Evaluating the Efficacy of Immune Checkpoint Inhibitors in Elderly Patients: A Systematic Review and Meta-analysis.

In this chapter, we outline the steps for designing and conducting a rigorous systematic review and meta-analysis, focusing on the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. ICIs have improved survival rates in advanced cancers, yet their effectiveness in older populations remains unclear. We detail the essential processes involved in both systematic reviews and meta-analyses. We can evaluate the efficacy of ICIs in elderly patients with advanced cancer, examining outcomes such as overall survival and progression-free survival.

Analysis of Cytokine-Inducible SH2-Containing Protein (CISH) in the Study of Immunosenescence.

The aging immune system undergoes significant changes, leading to a state known as immunosenescence. Understanding the molecular mechanisms underlying immunosenescence is crucial for developing targeted interventions to enhance immune functions in older individuals. This bio-protocol review focuses on the application of quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for the mRNA quantification of cytokine-inducible SH2-containing protein (CISH), an immune regulator overexpressed in T-cell responses from older adults. We outline a comprehensive protocol for the quantitative assessment of CISH mRNA expression, providing a valuable tool for researchers investigating immunosenescence.

Transcription Factor Analysis to Investigate Immunosenescence in Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is linked to various signs of advanced aging, such as premature immunosenescence which occurs due to decline in regenerative ability of T cells. RA T cells develop a unique aggressive inflammatory senescent phenotype with an imbalance of Th17/T regulatory (Treg) cell homeostasis and presence of CD28- T cells. The phenotypic analysis and characterization of T cell subsets become necessary to ascertain if any functional deficiencies exist within with the help of transcription factor (TF) analysis. These subset-specific TFs dictate the functional characteristics of T-cell populations, leading to the production of distinct effector cytokines and functions. Examining the expression, activity, regulation, and genetic sequence of TFs not only aids researchers in determining their importance in disease processes but also aids in immunological monitoring of patients enrolled in clinical trials, particularly in evaluating various T-cell subsets [Th17 (CD3+CD4+IL17+RORγt+) cells and T regulatory (Treg) (CD3+CD4+CD25+CD127-FOXP3+) cells], markers of T-cell aging [aged Th17 cells (CD3+CD4+IL17+RORγt+CD28-), and aged Treg cells (CD3+CD4+CD25+CD127-FOXP3+CD28-)]. In this context, we propose and outline the protocols for assessing the expression of TFs in aged Th17 and Treg cells, highlighting the crucial aspects of this cytometric approach.

Polyphenol Treatment of Peripheral Blood Mononuclear Cells from Individuals of Different Ages.

Human peripheral blood mononuclear cells (PBMCs) have been largely utilized to assess the cytotoxic, immunomodulatory, and anti-inflammatory properties of both synthetic and natural compounds. Within the latter category, polyphenols from dietary sources have been extensively analyzed. PBMCs represent a feasible in vitro model to study polyphenol hallmarks and activity according to quantitative and qualitative differences in immune responses in individuals of different age. In this chapter, we propose a method for PBMC treatment with polyphenols and analysis designed on age-dependent qualitative and quantitative variability in immune cell performance.

Review of evidence linking exposure to environmental stressors and associated alterations in the dynamics of immunosenescence (ISC) with the global increase in multiple sclerosis (MS).

Historical survey confirms that, over the latter part of the 20th century, autoimmune-based diseases, including multiple sclerosis (MS), have shown a worldwide increase in incidence and prevalence. Analytical population studies have established that the exponential rise in MS is not solely due to improvements in diagnosis and healthcare but relates to an increase in autoimmune risk factors. Harmful environmental exposures, including non-communicable social determinants of health, anthropogens and indigenous or transmissible microbes, constitute a group of causal determinants that have been closely linked with the global rise in MS cases. Exposure to environmental stressors has profound effects on the adaptive arm of the immune system and, in particular, the associated intrinsic process of immune ageing or immunosenescence (ISC). Stressor-related disturbances to the dynamics of ISC include immune cell-linked untimely or premature (p) alterations and an accelerated replicative (ar) change. A recognised immune-associated feature of MS is pISC and current evidence supports the presence of an arISC during the disease. Moreover, collated data illustrates the immune-associated alterations that characterise pISC and arISC are inducible by environmental stressors strongly implicated in causing duplicate changes in adaptive immune cells during MS. The close relationship between exposure to environmental risk factors and the induction of pISC and arISC during MS offers a valid mechanism through which pro-immunosenescent stressors may act and contribute to the recorded increase in the global rate and number of new cases of the disease. Confirmation of alterations to the dynamics of ISC during MS provides a rational and valuable therapeutic target for the use of senolytic drugs to either prevent accumulation and enhance ablation of less efficient untimely senescent adaptive immune cells or decelerate the dysregulated process of replicative proliferation. A range of senotherapeutics are available including kinase and transcriptase inhibitors, rapalogs, flavanols and genetically-engineered T cells and the use of selective treatments to control emerging and unspecified aspects of pISC and arISC are discussed.

Protecting the elderly from influenza in the context of immune system senescence. Elderly aged 65 and over are vulnerable to influenza and its associated complications.: Position paper by the Romanian Society of Gerontology and Geriatrics.

Influenza affects millions globally each year, often causing severe complications, hospitalizations, and deaths, particularly among the elderly. As the global population ages, infections will pose a growing health risk. Annual vaccination remains the most effective way to prevent influenza and its complications. After the age of 65, people suffering from chronic diseases become the majority of this population category. All the data support that most of the population over 65 years old, whose immune system goes through immunosenescence, presents multimorbidity, requiring age-appropriate anti-influenza protection. The immune response to the traditional influenza vaccine has been proven to be lower in the elderly, highlighting the need for a more immunogenic vaccine specifically tailored to the elderly population group. Therefore, high-dose (HD) influenza vaccines have demonstrated their safety and are more effective in preventing influenza and its associated complications compared to standard-dose (SD) vaccines in the elderly in the context of immunosenescence. These recommendations focus on the safety, effectiveness, and efficacy of HD influenza vaccines, adapted to the elderly and available on the Romanian market, to increase the vaccination rate and, thus, protect against influenza infection and its complications. Therefore, strategies such as increased accessibility and free immunizations, as well as ensuring that flu vaccines for the elderly are prescribed without restrictions based on the number of comorbidities, should be used.

Cutaneous adaptive immunity and uraemia: a narrative review.

Chronic kidney disease affects 1 in 10 people globally, with a prevalence twenty times that of cancer. A subset of individuals will progress to end-stage renal disease (ESRD) where renal replacement therapy is required to maintain health. Cutaneous disease, including xerosis and pruritus, are endemic amongst patients with ESRD. In the uraemia-associated immune deficiency of ESRD, impaired circulating immune responses contribute to increased infection risk and poorer vaccination response. Clinical manifestations of dysregulated adaptive immunity within the skin have been well-described and have been posited to play a role in cutaneous features of ESRD. However, our understanding of the mechanisms by which adaptive immunity within the skin is affected by uraemia is relatively limited. We provide an overview of how the cutaneous adaptive immune system is impacted both directly and indirectly by uraemia, highlighting that much work has been extrapolated from the circulating immune system and often has not been directly evaluated in the skin compartment. We identify knowledge gaps which may be addressed by future research. Ultimately, greater understanding of these pathways may facilitate novel therapeutic approaches to ameliorate widespread cutaneous symptomatology in ESRD.

Senescence-related genes are associated with the immunopathology signature of American Tegumentary Leishmaniasis lesions and may predict progression to mucosal leishmaniasis.

The American Tegumentary Leishmaniasis (ATL) is caused by protozoans of the genus Leishmania and varies from mild localized cutaneous leishmaniasis (LCL) form to more severe manifestations such as the diffuse cutaneous leishmaniasis (DCL) form and the mucosal leishmaniasis (ML) form. Previously, we demonstrated the accumulation of senescent cells in skin lesions of patients with LCL. Moreover, lesional transcriptomic analyses revealed a robust co-induction of senescence and pro-inflammatory gene signatures, highlighting the critical role of senescent T cells in orchestrating pathology. In this work we hypothesized that senescent cells might operate differently among the ATL spectrum, potentially influencing immunopathological mechanisms and clinical outcome. We analysed previously published RNA-Seq datasets of skin biopsies of healthy subjects and lesional skin from DCL patients, LCL patients and LCL patients that, after treatment, progressed to mucosal leishmaniasis (MLP). Our findings demonstrate a robust presence of a CD8 T cell signature associated with both LCL and MLP lesions. Moreover, both inflammatory and cytotoxic signatures were significantly upregulated, showing a strong increase in MLP and LCL groups, but not DCL. The senescence signature was elevated between LCL and MLP groups, representing the only distinguishable signature of immunopathology between them. Interestingly, our analyses further revealed the senescence signature's capacity to predict progression from LCL to mucosal forms, which was not observed with other signatures. Both the senescence-signature score and specific senescence-associated genes demonstrated an increased capacity to predict mucosal progression, with correct predictions exceeding 97% of cases. Collectively, our findings contribute to a comprehensive understanding of immunosenescence in ATL and suggest that senescence may represent the latest and most important signature of the immunopathogenisis. This highlights its potential value in predicting disease severity.

Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau.

BACKGROUND: The beneficial effects of Bacillus Calmette-Guérin (BCG) as an intervention against non-mycobacterial infections have been extensively studied in randomized trials. These non-specific effects have been linked to a heterologous increase of pro-inflammatory cytokine production by innate immune cells. It is unknown if BCG induces such responses in older individuals from TB-endemic countries. METHODS: In a single-blinded trial in Guinea-Bissau, 40 adults over 50 years of age were randomized 1:1 in a block of 40 to intradermal injection of BCG-Japan (intervention) or solvent (placebo). Production of interleukin (IL)-1ß, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was measured by ELISA in supernatant of peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis and heterologous pathogens. The trial was registered at clinicaltrials.gov (NCT02953327). FINDINGS: Between January 25 and March 7, 2017, 40 individuals were randomized. Two months after vaccination, BCG-Japan recipients (n = 11) had higher production of IFN-γ to M. tuberculosis stimulation (Geometric mean ratio (GMR): 3·91 [95 % Confidence Interval (CI), 1·53-9·96]) and increased release of the pro-inflammatory innate cytokines IL-1ß, IL-6 and TNF-α to non-specific stimuli (GMR TNF-α: 1·47 [95 % CI, 0·98-2·19]) than their controls (n = 13). Both the specific and non-specific responses were more pronounced among those with a positive QuantiFERON at baseline. INTERPRETATION: BCG-Japan can induce a trained immunity phenotype in older adults. These effects were particularly strong in previously M. tuberculosis exposed individuals. Future randomized trials are needed to determine BCG's potential to protect the older populations from infections-driven morbidity and mortality.

Inflammaging and Brain Aging.

Progress made by the medical community in increasing lifespans comes with the costs of increasing the incidence and prevalence of age-related diseases, neurodegenerative ones included. Aging is associated with a series of morphological changes at the tissue and cellular levels in the brain, as well as impairments in signaling pathways and gene transcription, which lead to synaptic dysfunction and cognitive decline. Although we are not able to pinpoint the exact differences between healthy aging and neurodegeneration, research increasingly highlights the involvement of neuroinflammation and chronic systemic inflammation (inflammaging) in the development of age-associated impairments via a series of pathogenic cascades, triggered by dysfunctions of the circadian clock, gut dysbiosis, immunosenescence, or impaired cholinergic signaling. In addition, gender differences in the susceptibility and course of neurodegeneration that appear to be mediated by glial cells emphasize the need for future research in this area and an individualized therapeutic approach. Although rejuvenation research is still in its very early infancy, accumulated knowledge on the various signaling pathways involved in promoting cellular senescence opens the perspective of interfering with these pathways and preventing or delaying senescence.

Ferroptosis and immunosenescence in colorectal cancer.

Colorectal cancer (CRC), ranked as the globe's third leading malignancy. Despite advancements in therapeutic approaches, the mortality rate remains distressingly high for those afflicted with advanced stages of the disease. Ferroptosis is a programmed form of cell death. The ways of ferroptosis mainly include promoting the accumulation of cellular ROS and increasing the level of cellular Labile iron pool (LIP). Immunosenescence is characterized by a gradual deterioration of the immune system's ability to respond to pathogens and maintain surveillance against cancer cells. In CRC, this decline is exacerbated by the tumor microenvironment, which can suppress the immune response and promote tumor progression. This paper reviews the relationship between iron prolapse and immune senescence in colorectal cancer, focusing on the following aspects: firstly, the different pathways that induce iron prolapse in colorectal cancer; secondly, immune-immune senescence in colorectal cancer; and lastly, the interactions between immune senescence and iron prolapse in colorectal cancer, e.g., immune-immune senescent cells often exhibit increased oxidative stress, leading to the accumulation of ROS, and consequently to lipid peroxidation and induction of iron-induced cell death. At the same time, ferroptosis induces immune cell senescence as well as alterations in the immune microenvironment by promoting the death of damaged or diseased cells and leading to the inflammation usually associated with it. In conclusion, by exploring the potential targets of ferroptosis and immune senescence in colorectal cancer therapy, we hope to provide a reference for future research.

Integrating aging biomarkers and immune function to predict kidney health: insights from the future of families and child wellbeing study.

Biomarkers of biological aging predict health outcomes more accurately than chronological age. This study examines the relationship between aging biomarkers, immune function, and kidney health using the Future of Families and Child Wellbeing Study Biomarker Dataset. Using Wave 5 (year 9) and Wave 6 (year 15), we examined biomarker data from a total of 4898 individuals. The panel of aging biomarkers, comprised of epigenetic clocks (GrimAge, Horvath), immune function markers (CD8 + T cells, plasmablasts), and metabolic indicators (GDF-15, leptin), was evaluated in depth. We used principal component analysis (PCA) and K-means clustering for subtype identification. A random forest regressor was employed to predict kidney function using Cystatin C levels, and the importance of features was assessed. Three clusters with unique biological age and immune function profiles were identified. Cluster 1 had younger biological age markers. In Cluster 2, both GrimAge and GDF-15 levels were significantly increased, indicating an elevated risk for age-related diseases. According to predictive modeling, GrimAge, Pack Years, and immune function markers had the strongest influence on Cystatin C levels (R2 = 0.856). The incorporation of immune aging markers enhanced the predictive power, emphasizing the importance of immunosenescence in renal health. Aging biomarkers and immune function significantly impact kidney health prediction. The study results call for the utilization of extensive biomarker tests for individualized elderly care and early recognition of kidney deterioration. Clinical practice can be improved by incorporating biological age assessments for the prevention and management of age-related diseases.

Deciphering the impact of TERT/telomerase on immunosenescence and T cell revitalization.

Immunosenescence impacts both the innate and adaptive immune systems, predominantly affecting certain immune cell types. A notable manifestation of immunosenescence is the diminished efficacy of adaptive immunity. The excessive senescence of immune cells, particularly T cells, leads to marked immune deficiency, consequently escalating the risk of infections, tumors, and age-associated disorders. Lymphocytes, especially T cells, are subject to both replicative and premature senescence. Telomerase reverse transcriptase (TERT) and telomerase have multifaceted roles in regulating cellular behavior, possessing the ability to counteract both replicative and premature senescence in lymphocytes. This review encapsulates recent advancements in understanding immunosenescence, with a focus on T cell senescence, and the regulatory mechanisms involving TERT/telomerase. Additionally, it comprehensively discusses strategies aimed at inhibiting immunosenescence by augmenting TERT/telomerase activity.

Antibiotic Resistance in the Elderly: Mechanisms, Risk Factors, and Solutions.

Antibiotic resistance presents a critical challenge in healthcare, particularly among the elderly, where multidrug-resistant organisms (MDROs) contribute to increased morbidity, mortality, and healthcare costs. This review focuses on the mechanisms underlying resistance in key bacterial pathogens and highlights how aging-related factors like immunosenescence, frailty, and multimorbidity increase the burden of infections from MDROs in this population. Novel strategies to mitigate resistance include the development of next-generation antibiotics like teixobactin and cefiderocol, innovative therapies such as bacteriophage therapy and antivirulence treatments, and the implementation of antimicrobial stewardship programs to optimize antibiotic use. Furthermore, advanced molecular diagnostic techniques, including nucleic acid amplification tests and next-generation sequencing, allow for faster and more precise identification of resistant pathogens. Vaccine development, particularly through innovative approaches like multi-epitope vaccines and nanoparticle-based platforms, holds promise in preventing MDRO infections among the elderly. The role of machine learning (ML) in predicting resistance patterns and aiding in vaccine and antibiotic development is also explored, offering promising solutions for personalized treatment and prevention strategies in the elderly. By integrating cutting-edge diagnostics, therapeutic innovations, and ML-based approaches, this review underscores the importance of multidisciplinary efforts to address the global challenge of antibiotic resistance in aging populations.

Immunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors.

The process of aging leads to a progressive decline in the immune system function, known as immunosenescence, which compromises both innate and adaptive responses. This includes impairments in phagocytosis and decreased production, activation, and function of T- and B-lymphocytes, among other effects. Bacteria exploit immunosenescence by using various virulence factors to evade the host's defenses, leading to severe and often life-threatening infections. This manuscript explores the complex relationship between immunosenescence and bacterial virulence, focusing on the underlying mechanisms that increase vulnerability to bacterial infections in the elderly. Additionally, it discusses how machine learning methods can provide accurate modeling of interactions between the weakened immune system and bacterial virulence mechanisms, guiding the development of personalized interventions. The development of vaccines, novel antibiotics, and antivirulence therapies for multidrug-resistant bacteria, as well as the investigation of potential immune-boosting therapies, are promising strategies in this field. Future research should focus on how machine learning approaches can be integrated with immunological, microbiological, and clinical data to develop personalized interventions that improve outcomes for bacterial infections in the growing elderly population.

Effect of a Multifactorial Weight Loss Intervention on HDL Cholesterol Efflux Capacity and Immunosenescence: A Randomized Controlled Trial.

OBJECTIVE: Life expectancy and obesity prevalence are increasing worldwide, leading to an increase in the prevalence of cardiovascular disease. High-density lipoprotein (HDL) functionality and immunosenescence play key roles in cardiovascular disease, longevity, and quality of aging. Both molecular hallmarks of aging are impacted by obesity and metabolic syndrome and can be modulated by lifestyle. We aimed to evaluate the effect of a lifestyle intervention focused on an energy-reduced Mediterranean diet (erMedDiet), physical activity (PA), and behavioral support on HDL cholesterol efflux capacity (CEC) and immunosenescence. METHOD: CEC and immunosenescent T cells were determined in 60 participants from the control group (CG) and 56 from the intervention group (IG) of the PREDIMED-Plus trial at baseline and after 1 and 3 years of follow-up. PREDIMED-Plus is a randomized, controlled, parallel-group trial with an IG of erMedDiet, PA promotion, and behavioral support for weight loss and a CG of usual primary care advice. The sample included 116 volunteers from the PREDIMED-Plus-IMDEA subsample of the PREDIMED-Plus trial. Men aged 55 to 75 years and women aged 60 to 75 years with a body mass index between 27 and 40 kg/m2 and metabolic syndrome were included. RESULTS: Participants within the IG had significantly improved CEC (2.42% and 10.69% after 1 and 3 years of follow-up) and a decreased in senescent T cell profile (-3.32% ± 12.54% and -6.74% ± 11.2%, p < 0.001, after 1 and 3 years of follow-up). Baseline obesity status impacted the response to the intervention. CONCLUSIONS: A weight loss intervention program with erMedDiet and PA ameliorated senescence markers.

Terminally differentiated effector memory T cells in kidney transplant recipients: New crossroads.

Immunosenescence, the age-related dysregulation of innate and adaptive immunity, impairs immune response and increases inflammation, leading to higher infection and cardiovascular risks, particularly outside the field of transplantation. In kidney transplant recipients (KTRs), conditions like cytomegalovirus infection, old age, uremia, smoking, and diabetes, linked to poor outcomes, are associated with enhanced immunosenescence. Recent studies highlight the pathogenic role of cytotoxic T cells, particularly terminally differentiated effector memory T cells that reexpress CD45RA (TEMRA), in graft dysfunction. A higher proportion of circulating CD8+ TEMRA cells is observed in KTRs with chronic rejection. In antibody-mediated rejection, they invade the graft by superior chemotactic properties and binding to human leukocyte antigen (HLA) antibodies through FcγRIIIa (CD16). Also in microvascular inflammation without donor-specific antibodies, and even in patients without rejection but faster decline of kidney function, intragraft CD8+ TEMRA cells were instrumental. CD8+ TEMRA cells may explain the unresolved dismal graft outcomes associated with donor age and cytomegalovirus-serostatus mismatching and could become a novel therapeutic target in KTRs.

Targeting immunosenescence for improved tumor immunotherapy.

Tumor immunotherapy has significantly transformed the field of oncology over the past decade. An optimal tumor immunotherapy would ideally elicit robust innate and adaptive immune responses within tumor immune microenvironment (TIME). Unfortunately, immune system experiences functional decline with chronological age, a process termed "immunosenescence," which contributes to impaired immune responses against pathogens, suboptimal vaccination outcomes, and heightened vulnerability to various diseases, including cancer. In this context, we will elucidate hallmarks and molecular mechanisms underlying immunosenescence, detailing alterations in immunosenescence at molecular, cellular, organ, and disease levels. The role of immunosenescence in tumorigenesis and senescence-related extracellular matrix (ECM) has also been addressed. Recognizing that immunosenescence is a dynamic process influenced by various factors, we will evaluate treatment strategies targeting hallmarks and molecular mechanisms, as well as methods for immune cell, organ restoration, and present emerging approaches in immunosenescence for tumor immunotherapy. The overarching goal of immunosenescence research is to prevent tumor development, recurrence, and metastasis, ultimately improving patient prognosis. Our review aims to reveal latest advancements and prospective directions in the field of immunosenescence research, offering a theoretical basis for development of practical anti-immunosenescence and anti-tumor strategies.

The effect of abnormal lipid metabolism on immunosenescence of the colonic lamina propria in mice of different ages.

Immunosenescence is an age-associated change in immunological function. The intestinal mucosal immune system is considered the largest immune system in the human body, and its immunosenescence is closely related to the occurrence and development of many diseases. In recent years, studies have identified a crucial correlation between abnormal lipid metabolism induced by high-fat diet (HFD) and immunity, but the effect and mechanism of HFD on colonic mucosal immunosenescence are still unclear. In this study, we established an abnormal lipid metabolism model at different ages by feeding male wild-type mice HFD and compared the immunosenescence of the spleen, which reflects systemic immunity, and the colonic lamina propria (LP), which reflects local immunity. The results showed that HFD could lead to abnormal lipid metabolism at different ages, accelerate systemic and local immunosenescence, and increase the expression of inflammatory factors in colonic tissue. The levels of abnormal biochemical indicators induced by HFD were closely related to the proportions of T cell subsets associated with immunosenescence. Overall, the results showed that HFD had the most significant impact on aged mice. This study provides new ideas for further understanding the relationship between abnormal lipid metabolism and intestinal mucosal immunosenescence.

Immunosenescence and inflammaging: Mechanisms and role in diseases.

Age-related changes initiate a cascade of cellular and molecular alterations that lead to immune system dysfunction or abnormal activation, predisposing individuals to age-related diseases. This phenomenon, commonly referred to as immunosenescence, highlighting aging-associated progressive decline of the immune system. Moreover, mounting evidence suggests that immunosenescence contributes to a related pathological phenomenon known as inflammaging. Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging, occurring despite the absence of overt stimuli. In the body, inflammation is typically activated in response to overt stimuli such as bacterial/microbial invasion or a pathological state, however, inflammaging occurrence and its underpinning mechanisms seem to be independent and in the absence of such stimuli. Despite recent advancements in molecular characterization and the scrutiny of disease relevance, these two interconnected concepts have remained largely unexplored and unrecognized. In this comprehensive review, we aim to shed light on the mechanistic and cellular aspects of immunosenescence and inflammaging, as well as their pivotal roles in the pathogenesis of aging-related diseases, including cancer, infections, dementia, and neurodegenerative disorders.