post-herpetic neuralgia. Those vaccines that possess the ability to enhance antigen presentation and reverse memory T-cell exhaustion, as well as diminish the immune suppressive effects of regulatory T cells, are most likely to be effective in older adults.