Identifying an immunosenescence-associated gene signature in gastric cancer by integrating bulk and single-cell sequencing data.

It has been believed that immunosenescence plays a crucial role in tumorigenesis and cancer therapy. Nevertheless, there is still a lack of understanding regarding its role in determining clinical outcomes and therapy selection for gastric cancer patients, due to the lack of a feasible immunosenescence signature. Therefore, this research aims to develop a gene signature based on immunosenescence, which is used for stratification of gastric cancer. By integrative analysis of bulk transcriptome and single-cell data, we uncovered immunosenescence features in gastric cancer. Random forest algorithm was used to select hub genes and multivariate Cox algorithm was applied to construct a scoring system to evaluate the prognosis and the response to immunotherapy and chemotherapy. The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) cohort was implemented as the training cohort and two independent cohorts from the Gene Expression Omnibus (GEO) database were used for validation. The model was further tested by our Fudan cohort. In this study, immunosenescence was identified as a hallmark of gastric cancer that is linked with transcriptomic features, genomic variations, and distinctive tumor microenvironment (TME). Four immunosenescence genes, including APOD, ADIPOR2, BRAF, and C3, were screened out to construct a gene signature for risk stratification. Higher risk scores indicated strong predictive power for poorer overall survival. Notably, the risk score signature could reliably predict response to chemotherapy and immunotherapy, with patients with high scores benefiting from immunotherapy and patients with low scores responding to chemotherapy. We report immunosenescence as a hitherto unheralded hallmark of gastric cancer that affects prognosis and treatment efficiency.

Relations of optimism and purpose in life to immune markers in aging.

OBJECTIVE: Optimism and purpose in life are associated with improved health outcomes. More information is needed on biological mechanisms, including immunosenescence. We investigated if psychological well-being is associated with healthier immunosenescence-related measures including naïve and terminally differentiated CD4+ and CD8+ T cell percentages, CD4+:CD8+, and cytomegalovirus (CMV) IgG response. METHODS: Participants were adults over age 50 from the Health and Retirement Study. Optimism was measured using the Life Orientation Test Revised. Purpose in life was assessed using the subscale from the Ryff psychological well-being measure. We examined the cross-sectional associations of optimism and purpose in life with measures of T cell subsets using linear regression and with CMV IgG using ordered logit regression, controlling for potential confounding factors. RESULTS: The final analytic sample ranged from 7250 to 7870. After adjusting for sociodemographic factors, a 1-SD increment in optimism was associated with the percentage of naïve CD4+ T cells increasing by 0.6 (95%CI 0.2%, 1.0%). A 1-SD increment in purpose in life was associated with the percentage of naïve CD4+ T cells increasing by 0.9 (95%CI 0.5%, 1.3%) after adjusting for sociodemographic factors and the association was maintained after further adjustments for health conditions, depression, and health behaviors. For naïve CD8+ T cell percentages, CD4:CD8 ratios, and CMV IgG antibodies, associations were seen only in models that adjusted for age. No significant associations were seen in any models for the terminally differentiated CD4+ and CD8+ T cells. CONCLUSIONS: We found associations of optimism and purpose in life with naïve CD4+ T cell percentages.

Multi-omics and single cell characterization of cancer immunosenescence landscape.

Cellular senescence (CS) is closely related to tumor progression. However, the studies about CS genes across human cancers have not explored the relationship between cancer senescence signature and telomere length. Additionally, single-cell analyses have not revealed the evolutionary trends of malignant cells and immune cells at the CS level. We defined a CS-associated signature, called "senescence signature", and found that patients with higher senescence signature had worse prognosis. Higher senescence signature was related to older age, higher genomic instability, longer telomeres, increased lymphocytic infiltration, higher pro-tumor immune infiltrates (Treg cells and MDSCs), and could predict responses to immune checkpoint inhibitor therapy. Single-cell analysis further reveals malignant cells and immune cells share a consistent evolutionary trend at the CS level. MAPK signaling pathway and apoptotic processes may play a key role in CS, and senescence signature may effectively predict sensitivity of MEK1/2 inhibitors, ERK1/2 inhibitors and BCL-2 family inhibitors. We also developed a new CS prediction model of cancer survival and established a portal website to apply this model ( https://bio-pub.shinyapps.io/cs_nomo/ ).

Diverging patterns in innate immunity against respiratory viruses during a lifetime: lessons from the young and the old.

Respiratory viral infections frequently lead to severe respiratory disease, particularly in vulnerable populations such as young children, individuals with chronic lung conditions and older adults, resulting in hospitalisation and, in some cases, fatalities. The innate immune system plays a crucial role in monitoring for, and initiating responses to, viruses, maintaining a state of preparedness through the constant expression of antimicrobial defence molecules. Throughout the course of infection, innate immunity remains actively involved, contributing to viral clearance and damage control, with pivotal contributions from airway epithelial cells and resident and newly recruited immune cells. In instances where viral infections persist or are not effectively eliminated, innate immune components prominently contribute to the resulting pathophysiological consequences. Even though both young children and older adults are susceptible to severe respiratory disease caused by various respiratory viruses, the underlying mechanisms may differ significantly. Children face the challenge of developing and maturing their immunity, while older adults contend with issues such as immune senescence and inflammaging. This review aims to compare the innate immune responses in respiratory viral infections across both age groups, identifying common central hubs that could serve as promising targets for innovative therapeutic and preventive strategies, despite the apparent differences in underlying mechanisms.

"Boosting" tumor immunity in elderly mice by hyperactivating dendritic cells.

Immunosenescence poses a significant challenge to tumor immunotherapy in elderly individuals. In this issue of Cell, Zhivaki et al. elucidate that dendritic cells "hyperactivated" by specific adjuvants elicit TH1-skewed CD4+ T cell responses in a manner contingent on the NLRP3 inflammasome, which can eliminate tumors in aged mice.

An updated immunosenescence exploration in healthy Chinese donors: circular elevated PD-1 on T cell and increased Ki67 on CD8+ T cell towards aging.

Immunosenescence is a process of immune dysfunction that occurs along with aging. Many studies have focused on the changes of different lymphocyte subsets in diseases and immune aging. However, the fluctuation in the number and phenotype of lymphocyte subset caused by aging have not been comprehensively analyzed, especially the effects of new indicators such as PD-1 and Ki67 in peripheral blood have been rarely reported. We further investigated the humoral and cellular immune parameters of 150 healthy donors over 18 years old. Age was associated with decreased CD4+CD45RA+CD62L+ T cells, decreased CD4+CD45RA+CD31+ T cells, and increased memory CD4+ or CD8+ T cells, dominated by male CD8+ T cells. The loss of CD28 expression on T cells and the transverse trend of activated CD38 and HLA-DR were also related to the increased age. In addition, CD8+ T cells in men were more prominent in activation indicators, and the difference between the old and young groups was obvious. CD4+CD25+CD127- T cells percentage tended to decrease with age and did not differ significantly between gender. Interestingly, we found that age was positively associated with PD-1+ T cells and showed significant age-related variability in men. Similarly, the percentage of CD8+ki-67+ also showed an increasing trend, with significant differences between the young group and other elderly groups in males. Our findings can provide immunological clues for future aging research, offering new insights for clinical monitoring and prevention of certain diseases.

Impact and potential value of immunosenescence on solid gastrointestinal tumors.

Solid gastrointestinal tumors often respond poorly to immunotherapy for the complex tumor microenvironment (TME), which is exacerbated by immune system alterations. Immunosenescence is the process of increased diversification of immune genes due to aging and other factors, leading to a decrease in the recognition function of the immune system. This process involves immune organs, immune cells, and the senescence-associated secretory phenotype (SASP). The most fundamental change is DNA damage, resulting in TME remodeling. The main manifestations are worsening inflammation, increased immunosuppressive SASP production, decreased immune cell antitumor activity, and the accumulation of tumor-associated fibroblasts and myeloid-derived suppressor cells, making antitumor therapy less effective. Senotherapy strategies to remove senescent cells and block key senescence processes can have synergistic effects with other treatments. This review focuses on immunoenescence and its impact on the solid TME. We characterize the immunosenescent TME and discuss future directions for antitumor therapies targeting senescence.

CAR, mGPS and hs-mGPS: What is among them the best gero-biomarker for age-related diseases? And for what clinical application?

The identification of biomarkers linked to the onset, progression, and prevention of age-related diseases (ARD), in the era of personalized medicine, represents the best goal of geroscience. Geroscience has the fundamental role of exploring and identifying the biological mechanisms of aging to suggest interventions capable of stopping/delaying the many pathological conditions and disabilities related to age. Therefore, it has become its key priority, as well as that of clinical practice and research, based on identifying and validating a range of biomarkers, geromarkers, which can be used to diagnostic, prognostic, or predictive clinical purposes. Indeed, geromarkers have, the potential to predict ARD trajectories and facilitate targeted interventions to slow down the related disabilities. Here our attention is paid to the inflammatory indexes (CAR, mGPS, hs-mGPS) linked to the relationship between the plasma levels of two inflammatory analytes, the typical positive protein of the acute phase, and the negative one, i.e. c-reactive protein (CRP) and albumin, respectively. These indexes allow us to understand the magnitude of the two main mechanisms predicted to influence the aging process, including inflammation and immunosenescence, as well as the degree of ARD severity. Evidence on their relationship with ARD is widely reported and discussed, to understand which can represent the best ARD geromarker, and its clinical application.

Premature thymic functional senescence is a hallmark of childhood acute lymphoblastic leukemia survivorship.

Childhood acute lymphoblastic leukemia (cALL) survivors suffer early-onset chronic diseases classically associated with aging. Normal aging is accompanied by organ dysfunctions, including immunological ones. We hypothesize that thymic immunosenescence occurs in cALL survivors and that its severity may correlate with early-onset chronic diseases. The PETALE study is a cALL survivor cohort with an extensive cardiovascular and metabolic evaluation. The thymic immunosenescence biomarker, signal joint T-cell receptor excision circles (TREC), was evaluated and was highly correlated with age in healthy participants (n = 281) and cALL survivors (n = 248). We observed a systematic thymic immunoage accentuation in each cALL survivor compared to controls ranging from 5.9 to 88.3 years. The immunoage gain was independent of age at diagnosis and treatment modalities and was more severe for females. Thymic aging was associated with several pathophysiological parameters, was greater in survivors suffering from metabolic syndrome, but there was no significant association with global physical condition. The decrease in TREC was independent from blood cell counts, which were normal, suggesting a segmental aging of the thymic compartment. Indeed, increased plasmatic T cell regulatory cytokines IL-6, IL-7 and GM-CSF accompanied high immunoage gain. Our data reveal that cALL or its treatment trigger a rapid immunoage gain followed by further gradual thymic immunosenescence, similar to normal aging. This leads to an enduring shift in accentuated immunoage compared to chronological age. Thus, accentuated thymic immunosenescence is a hallmark of cALL survivorship and TREC levels could be useful immunosenescence biomarkers to help monitoring the health of cancer survivors.

Potential relationship between cytomegalovirus and immunosenescence: Evidence from observational studies.

Immunosenescence (IS) occurs as a natural outcome of ageing and may be described as a decline in immune system flexibility and adaptability to sufficiently respond to new, foreign antigens. Potential factors that may precipitate IS include persistent herpesvirus infections, such as cytomegalovirus (CMV). Here, we conducted a review of the literature evaluating the potential association between CMV and IS. Twenty-seven epidemiologic studies that included direct comparisons between CMV-seropositive and CMV-seronegative immunocompetent individuals were analysed. The majority of these studies (n = 20) were conducted in European populations. The strength of evidence supporting a relationship between CMV, and various IS-associated immunologic endpoints was assessed. T-cell population restructuring was the most prominently studied endpoint, described in 21 studies, most of which reported a relationship between CMV and reduced CD4:CD8 T-cell ratio or modified CD8+ T-cell levels. Telomere length (n = 4) and inflammageing (n = 3) were less frequently described in the primary literature, and the association of these endpoints with CMV and IS was less pronounced. An emergent trend from our review is the potential effect modification of the CMV-IS relationship with both sex and age, indicating the importance of considering various effector variables when evaluating associations between CMV and IS. Our analysis revealed plausible mechanisms that may underlie the larger epidemiologic trends seen in the literature that support the indirect effect of CMV on IS. Future studies are needed to clarify CMV-associated and IS-associated immunologic endpoints, as well as in more diverse global and immunocompromised populations.

Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development.

Cancer represents a significant threat to human health, and traditional chemotherapy or cytotoxic therapy is no longer the sole or preferred approach for managing malignant tumors. With advanced research into the immunogenicity of tumor cells and the growing elderly population, tumor immunotherapy has emerged as a prominent therapeutic option. Its significance in treating elderly cancer patients is increasingly recognized. In this study, we review the conceptual classifications and benefits of immunotherapy, and discuss recent developments in new drugs and clinical progress in cancer treatment through various immunotherapeutic modalities with different mechanisms. Additionally, we explore the impact of immunosenescence on the effectiveness of cancer immunotherapy and propose innovative and effective strategies to rejuvenate senescent T cells.

Immunosenescence-related T cell phenotypes and white matter in schizophrenia patients with tardive dyskinesia.

Schizophrenia patients with tardive dyskinesia (TD) are associated with accelerated biological aging, immunological dysfunction, and premature morbidity and mortality. Older individuals are particularly vulnerable to TD development. As a characteristic of immunosenescence, alterations in the relative proportions of naïve or memory T cell subpopulations may be negatively or positively associated with brain structure abnormalities; however, whether these changes are correlated with TD remains unclear. In this study, we investigated correlations between distributions of T cell phenotypes and brain structure abnormalities (especially white matter) in schizophrenia patients with (TD) and without (NTD) TD (n = 50 and 58, respectively) relative to healthy controls (HC, n = 41). Immune markers, including naïve (CD45RA+), memory (CD45RO+), and apoptotic (CD95+) CD4+ and CD8+ T cells, were examined by flow cytometry, as were the intracellular levels of cytokines (interferon (IFN)-γ, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α) in CD8 + CD45RA + CD95+ and CD8 + CD45RO + CD95+ T cells. MRI was employed to evaluate the fractional anisotropy (FA) of white matter tracts and subcortical volumes, following published routines. The percentage of CD8 + CD45RO + CD95+ T cells was higher in TD compared with NTD and HC groups and correlated with the choroid plexus volume in TD group. The intracellular level of IFN-γ in CD8 + CD45RO + CD95+ T cells, the FA of the fornix/stria terminalis, and the pallidum volume were correlated with orofacial TD, whereas the FAs of the inferior fronto-occipital fasciculus, cingulum, and superior longitudinal fasciculus were correlated with limb-truncal TD. These findings provide preliminary evidence that the association between immunosenescence-related T cell subpopulations and brain structure may underline the pathological process of TD.

Machine learning-derived immunosenescence index for predicting outcome and drug sensitivity in patients with skin cutaneous melanoma.

The functions of immunosenescence are closely related to skin cutaneous melanoma (SKCM). The aim of this study is to uncover the characteristics of immunosenescence index (ISI) to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried out to identify risk prognostic genes, and their expression and prognostic value were evaluated. Then, we used the computational algorithm to estimate ISI. Finally, the distribution characteristics and clinical significance of ISI in SKCM by using multi-omics analysis. Patients with a lower ISI had a favorable survival rate, lower chromosomal instability, lower somatic copy-number alterations, lower somatic mutations, higher immune infiltration, and sensitive to immunotherapy. The ISI exhibited robust, which was validated in multiple datasets. Besides, the ISI is more effective than other published signatures in predicting survival outcomes for patients with SKCM. Single-cell analysis revealed higher ISI was specifically expressed in monocytes, and correlates with the differentiation fate of monocytes in SKCM. Besides, individuals exhibiting elevated ISI levels could potentially receive advantages from chemotherapy, and promising compounds with the potential to target high ISI were recognized. The ISI model is a valuable tool in categorizing SKCM patients based on their prognosis, gene mutation signatures, and response to immunotherapy.

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity.

Introduction: Immunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects. Methods: The 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli. Results: The discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production. Conclusions: INR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

Aging brain: exploring the interplay between bone marrow aging, immunosenescence, and neuroinflammation.

Aging is a complex process characterized by a myriad of physiological changes, including alterations in the immune system termed immunosenescence. It exerts profound effects on both the bone marrow and the central nervous system, with significant implications for immunosenescence in neurological contexts. Our mini-review explores the complex relationship between bone marrow aging and its impact on immunosenescence, specifically within the context of neurological diseases. The bone marrow serves as a crucial hub for hematopoiesis and immune cell production, yet with age, it undergoes significant alterations, including alterations in hematopoietic stem cell function, niche composition, and inflammatory signaling. These age-related shifts in the bone marrow microenvironment contribute to dysregulation of immune cell homeostasis and function, impacting neuroinflammatory processes and neuronal health. In our review, we aim to explore the complex cellular and molecular mechanisms that link bone marrow aging to immunosenescence, inflammaging, and neuroinflammation, with a specific focus on their relevance to the pathophysiology of age-related neurological disorders. By exploring this interplay, we strive to provide a comprehensive understanding of how bone marrow aging impacts immune function and contributes to the progression of neurological diseases in aging individuals. Ultimately, this knowledge can hold substantial promise for the development of innovative therapeutic interventions aimed at preserving immune function and mitigating the progression of neurological disorders in the elderly population.

A nationwide study on immunosenescence biomarkers profile in older adults: ELSI-Brazil.

Immunosenescence is a phenomenon caused by changes in the immune system, and part of these changes involves an increase in circulating immunological biomarkers, a process known as "Inflammaging." Inflammaging can be associated with many diseases related to older people. As the older population continues to grow, understanding changes in the immune system becomes essential. While prior studies assessing these alterations have been conducted in countries with Caucasian populations, this investigation marks a pioneering effort. The object of the study is to describe for the first time that the distribution of cytokines, chemokines, and growth factors serum levels, assessed by Luminex platform, has been examined in a Brazilian population-based study of older adult females and males by age. Blood samples from 2111 participants (≥50 years old) were analyzed at the baseline (2015/2016) of the ELSI-Brazil study. The exploratory variables considered in the study were age, sex, educational level, residence area, geographic region, alcohol and smoking consumption, physical activity, and self-reported medical diagnoses of hypertension, diabetes, asthma, arthritis, and cancer. The association between serum biomarker levels and age was assessed by a quantile regression model adjusted in the total population and stratified by sex. The significance level considered in the analysis was 0.05. The mean age of the participants was 62.9 years, with a slight majority of female (52.7 %). Differences were found between the sexes in the median circulating levels of the CCL11, CXCL10, and FGF biomarkers. Eight biomarkers showed significant associations with age, including the pro-inflammatory CXCL10, TNF-α, IL-6, IL-17, and IL-2; and type 2/regulatory CCL11 and IL-4, showing positive associations, and anti-inflammatory IL-1Ra showing a negative association. The results suggest similar associations between the sexes, revealing an inflammatory profile characterized by types 1 and 2. Remarkably, these findings reinforce the concept of the Inflammaging process in Brazilian population. These findings add novel insights to about the immunosenescence aspects in middle-income countries and help define biomarkers capable of monitoring inflammation in older adults.

Adaptive immunity and atherosclerosis: aging at its crossroads.

Adaptive immunity plays a profound role in atherosclerosis pathogenesis by regulating antigen-specific responses, inflammatory signaling and antibody production. However, as we age, our immune system undergoes a gradual functional decline, a phenomenon termed "immunosenescence". This decline is characterized by a reduction in proliferative naïve B- and T cells, decreased B- and T cell receptor repertoire and a pro-inflammatory senescence associated secretory profile. Furthermore, aging affects germinal center responses and deteriorates secondary lymphoid organ function and structure, leading to impaired T-B cell dynamics and increased autoantibody production. In this review, we will dissect the impact of aging on adaptive immunity and the role played by age-associated B- and T cells in atherosclerosis pathogenesis, emphasizing the need for interventions that target age-related immune dysfunction to reduce cardiovascular disease risk.

An Aloe-Based Composition Constituting Polysaccharides and Polyphenols Protected Mice against D-Galactose-Induced Immunosenescence.

A decline in immune response, exhibited in the form of immunosenescence and inflammaging, is an age-associated disturbance of the immune system known to predispose the elderly to a greater susceptibility to infection and poor vaccine response. Polysaccharides and polyphenols from botanicals are known for their immune modulation effects. Here we evaluated a standardized mushroom-based composition, UP360, from Aloe barbadensis, Poria cocos, and Rosmarinus officinalis, as a natural nutritional supplement for a balanced immune response in an accelerated aging mouse model. Immunosenescence was induced by continual subcutaneous injection of D-galactose (D-gal) at a dose of 500 mg/kg/day to CD-1 mice. UP360 was administered at oral doses of 200 and 400 mg/kg to the mice starting on the 5th week of D-gal injection. The study lasted for a total of 9 weeks. All mice were given a quadrivalent influenza vaccine at 3 µg/animal via intramuscular injection 14 days before the end of the study. A group of D-gal-treated mice treated at 400 mg/kg/day UP360 was kept without vaccination. Whole blood, serum, spleen homogenate, and thymus tissues were used for analysis. UP360 was found to improve the immune response as evidenced by stimulation of innate and adaptive immune responses, increase antioxidant capacity as reflected by augmented SOD and Nrf2, and preserve vital immune organs, such as the thymus, from aging-associated damage. The findings depicted in this report show the effect of the composition in activating and maintaining homeostasis of the immune system both during active infections and as a preventive measure to help prime the immune system. These data warrant further clinical study to explore the potential application of the mushroom-based composition as an adjunct nutritional supplement for a balanced immune response.

Immunosenescence and immunotherapy in older NSCLC patients.

Nonsmall cell lung cancer (NSCLC) predominantly affects the elderly since its incidence and mortality rates skyrocket beyond the age of 65. The landscape of NSCLC treatment has been revolutionized by immune checkpoint inhibitors (ICIs), which have emerged after a long and mostly inactive period of conventional treatment protocols. However, there is limited data on the exact effects of these chemicals on older patients, whose care can be complicated by a variety of conditions. This highlights the need to understand the efficacy of emerging cancer medicines in older patients. In this study, we will review the data of ICIs from clinical trials that were relevant to older people with NSCLC and poor performance status. We will also discuss the role of immunosenescence in immunotherapy and biomarkers in predicting the efficacy of ICIs in patients with advanced NSCLC.