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Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging‐associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non‐activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito‐transferred aged CD4+ T cells showed improvements in activation‐induced TCR‐signaling kinetics displaying markers of activation (CD25), increased IL‐2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG‐KO) showed that adoptive transfer of mito‐transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging. [ABSTRACT FROM AUTHOR]

Abstract Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging‐associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non‐activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito‐transferred aged CD4+ T cells showed improvements in activation‐induced TCR‐signaling kinetics displaying markers of activation (CD25), increased IL‐2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG‐KO) showed that adoptive transfer of mito‐transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.

The aging population is increasing worldwide, and there is also an increase in the aging population living with overweight and obesity, due to changes in lifestyle and in dietary patterns that elderly individuals experience later in life. Both aging and obesity are conditions of accelerated metabolic dysfunction and dysregulated immune responses. In this review, we summarize published findings showing that obesity induces changes in humoral immunity similar to those induced by aging and that the age-associated B cell defects are mainly due to metabolic changes. We discuss the role of the obese adipose tissue in inducing dysfunctional humoral responses and autoimmune Ab secretion., (Copyright © 2024 by The American Association of Immunologists, Inc.)

The immune system is a major regulatory system of the body, that is composed of immune cells, immune organs, and related signaling factors. As an organism ages, observable age-related changes in the function of the immune system accumulate in a process described as 'immune aging. Research has shown that the impact of aging on immunity is detrimental, with various dysregulated responses that affect the function of immune cells at the cellular level. For example, increased aging has been shown to result in the abnormal chemotaxis of neutrophils and decreased phagocytosis of macrophages. Age-related diminished functionality of immune cell types has direct effects on host fitness, leading to poorer responses to vaccination, more inflammation and tissue damage, as well as autoimmune disorders and the inability to control infections. Similarly, age impacts the function of the immune system at the organ level, resulting in decreased hematopoietic function in the bone marrow, a gradual deficiency of catalase in the thymus, and thymic atrophy, resulting in reduced production of related immune cells such as B cells and T cells, further increasing the risk of autoimmune disorders in the elderly. As the immune function of the body weakens, aging cells and inflammatory factors cannot be cleared, resulting in a cycle of increased inflammation that accumulates over time. Cumulatively, the consequences of immune aging increase the likelihood of developing age-related diseases, such as Alzheimer's disease, atherosclerosis, and osteoporosis, among others. Therefore, targeting the age-related changes that occur within cells of the immune system might be an effective anti-aging strategy. In this article, we summarize the relevant literature on immune aging research, focusing on its impact on aging, in hopes of providing new directions for anti-aging research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In a Science paper, Park et al. identified interleukin (IL)-1α as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1α production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the LRRK2 gene affects risk for both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from R1441C-Lrrk2 knock-in mice and observed a biphasic, age-dependent effect of the R1441C-Lrrk2 mutation on peritoneal macrophage function. We report increases in antigen presentation, anti-inflammatory cytokine production, lysosomal activity, and pathogen uptake in peritoneal macrophages from young (2- to 3-month-old) female R1441C-Lrrk2 mice. Conversely, macrophages from aged (18- to 21-month-old) female R1441C-Lrrk2 mice exhibited decreased antigen presentation after inflammatory insult, decreased lysosomal function, and pathogen uptake, with a concomitant increase in DNA fragmentation in the presence of pathogens. This immune cell exhaustion phenotype was not observed in male R1441C-Lrrk2 mice and was driven by increased LRRK2 protein kinase activity. This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the R1441C- or Y1699C-LRRK2 mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.

Progressive decline of the adaptive immune system with increasing age coincides with a sharp increase in cancer incidence. In this study, we set out to understand whether deficits in antitumor immunity with advanced age promote tumor progression and/or drive resistance to immunotherapy. We found that multiple syngeneic cancers grew more rapidly in aged versus young adult mice, driven by dysfunctional CD8+ T-cell responses. By systematically mapping immune cell profiles within tumors, we identified loss of tumor antigen-specific CD8+ T cells as a primary feature accelerating the growth of tumors in aged mice and driving resistance to immunotherapy. When antigen-specific T cells from young adult mice were administered to aged mice, tumor outgrowth was delayed and the aged animals became sensitive to PD-1 blockade. These studies reveal how age-associated CD8+ T-cell dysfunction may license tumorigenesis in elderly patients and have important implications for the use of aged mice as preclinical models of aging and cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Intervertebral disc degeneration (IDD) is a major cause for low back pain. Studies showed the association between senescence and degenerative diseases. Cell senescence can promote the occurrence and development of degenerative diseases through multiple mechanisms including inflammatory stress, oxidative stress and nutritional deprivation. The roles of senescence and senescence-associated genes (SAGs) remains unknown in IDD., Methods: Four differently expressed SAGs were identified as hub SAGs using "limma" package in R. We then calculated the immune infiltration of IDD patients, and investigated the relation between hub SAGs and immune infiltration. Enrichment analysis was performed to explore the functions of hub SAGs in IDD. Nomogram and LASSO model based on hub SAGs was constructed to predict the risk of severe degeneration (SD) for IDD patients. Subsequently, single cell analysis was conducted to describe the expression pattern of hub SAGs in intervertebral disc tissue., Results: We identified ASPH, CCND1, IGFBP3 and SGK1 as hub SAGs. Further analysis demonstrated that the hub SAGs might mediate the development of IDD by regulating immune infiltration and multiple pathways. The LASSO model based on the four hub SAGs showed good performance in predicting the risk of SD. Single cell analysis revealed that ASPH, CCND1 and SGK1 mainly expressed in nucleus pulposus cells, while IGFBP3 mainly expressed in epithelial cells. Eleven candidate drugs targeting hub SAGS were predicted for IDD patients through Comparative Toxicogenomics Database (CDT). PCR and immunohistochemical analysis showed that the levels of four hub SAGs were higher in SD than MD (mild degeneration) patients., Conclusions: We performed a comprehensive analysis of SAGs in IDD, which revealed their functions and expression pattern in intervertebral disc tissue. Based on hub SAGs, we established a predictive model and explored the potential drugs. These findings provide new understandings of SAG mechanism and promising therapeutic strategies for IDD., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of Competing Interest None of the authors of this manuscript have anything to disclose regarding the conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The global spread of the Omicron variant strain BA.5/BF.7 has led to an increase in breakthrough infections. The elderly population shows different immune responses after infection due to the aging of the immune system, which has not been fully studied. The aim of this study was to investigate the effect of aging on immune response after breakthrough infection of Omicron BA.5/BF.7 variant, especially the changes of protein immune mechanism. The study analyzed the concentration of antibodies in serum and their ability to neutralize the mutant strain by comparing the immune response of the elderly population and the young population after infection. Proteomics techniques were used to assess differences in the expression of key proteins in immune cells of different age groups. The study found that older subjects produced lower levels of antibodies after infection than younger subjects and showed a significantly reduced ability to neutralize against BA.5/BF.7. In addition, proteomic analysis showed that the expression of proteins related to inflammation and apoptosis significantly increased in the immune cells of the elderly, while the proteins related to antiviral response and cell repair significantly decreased. These findings provide new ideas for immune intervention strategies in the elderly population, and emphasize the targeted research of anti-virus vaccines., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mosquitoes cannot use metabolism to regulate their body temperature and therefore climate warming is altering their physiology. Mosquitoes also experience a physiological decline with aging, a phenomenon called senescence. Because both high temperature and aging are detrimental to mosquitoes, we hypothesized that high temperatures accelerate senescence. Here, we investigated how temperature and aging, independently and interactively, shape the antimicrobial immune response of the mosquito Anopheles gambiae. Using a zone-of-inhibition assay that measures the antimicrobial activity of hemolymph, we found that antimicrobial activity increases following infection. Moreover, in infected mosquitoes, antimicrobial activity weakens as the temperature rises to 32°C, and antimicrobial activity increases from 1 to 5 days of age and stabilizes with further aging. Importantly, in E. coli-infected mosquitoes, higher temperature causes an aging-dependent decline in antimicrobial activity. Altogether, this study demonstrates that higher temperature can accelerate immune senescence in infected mosquitoes, thereby interactively shaping their ability to fight an infection., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan., Competing Interests: Competing interests J.G. has been a consultant for Unity Biotechnology, Geras Bio, Myricx Pharma and Merck KGaA. Pfizer and Unity Biotechnology have funded research in J.G.’s laboratory (unrelated to the work presented here). J.G. owns equity in Geras Bio. J.G. is a named inventor in Medical Research Council and Imperial College patents, both related to senolytic therapies (the patents are not related to the work presented here). The remaining authors declare no competing interests., (© 2024. The Author(s).)

While the main role of phagocytic scavenger cells consists of the neutralization and elimination of pathogens, they also keep the body fluids clean by taking up and breaking down waste material. Since a build-up of waste is thought to contribute to the aging process, these cells become particularly pertinent in the research field of aging. Nevertheless, a direct link between their scavenging functions and the aging process has yet to be established. Integrative approaches involving various model organisms hold promise to elucidate this potential, but are lagging behind since the diversity and evolutionary relationship of these cells across animal species remain unclear. In this perspective, we review the current knowledge associating phagocytic scavenger cells with aging in vertebrate and invertebrate animals, as well as put forward important questions for further exploration. Additionally, we highlight future challenges and propose a constructive approach for tackling them., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Inflammation and immunity contribute pivotally to diverse acute and chronic diseases. Inflammatory pathways have become increasingly targets for therapy. Yet, despite substantial similarity in mechanisms and pathways, the scientific, medical, pharma and biotechnology sectors have generally focused programs finely on a single disease entity or organ system. This insularity may impede progress in innovation and the harnessing of powerful new insights into inflammation biology ripe for clinical translation., Methods: A multidisciplinary thinktank reviewed highlights how inflammation contributes to diverse diseases, disturbed homeostasis, ageing and impaired healthspan. We explored how common inflammatory and immune mechanisms that operate in key conditions in their respective domains. This consensus review highlights the high degree of commonality of inflammatory mechanisms in a diverse array of conditions that together contribute a major part of the global burden of morbidity and mortality and present an enormous challenge to public health and drain on resources., Results: We demonstrate how that shared inflammatory mechanisms unite many seemingly disparate diseases, both acute and chronic. The examples of infection, cardiovascular conditions, pulmonary diseases, rheumatological disorders, dementia, cancer and ageing illustrate the overlapping pathogenesis. We outline opportunities to synergize, reduce duplication and consolidate efforts of the clinical, research and pharmaceutical communities. Enhanced recognition of these commonalties should promote cross-fertilization and hasten progress in this rapidly moving domain., Conclusions: Greater appreciation of the shared mechanisms should simplify understanding seemingly disparate diseases for clinicians and help them to recognize inflammation as a therapeutic target which the development of novel therapies is rendering actionable., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Immunosenescence, the aging of the immune system, leads to functional deficiencies, particularly in T cells, which undergo significant changes. While numerous studies have investigated age-related T-cell phenotypes in healthy aging, senescent T cells have also been observed in younger populations during pathological conditions like cancer. This review summarizes the recent advancements in age-associated alterations and markers of T cells, mechanisms, and the relationship between senescent T cells and the tumor microenvironment. We also discuss potential strategies for targeting senescent T cells to prevent age-related diseases and enhance tumor immunotherapy efficacy., (© 2024 Wiley‐VCH GmbH.)

Aging profoundly affects the immune system leading to an increased propensity for inflammation. Age-related dysregulation of immune cells is implicated in the development and progression of numerous age-related diseases such as: cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Monocytes and monocyte-derived macrophages, being important players in the inflammatory response, significantly influence the aging process and the associated increase in inflammatory disease risk. Ischemic stroke is among age-related diseases where inflammation, particularly monocyte-derived macrophages, plays an important deteriorating role but could also strongly promote post-stroke recovery. Also, biological sex influences the incidence, presentation, and outcomes of ischemic stroke, reflecting both biological differences between men and women. Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of genes implicated in stroke-related inflammation and post-stroke tissue regeneration depends on age and sex. A flow cytometry analysis of blood samples from 44 healthy volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of NK-cells increased in females. The proportion of B-cells decreased in both sexes with age. Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly, ANXA1 and CD36 showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increasing age. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes. Understanding these dynamics could pave the way for targeted interventions and personalized approaches in post-stroke care, particularly for the aging population and individuals of different sexes., Competing Interests: Dr Lindgren has served as a national leader for Sweden and Denmark for the NAVIGATE study. He is a national leader for Sweden for 2 ongoing stroke trials and the local PI for the StrokeCLOSE study. He reports personal fees from Arega, Bayer, Astra Zeneca, BMS Pfizer, and Novo Nordisk. The reported competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Tampé et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: It has been previously demonstrated that intestinal barrier damage is one of the underlying mechanisms leading to frailty in non-HIV-infected aging populations. However, there is a paucity of direct evidence which demonstrates the association between intestinal barrier damage and frailty in people living with HIV (PLWH)., Methods: The present study is a retrospective case control study. Participants older than 50 years old were stratified into a frail/pre-frail group (case group) and non-frail group (control group) according to the Fried frailty phenotype. We collected and curated data concerning socio-demographic variables, psychological states and social functioning, and clinical information associated with the identification of biomarkers of intestinal barrier damage, microbial translocation, and levels of inflammatory cytokines of participants., Results: The case group had significantly higher levels of Reg-3α ( p =0.042) and I-FABP ( p =0.045) compared to the control group. We further observed, after adjusting for confounding factors by logistic regression analysis, that I-FABP levels remained significantly higher in the case group compared to the control group ( p =0.033). Also, Fried Phenotype scores positively correlated with I-FABP levels (r s =0.21, p =0.01), LPS levels (r s =0.20, p =0.02), and sCD14 levels (r s =0.18, p =0.04). Moreover, the study confirmed both the positive correlation between inflammatory cytokines (IL-6 and IP-10) with frailty in aging PLWH, and between inflammatory cytokines (IL-6, IL-8 and IP-10) with biomarkers of intestinal barrier dysfunction in older PLWH., Conclusion: The present study indicates that the inflammation induced by intestinal barrier damage/dysfunction is likely to contribute to frailty in aging PLWH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Ouyang, Yan, Lu, Harypursat, Wu and Chen.)

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

Modified cholesterols such as oxidized low-density lipoprotein (OxLDL) contribute to atherosclerosis and other disorders through the promotion of foam cell formation and inflammation. In recent years, it has become evident that immune cell responses to inflammatory molecules such as OxLDLs depend on cellular metabolic functions. This review examines the known effects of OxLDL on immunometabolism and immune cell responses in atherosclerosis and several other diseases. We additionally provide context on the relationship between OxLDL and aging/senescence and identify gaps in the literature and our current understanding in these areas.

Introduction: The proteome profile of the female Tenualosa ilisha (Hamilton, 1822), a species of great ecological and economic importance, across various age groups was investigated to comprehend the functional dynamics of the serum proteome for conservation and aquaculture, as well as sustain the population., Methods: Advanced liquid chromatography-tandem mass spectrometry LC-MS/MS-based proteomic data were analysed and submitted to the ProteomeXchange Consortium via PRIDE (PRoteomics IDEntifications database). Bioinformatics analysis of serum proteome have been done and it showed different proteins associated with GO Gene Ontology () terms, and the genes associated with enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways (such as phagosome, mTOR, Apelin signalling pathways, herpes simplex virus) implicated in immune responses., Results: The expression levels of important immunological proteins, such as those involved in cellular defence and inflammatory responses, were significantly different age-dependently. In this study, we annotated 952, 494, 415, and 282 proteins in year classes IV, III, II, and I Hilsa, respectively, and analysed their Protein-Protein Interaction (PPI) networks based on their functional characteristics. From year classes I to IV, new proteins appeared and were more than three-fold. Notably, class I hilsa displayed a lower abundance of proteins than class IV hilsa., Discussion: This is the first study, to the best of our knowledge, to report the analysis of the serum proteome of hilsa at different developmental stages, and the results can help improve the understanding of the mechanisms underlying the different changes in protein enrichment during migration in hilsa. This analysis also offers crucial insights into the immune system for hilsa conservation and management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chakraborty, Chakraborty, Das and Maity.)

Neonatal immune activation (NIA) through exposure to lipopolysaccharide (LPS) induces adult behavioral changes in rodents that resemble symptoms of developmental disorders, such as autism spectrum disorder. The neonatal timing of LPS exposure appears to play a crucial role in determining the nature and extent of long-term changes. This study aims to explore whether a 3-day LPS-NIA triggers sex- and age-related changes in gut function, potentially linking LPS-NIA to gastrointestinal dysfunction. Male and female Swiss mice received intraperitoneal injections of LPS or saline on postnatal days (PN) 3, 5, and 7. At PN35 (juvenile) and PN70 (adult), gut inflammation and oxidative stress were evaluated in addition to assessments of working memory, depressive-like symptoms, sociability, and repetitive behavior. Gut examination showed elevated C-X-C motif chemokine receptor 3 (CXCR3) in LPS-NIA mice, while MyD88 and Zonulin expressions were significantly higher only in adult LPS-NIA females. Interleukin (IL)-23 expression increased in juvenile and adult male and juvenile female LPS-NIA mice. Oxidative changes included decreased duodenal reduced glutathione (GSH) in juvenile females and ileal GSH in adult females exposed to LPS-NIA. Regarding behavioral alterations, adult LPS-NIA females exhibited depressive-like behavior. Working memory deficits were observed across all LPS-NIA groups. Only juvenile LPS-NIA females increased grooming, while rearing was higher in adult LPS-NIA mice of both sexes. The findings imply that LPS-NIA impacts intestinal barrier function and causes gut inflammatory alterations that are sex- and age-specific. These findings pave the way for exploring potential mechanisms that could contribute to LPS-induced gastrointestinal disturbances among individuals with ASD., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38 hi expression universally identified CD8 + and CD4 + RTEs. We further determined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-associated transcriptional reprogramming and shifts in cytokine production. Spectral cytometry profiling revealed two axes of aging common to naive CD8 + and CD4 + T cells: (1) a decrease in CD38 ++ cells (RTEs) and (2) an increase in CXCR3 hi cells. Identification of RTEs enables direct assessment of thymic health. Furthermore, resolving the dynamics of naive T cell remodeling yields insight into vaccination and infection responsiveness throughout aging., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

With the increasing prevalence of diabetes mellitus worldwide, type 2 diabetes mellitus (T2D) combined with cognitive impairment and aging has become one of the common and important complications of diabetes mellitus, which seriously affects the quality of life of the patients, and imposes a heavy burden on the patients' families and the society. Currently, there are no special measures for the treatment of cognitive impairment and aging in type 2 diabetes mellitus. Therefore, the search for potential biological markers of type 2 diabetes mellitus combined with cognitive impairment and aging is of great significance for future precisive treatment. We downloaded three gene expression datasets from the GEO database: GSE161355 (related to T2D with cognitive impairment and aging), GSE122063, and GSE5281 (related to Alzheimer's disease). Differentially expressed genes (DEGs) were identified, followed by gene set enrichment analysis (GSEA). A protein-protein interaction (PPI) network was constructed using the STRING database, and the top 15 hub genes were identified using the CytoHubba plugin in Cytoscape. Core genes were ultimately determined using three machine learning methods: LASSO regression, Support Vector Machine Recursive Feature Elimination (SVM-RFE), and Linear Discriminant Analysis (LDA). The diagnostic performance of these genes was assessed using ROC curve analysis and validated in an independent dataset (GSE5281). Regulatory genes related to ferroptosis were screened from the FerrDb database, and their biological functions were further explored through GO and KEGG enrichment analyses. Finally, the CIBERSORT algorithm was used to analyze immune cell infiltration, and the correlation between core genes and immune cell infiltration levels was calculated, leading to the construction of an mRNA-miRNA regulatory network. In the GSE161355 and GSE122063 datasets, 217 common DEGs were identified. GSEA analysis revealed their enrichment in the PI3K-PLC-TRK signaling pathway, TP53 regulation of metabolic genes pathway, Notch signaling pathway, among others. PPI network analysis identified 15 candidate core genes, and further selection using LASSO, LDA, and SVM-RFE machine learning algorithms resulted in 6 core genes: BCL6, TP53, HSP90AA1, CRYAB, IL1B, and DNAJB1. ROC curve analysis indicated that these genes had good diagnostic performance in the GSE161355 dataset, with TP53 and IL1B achieving an AUC of 0.9, indicating the highest predictive accuracy. BCL6, HSP90AA1, CRYAB, and DNAJB1 also had AUCs greater than 0.8, demonstrating moderate predictive accuracy. Validation in the independent dataset GSE5281 showed that these core genes also had good diagnostic performance in Alzheimer's disease samples (AUC > 0.6). Ferroptosis-related analysis revealed that IL1B and TP53 play significant roles in apoptosis and immune response. Immune cell infiltration analysis showed that IL1B is significantly positively correlated with infiltration levels of monocytes and NK cells, while TP53 is significantly negatively correlated with infiltration levels of follicular helper T cells. The construction of the miRNA-mRNA regulatory network suggested that miR-150a-5p might play a key role in the regulation of T2D-associated cognitive impairment and aging by TP53. This study, by integrating bioinformatics and machine learning methods, identified BCL6, TP53, HSP90AA1, CRYAB, IL1B, and DNAJB1 as potential diagnostic biomarkers for T2D with cognitive impairment and aging, with a particular emphasis on the significance of TP53 and IL1B in immune cell infiltration. These findings not only enhance our understanding of the molecular mechanisms linking type 2 diabetes to cognitive impairment and aging, providing new targets for early diagnosis and treatment, but also offer new directions and targets for basic research., (© 2024. The Author(s).)

The CD8＋ T cell response is the main determinant of viral clearance during influenza infection. However, influenza viral dynamics and the respective immune responses are affected by the host's age. To investigate age-related differences in the CD8＋ T cell immune response dynamics, we propose 16 ordinary differential equation models of existing experimental data. These data consist of viral titer and CD8＋ T cell counts collected periodically over a period of 19 days from adult and aged mice infected with influenza A/Puerto Rico/8/34 (H1N1). We use the corrected Akaike Information Criterion to identify the models which best represent the considered data. Our model selection process indicates differences in mechanisms which reduce the CD8＋ T cell response: linear downregulation is favored for adult mice, while baseline exponential decay is favored for aged mice. Parameter fitting of the top ranked models suggests that the aged population has reduced CD8＋ T cell proliferation compared to the adult population. More experimental work is needed to determine the specific immunological features through which age might cause these differences. A better understanding of the immunological mechanisms by which aging leads to discrepant CD8＋ T cell dynamics may inform future treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

PACAP (pituitary adenylate cyclase activating polypeptide) is a widespread neuropeptide with cytoprotective and anti-inflammatory effects. It plays a role in innate and adaptive immunity, but data are limited about gut-associated lymphoid tissue. We aimed to reveal differences in Peyer's patches between wild-type (WT) and PACAP-deficient (KO) mice. Peyer's patch morphology from young (3-months-old) and aging (12-15-months-old) mice was examined, along with flow cytometry to assess immune cell populations, expression of checkpoint molecules (PD-1, PD-L1, TIM-3, Gal-9) and functional markers (CD69, granzyme B, perforin) in CD3+, CD4+, and CD8+ T cells. We found slight differences between aging, but not in young, WT, and KO mice. In WT mice, aging reduced CD8+ T cell numbers frequency and altered checkpoint molecule expression (higher TIM-3, granzyme B; lower Gal-9, CD69). CD4+ T cell frequency was higher with similar checkpoint alterations, indicating a regulatory shift. In PACAP KO mice, aging did not change cell population frequencies but led to higher TIM-3, granzyme B and lower PD-1, PD-L1, Gal-9, and CD69 expression in CD4+ and CD8+ T cells, with reduced overall T cell activity. Thus, PACAP deficiency impacts immune dysfunction by altering checkpoint molecules and T cell functionality, particularly in CD8+ T cells, suggesting complex immune responses by PACAP, highlighting its role in intestinal homeostasis and potential implications for inflammatory bowel diseases.

The use of immunotherapy agents especially immune checkpoint inhibitors is growing, and toxicities known as immune-related adverse events affecting any organ system may develop as a consequence of the treatment. With an ageing population, a considerable number of patients who will receive these therapies will be older adults. However, older patients who have highly heterogenous clinical characteristics, age-related changes in the immune system, a higher prevalence of comorbidities and frailty have been poorly represented in clinical trials, leaving gaps in understanding the safety of immune checkpoint inhibitor agents in this subgroup. Therefore, the safety of immune checkpoint inhibitors is a primary point of consideration when treating older patients with cancer. The available evidence is conflicting, but it generally suggests that the incidence of immune-related adverse events is not necessarily higher in older patients, but it may have a different profile. It is important to also note that the management of immune-related adverse events can be a challenge in these patients, owing to the risks associated with the use of corticosteroids and a reduced physiological reserve. A comprehensive characterisation of immune ageing, potential biomarkers to predict immune-related adverse events, the use of measures for frailty, enrolling older patients with cancer to clinical trials and analysis of real-world data are necessary to improve the evidence-based decision making for immune checkpoint inhibitor treatment in a geriatric oncology population., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Extrahepatic, cell-autonomous, and/or intracellularly active complement components are increasingly recognized as key orchestrators of cell physiological processes. A recent study by Scott-Hewitt et al. demonstrates that microglia-derived C1q unexpectedly associates with the ribosomes of neurons in the aging murine brain, where it impacts protein translation and impairs the extinction of conditioned fear responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Ltd.)

During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Anti-aging immunity induced by vaccines was recently reported to enable the elimination of senescent cells. However, the initial immune response to vaccination declines with age, and there is evidence that elderly dendritic cells (DCs) have a reduced capacity to stimulate T cells. Identification of alternative anti-aging vaccine is therefore warranted. Here, we developed a DC vaccine that delivers a cationic protein (CP) fused with the seno-antigen peptides Gpnmb (Gpnmb-CP) into DCs. The Gpnmb-CP-pulsed DC vaccine (Gpnmb-CP-DC) efficiently presented antigens and activated CD8 + T cells, leading to enhanced immune cytotoxicity and memory responses in CD8 + T cells. Thus, the targeted anti-aging immunity triggered by Gpnmb-CP-DC has the ability to selectively eliminate senescent adipocytes and effectively improve age-related metabolic abnormalities in both high-fat diet (HFD)-induced young and aged mice models, as well as in natural aging mouse model. In contrast, the Gpnmb-CP protein vaccine exhibits minimal efficacy in aged mice model. Furthermore, we observed a decreased phagocytic capacity for antigens in aging DCs, accompanied by an upregulation of the immune checkpoint PDL1 expression and a noticeable decline in activated CD8 + T cell. Hence, Gpnmb-CP-DC emerges as a promising vaccine candidate, demonstrating the capacity to induce potent anti-aging immunity, mitigating adipose tissue senescence and metabolic abnormalities, while resilient to the senescent environment of the organism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Neuroinflammation is a feature of both neurodegenerative disease and normal brain aging. The roles of type I interferon (IFN-I) in the aged brain are incompletely understood. A recent article by Roy et al. reveals pervasive IFN-I activity in normal mouse brain aging, and highlights the importance of microglial IFN-I signaling in neuroinflammation., Competing Interests: Declaration of interests The authors declare no competing interests in relation to this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neutrophils are important effector cells of innate immunity and undergo several phenotypic changes after release from the bone marrow. Neutrophils with a late life cycle phenotype are often referred to as "aged" neutrophils. These neutrophils undergo functional changes that accompany stimuli of inflammation, tissue senescence and injury, inducing their maturation and senescence in the circulation and locally in damaged tissues, forming a unique late-life neutrophil phenotype. "Aged" neutrophils, although attenuated in antibacterial capacity, are more active in aging and age-related diseases, exhibit high levels of mitochondrial ROS and mitochondrial DNA leakage, promote senescence of neighboring cells, and exacerbate cardiac and vascular tissue damage, including vascular inflammation, myocardial infarction, atherosclerosis, stroke, abdominal aortic aneurysm, and SARS-CoV-2 myocarditis. In this review, we outline the phenotypic changes of "aged" neutrophils characterized by CXCR4 high /CD62L low , investigate the mechanisms driving neutrophil aging and functional transformation, and analyze the damage caused by "aged" neutrophils to various types of heart and blood vessels. Tissue injury and senescence promote neutrophil infiltration and induce neutrophil aging both in the circulation and locally in damaged tissues, resulting in an "aged" neutrophil phenotype characterized by CXCR4 high /CD62L low . We also discuss the effects of certain agents, such as neutralizing mitochondrial ROS, scavenging IsoLGs, blocking VDAC oligomers and mPTP channel activity, activating Nrf2 activity, and inhibiting neutrophil PAD4 activity, to inhibit neutrophil NET formation and ameliorate age-associated cardiovascular disease, providing a new perspective for anti-aging therapy in cardiovascular disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Peritoneal immune cell function is a reliable indicator of aging and longevity in mice and inflammaging is associated with a shorter lifespan. Nevertheless, it is unknown if the content of cytokines in these immune cells is linked to individual differences in lifespan. Therefore, this work aimed to investigate different peritoneal leukocyte populations and their content in intracellular pro-inflammatory (TNF and IL-6) and anti-inflammatory (IL-10) cytokines by flow cytometry in adult (10 months-old, n = 8) and old (18 months-old, n = 20) female Swiss/ICR mice. In addition, old mice were monitored longitudinally throughout their aging process, and the same markers were analyzed at the very old (24 months-old, n = 8) and long-lived (30 months-old, n = 4) ages. The longitudinal follow-up allowed us to relate the investigated parameters to individual lifespans. The results show that long-lived female mice exhibit an adult-like profile in most parameters investigated but also display specific immune adaptations, such as increased CD4+ and CD8+ T cells containing the pro-inflammatory TNF cytokine and CD4+ T cells and macrophages containing the anti-inflammatory cytokine IL-10. These adaptations may underlie their exceptional longevity. In addition, a negative correlation was obtained between the percentage of cytotoxic T cells, KLRG-1/CD4, large peritoneal macrophages, and the percentage of CD4+ T cells containing IL-6 and macrophages containing IL-10 in old age and lifespan, whereas a positive correlation was found between the CD4/CD8 ratio and the longevity of the animals at the same age. These results highlight the crucial role of peritoneal leukocytes in inflammaging and longevity., (© 2024. The Author(s).)

CMV drives the accumulation of virus-specific, highly differentiated CD8 memory T cells (memory inflation [MI]). In mice, MI was shown to directly correlate with the CMV infection dose, yet the CMV-associated CD8 MI plateaus over time. It is unclear how MI is regulated with aging. We infected young mice with 102, 104, and 106 PFU of murine CMV and confirmed that MI magnitude was directly proportional to the infectious dose, reaching a setpoint by midlife. By old age, MI subsided, most prominently in mice infected with 106 PFU, and reached statistical parity between groups in 26-mo-old mice. This corresponded to an age-related loss in lymphatic endothelial cells in lymph nodes, recently shown to be sufficient to drive MI in mice. We propose that MI size and persistence over the lifespan is controlled by the size of the lymphatic endothelial cell niche, whose shrinking leads to reduced MI with aging., (Copyright © 2024 by The American Association of Immunologists, Inc.)

The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues. Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8 + T and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8 + T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors. Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process., (© 2024. The Author(s).)

Objective: Polyphenols are organic compounds with diverse biological activities such as anti-inflammatory and antioxidant effects, making them important candidates for the development of anti-aging drugs. In this systematic review, we aimed to answer the question: can plant-derived polyphenols have an immunomodulatory effect in experimental models of aging?, Methods: We systematically searched Web of Science, MEDLINE/Pubmed, and Embase to select articles using the following combinations of terms and synonyms: polyphenols, phenols, senescence, aging, and immune. The selected articles were evaluated for reporting quality and risk-of-bias according to standard guidelines., Results: The most used polyphenol was resveratrol, followed by curcumin, salidroside, and gallic acid. These molecules demonstrated an ability to restore immune function both in vitro and in vivo . The mechanism of action was not completely elucidated in these studies, but inhibition of NF-kB signaling, and antioxidant properties seemed to account for the anti-aging effects. All articles included in the review had good quality of reporting but failed to describe an adequate sample size, criteria for inclusion/exclusion, randomization, and blinding., Conclusion: We conclude that polyphenols are promising immunomodulatory substances for use in anti-aging therapies. However, more research with standardized analysis is needed to understand the role of these molecules in the prevention or reduction of damage associated with the aging process, as well as to determine the safety profile and consequences of systemic action.

Aging is one of the biggest risk factors for cancer development. More than 85% of all cancers occur in individuals above 55 years old, often accompanied by age-associated immune defects. Previous studies on the tumor microenvironment during aging have identified several factors, such as the roles of fibroblasts, immunosuppression, and metastasis. However, the aging-associated defects in antitumor immunity, particularly with regard to T cells, remain underexplored. Recent findings by Zhivaki and colleagues suggest that age-related immune defects affecting antitumor responses involve reduced levels of CD8+ T cells and compromised dendritic cell (DC) functions such as antigen presentation and migration. Their study demonstrates that a hyperactive DC vaccine can restore DC functions in older mice. Furthermore, these hyperactive DCs, characterized by increased IL1β production and better migratory capability to the lymph node, promote the development of cytolytic CD4+ T cells exhibiting Th1-like phenotypes. This research reveals mechanisms underlying the response to hyperactive DC vaccines in older mice and highlights the critical role of cytolytic CD4+ T cells as substitutes for CD8+ T cells in driving antitumor immunity and achieving long-term tumor control in older mice., (©2024 American Association for Cancer Research.)

The California sea hare (Aplysia californica) is a model for age associated cognitive decline. Recent researched identified a novel nidovirus, Aplysia Abyssovirus 1, with broad tropism enriched in the Aplysia nervous system. This virus is ubiquitous in wild and maricultured, young and old animals without obvious pathology. Here we re-evaluated gene expression data from several previous studies to investigate differential expression in the nervous system and gill in response to virus and aging as well as the mutational spectrum observed in the viral sequences obtained from these datasets. Viral load and age were highly correlated, indicating persistent infection. Upregulated genes in response to virus were enriched for immune genes and signatures of ER and proteostatic stress, while downregulated genes were enriched for mitochondrial metabolism. Differential expression with respect to age suggested increased iron accumulation and decreased glycolysis, fatty acid metabolism, and proteasome function. Interaction of gene expression trends associated with viral infection and aging suggest that viral infection likely plays a role in aging in the Aplysia nervous system. Mutation analysis of viral RNA identified signatures suggesting ADAR and AID/APOBEC like deaminase act as part of Aplysia anti-viral defense., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, it is characterized how aging induces changes in immunological signatures that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment both locally and regionally in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improves healing and restores therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers., Competing Interests: Declaration of competing interest Alexis E Carey reports financial support was provided by Howard Hughes Medical Institute. Ashani Weeraratna reports a relationship with Melanoma Research Foundation that includes: board membership. Ashani Weeraratna reports a relationship with Samuel Waxman Cancer Research Foundation that includes: consulting or advisory. Ashani Weeraratna reports a relationship with Regain Therapeutics that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Loss of proper T-cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG-1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age-related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro-inflammatory factors. To develop therapies against pathologies caused by defective T-cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age-related diseases., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Age-related thymic involution is characterized by the loss of T cell development and the supporting epithelial network, which are replaced by adipose tissue. We previously showed that aging functionally impairs lymphohematopoietic progenitor cells, including thymic early T cell progenitors (ETPs), contributing to thymic involution. Considering that the thymic microenvironment is essential for thymocyte incubation, we aimed to investigate its role in age-related thymic involution and the mechanisms underlying these changes. The challenge in studying these processes led us to transplant T cell-depleted fetal thymus tissue into the kidney capsule of aged mice. This model allowed us to identify the mechanisms driving age-related changes in the thymic microenvironment and to assess whether these changes could be reversed. Flow cytometry was used to detect naïve T cells (CD62L + CD44 - ), including CD4 CD8 double-negative, double-positive, and single-positive T cells. Real-time PCR was used to detect and quantify signal-joint T cell receptor excision circles. We rearranged δRec-ΨJα in murine peripheral blood leukocytes to evaluate the thymic output of newly developed naïve T cells in the mice and gene expression in the thymus. Age-related thymic involution decreased naïve T cells and increased memory T cells, while fetal thymus transplantation improved thymic output and T cell production and reversed the impairment of thymopoiesis due to thymic involution in aged mice. Furthermore, the expression of key cytokines was restored and ETPs in the aged mice showed normal thymic T cell development. Our study suggests that degenerative changes in the thymic microenvironment are the primary cause of thymic dysfunction, leading to immunosenescence associated with age-related thymic involution., Competing Interests: Declarations Ethical approval All animal experiments were approved by Shenzhen Guangming District People’s Hospital in accordance with the National Institutes of Health’s Guidelines for the Care and Use of Laboratory Animals (approval number: LL-KT-2021042). Conflict of interest The authors declare no Conflict of interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

CD4 + T cells play a notable role in immune protection at different stages of life. During aging, the interaction between the body's internal and external environment and CD4 + T cells results in a series of changes in the CD4 + T cells pool making it involved in immunosenescence. Many studies have extensively examined the subsets and functionality of CD4 + T cells within the immune system, highlighted their pivotal role in disease pathogenesis, progression, and therapeutic interventions. However, the underlying mechanism of CD4 + T cells senescence and its intricate association with diseases remains to be elucidated and comprehensively understood. By summarizing the immunosenescent progress and network of CD4 + T cell subsets, we reveal the crucial role of CD4 + T cells in the occurrence and development of age-related diseases. Furthermore, we provide new insights and theoretical foundations for diseases targeting CD4 + T cell subsets aging as a treatment focus, offering novel approaches for therapy, especially in infections, cancers, autoimmune diseases, and other diseases in the elderly., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

As a consequence of increased lifespan and rising number of elderly individuals developing end-stage organ disease, the higher demand for organs along with a growing availability for organs from older donors pose new challenges for transplantation. During aging, dynamic adaptations in the functionality and structure of the biological systems occur. Consistently, immunosenescence (IS) accounts for polydysfunctions within the lymphocyte subsets, and the onset of a basal but persistent systemic inflammation characterized by elevated levels of pro-inflammatory mediators. There is an emerging consensus about a causative link between such hallmarks and increased susceptibility to morbidities and mortality, however the role of IS in solid organ transplantation (SOT) remains loosely addressed. Dissecting the immune-architecture of immunologically-privileged sites may prompt novel insights to extend allograft survival. A deeper comprehension of IS in SOT might unveil key standpoints for the clinical management of transplanted patients., Competing Interests: Declaration of competing interest The Authors have no conflict of interests to disclosure., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Human cytomegalovirus (hCMV) is a ubiquitous latent persistent herpesvirus infecting 60-90% of the population worldwide. hCMV carriage in immunocompetent people is asymptomatic; thus, hCMV can be considered a component of normative aging. However, hCMV powerfully modulates many features of the immune, and likely other, systems and organs. Questions remain as to how hCMV carriage affects the human host. We used anti-CMV antibody titers as a stratifying criterion to examine the impact of "intensity" of hCMV infection as a potential biomarker of aging, inflammation, and immune homeostasis in a cohort of 247 participants stratified into younger (21-40 years) and older (> 65 years of age) groups. We showed that anti-CMV antibody titers increased with age and directly correlated to increased levels of soluble tumor necrosis factor (sTNFR) I in younger but not older participants. CD8 + cell numbers were reduced in the older group due to the loss in CD8 + T naïve (Tn) cells. In CMV carriers and, in particular, in anti-CMV Ab-high participants, this loss was mitigated or reversed by an increase in the numbers of CD8 + T effector memory (Tem) and T effector memory reexpressing CD45RA (Temra) cells. Analysis of CD38, HLA-DR, and CD57 expression revealed subset (CD4 or CD8)-specific changes that correlated with anti-CMV Ab levels. In addition, anti-CMV Ab levels predicted anti-CMV CD8 T cell responsiveness to different CMV open reading frames (ORFs) selectively in older participants, which correlated to the transcriptional order of expression of specific CMV ORFs. Implications of these results for the potential predictive value of anti-CMV Ab titers during aging are discussed., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

The transcription factor HSF-1 (heat shock factor 1) acts as a master regulator of heat shock response in eukaryotic cells to maintain cellular proteostasis. The protein has a protective role in preventing cells from undergoing ageing, and neurodegeneration, and also mediates tumorigenesis. Thus, modulating HSF-1 activity in humans has a promising therapeutic potential for treating these pathologies. Loss of HSF-1 function is usually associated with impaired stress tolerance. Contrary to this conventional knowledge, we show here that inactivation of HSF-1 in the nematode Caenorhabditis elegans results in increased thermotolerance at young adult stages, whereas HSF-1 deficiency in animals passing early adult stages indeed leads to decreased thermotolerance, as compared to wild-type. Furthermore, a gene expression analysis supports that in young adults, distinct cellular stress response and immunity-related signaling pathways become induced upon HSF-1 deficiency. We also demonstrate that increased tolerance to proteotoxic stress in HSF-1-depleted young worms requires the activity of the unfolded protein response of the endoplasmic reticulum and the SKN-1/Nrf2-mediated oxidative stress response pathway, as well as an innate immunity-related pathway, suggesting a mutual compensatory interaction between HSF-1 and these conserved stress response systems. A similar compensatory molecular network is likely to also operate in higher animal taxa, raising the possibility of an unexpected outcome when HSF-1 activity is manipulated in humans., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Vaccination-induced protection against influenza is greatly diminished and increasingly heterogeneous with age. We investigated longitudinally (up to five time points) a cohort of 234 vaccinated >65-year-old vaccinees with adjuvanted vaccine FluAd across two independent seasons. System-level analyses of multiomics datasets measuring six modalities and serological data revealed that poor responders lacked time-dependent changes in response to vaccination as observed in responders, suggestive of systemic dysregulation in poor responders. Multiomics integration revealed key molecules and their likely role in vaccination response. High prevaccination plasma interleukin-15 (IL-15) concentrations negatively associated with antibody production, further supported by experimental validation in mice revealing an IL-15-driven natural killer cell axis explaining the suppressive role in vaccine-induced antibody production as observed in poor responders. We propose a subset of long-chain fatty acids as modulators of persistent inflammation in poor responders. Our findings provide a potential link between low-grade chronic inflammation and poor vaccination response and open avenues for possible pharmacological interventions to enhance vaccine responses.