RESUMO
The unique amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] is exclusively formed on the translational regulator eukaryotic initiation factor 5A (eIF5A) via a process coined hypusination. Hypusination is mediated by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), and hypusinated eIF5A (eIF5AHyp) promotes translation elongation by alleviating ribosome pauses at amino acid motifs that cause structural constraints, and it also facilitates translation initiation and termination. Accordingly, eIF5AHyp has diverse biological functions that rely on translational control of its targets. Homozygous deletion of Eif5a, Dhps, or Dohh in mice leads to embryonic lethality, and heterozygous germline variants in EIF5A and biallelic variants in DHPS and DOHH are associated with rare inherited neurodevelopmental disorders, underscoring the importance of the hypusine circuit for embryonic and neuronal development. Given the pleiotropic effects of eIF5AHyp, a detailed understanding of the cell context-specific intrinsic roles of eIF5AHyp and of the chronic versus acute effects of eIF5AHyp inhibition is necessary to develop future strategies for eIF5AHyp-targeted therapy to treat various human health problems. Here, we review the most recent studies documenting the intrinsic roles of eIF5AHyp in different tissues/cell types under normal or pathophysiological conditions and discuss these unique aspects of eIF5AHyp-dependent translational control.
Assuntos
Fator de Iniciação de Tradução Eucariótico 5A , Lisina , Fatores de Iniciação de Peptídeos , Proteínas de Ligação a RNA , Fatores de Iniciação de Peptídeos/metabolismo , Fatores de Iniciação de Peptídeos/genética , Humanos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Animais , Lisina/metabolismo , Lisina/análogos & derivados , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Biossíntese de Proteínas , CamundongosRESUMO
Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.
Assuntos
Diabetes Mellitus , Humanos , Diabetes Mellitus/imunologia , Diabetes Mellitus/patologia , Animais , Senescência Celular/imunologia , Inflamação/imunologia , Inflamação/patologia , Sistema Imunitário/imunologiaRESUMO
Aging is considered part of the natural process of life, however in recent years medical literature has started to show that specific facets of aging are beginning to be understood and those factors may even be considered preventable with various measures. Aging is also considered the number one cause of poor quality of life, disease, disability, and death, so the importance of understanding the aging process and how to control certain aspects of it cannot be underestimated when age related suffering is factored in. The causes of aging are now becoming well understood, and in recent years many therapies have already become available to the public to attenuate specific corridors of aging. The heterogeneity of the aging process and the biological drivers involved is examined here in parallel with various compounds and therapies to combat biological decline. The benefits for governments in keeping their populations healthy and vibrant are vast, and at the same time offer a great incentive to invest into newly emerging technologies that may prevent the onset of preventable disease. Whilst this paper only discusses nine pathways to the aging process, many more exist.
RESUMO
The primary objective of this meta-analysis was to provide the comprehensive understanding of the intricate correlation that existed between immune senescence and its effects on the advancement of lung cancer as well as recovery of cutaneous wounds. By conducting this systematic review of six rigorous studies utilizing databases such as PubMed and Web of Science, this research examined the multitude of facets pertaining to immune aging and consequences it bear on the health outcomes. The incorporated studies encompassed wide range of geographical and methodological viewpoints, with the specific emphasis on non-small-cell lung cancer and diverse scenarios related to wound recovery. This analysis synthesized discoveries regarding therapeutic responses, cellular and molecular mechanisms and impact of lifestyle factors on immune senescence. The findings suggested that immune senescence has substantial impact on the effectiveness of treatments for lung cancer and cutaneous wounds healing process; therefore, targeted therapies and holistic approaches may be able to mitigate these effects. By following the revised PRISMA guidelines, this meta-analysis guarantee thorough and ethically sound methodology for amalgamating pre-existing literature. The study concluded by emphasizing the critical nature of comprehending immune senescence in the context of clinical practice and proposed avenues for further investigation to enhance health results among the elderly.
Assuntos
Neoplasias Pulmonares , Cicatrização , Humanos , Neoplasias Pulmonares/imunologia , Idoso , Masculino , Feminino , Progressão da Doença , Carcinoma Pulmonar de Células não Pequenas/imunologia , Pessoa de Meia-Idade , Imunossenescência , Idoso de 80 Anos ou mais , AdultoRESUMO
T cell senescence is an indication of T cell dysfunction. The ability of senescent T cells to respond to cognate antigens is reduced and they are in the late stage of differentiation and proliferation; therefore, they cannot recognize and eliminate tumor cells in a timely and effective manner, leading to the formation of the suppressive tumor microenvironment. Establishing methods to reverse T cell senescence is particularly important for immunotherapy. Aging exacerbates profound changes in the immune system, leading to increased susceptibility to chronic, infectious, and autoimmune diseases. Patients with malignant lung tumors have impaired immune function with a high risk of recurrence, metastasis, and mortality. Immunotherapy based on PD-1, PD-L1, CTLA-4, and other immune checkpoints is promising for treating lung malignancies. However, T cell senescence can lead to low efficacy or unsuccessful treatment results in some immunotherapies. Efficiently blocking and reversing T cell senescence is a key goal of the enhancement of tumor immunotherapy. This study discusses the characteristics, mechanism, and expression of T cell senescence in malignant lung tumors and the treatment strategies.
Assuntos
Neoplasias Pulmonares , Humanos , Senescência de Células T , Linfócitos T , Imunoterapia/métodos , Envelhecimento , Microambiente TumoralRESUMO
Innate immune system activation is crucial in the inflammatory response, but uncontrolled activation can lead to autoimmune diseases. Cellular exhaustion and senescence are two processes that contribute to innate immune tolerance breakdown. Exhausted immune cells are unable to respond adequately to specific antigens or stimuli, while senescent cells have impaired DNA replication and metabolic changes. These processes can impair immune system function and disrupt homeostasis, leading to the emergence of autoimmunity. However, the influence of innate immune exhaustion and senescence on autoimmune disorders is not well understood. This review aims to describe the current findings on the role of innate immune exhaustion and senescence in autoimmunity, focusing on the cellular and molecular changes involved in each process. Specifically, the article explores the markers and pathways associated with immune exhaustion, such as PD-1 and TIM-3, and senescence, including Β-galactosidase (β-GAL), lamin B1, and p16ink4a, and their impact on autoimmune diseases, namely type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and immune-mediated myopathies. Understanding the mechanisms underlying innate immune exhaustion and senescence in autoimmunity may provide insights for the development of novel therapeutic strategies.
RESUMO
Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.
Assuntos
Amianto , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Humanos , Estados Unidos , Idoso , Filogenia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mesotelioma/genética , Mesotelioma/terapia , Mesotelioma Maligno/genética , Genes Supressores de Tumor , Microambiente TumoralRESUMO
BACKGROUND: Thymus is the most crucial organ connecting immunity and aging. The progressive senescence of thymic epithelial cells (TECs) leads to the involution of thymus under aging, chronic stress and other factors. Ligustilide (LIG) is a major active component of the anti-aging Chinese herbal medicine Angelica sinensis (Oliv.) Diels, but its role in preventing TEC-based thymic aging remains elusive. PURPOSE: This study explored the protective role of Ligustilide in alleviating ADM (adriamycin) -induced thymic immune senescence and its underlying molecular mechanisms. METHOD: The protective effect of Ligustilide on ADM-induced thymic atrophy was examined by mouse and organotypic models, and conformed by SA-ß-gal staining in TECs. The abnormal spatial distribution of TECs in the senescent thymus was analyzed using H&E, immunofluorescence and flow cytometry. The possible mechanisms of Ligustilide in ADM-induced thymic aging were elucidated by qPCR, fluorescence labeling and Western blot. The mechanism of Ligustilide was subsequently validated through actin polymerization inhibitor, genetic engineering to regulate Thymosin ß15 (Tß15) and Tß4 expression, molecular docking and ß Thymosin-G-actin cross-linking assay. RESULTS: At a 5 mg/kg dose, Ligustilide markedly ameliorated ADM-induced weight loss and limb grip weakness in mice. It also reversed thymic damage and restored positive selection impaired by ADM. In vitro, ADM disrupted thymic structure, reduced TECs number and hindered double negative (DN) T cell differentiation. Ligustilide counteracted these effects, promoted TEC proliferation and reticular differentiation, leading to an increase in CD4+ single positive (CD4SP) T cell proportion. Mechanistically, ADM diminished the microfilament quantity in immortalized TECs (iTECs), and lowered the expression of cytoskeletal marker proteins. Molecular docking and cross-linking assay revealed that Ligustilide inhibited the protein binding between G-actin and Tß15 by inhibiting the formation of the Tß15-G-actin complex, thus enhancing the microfilament assembly capacity in TECs. CONCLUSION: This study, for the first time, reveals that Ligustilide can attenuate actin depolymerization, protects TECs from ADM-induced acute aging by inhibiting the binding of Tß15 to G-actin, thereby improving thymic immune function. Moreover, it underscores the interesting role of Ligustilide in maintaining cytoskeletal assembly and network structure of TECs, offering a novel perspective for deeper understanding of anti thymic aging.
Assuntos
4-Butirolactona/análogos & derivados , Actinas , Timosina , Camundongos , Animais , Actinas/metabolismo , Timosina/farmacologia , Timosina/metabolismo , Simulação de Acoplamento Molecular , Células EpiteliaisRESUMO
INTRODUCTION: Dysregulation of pro-inflammatory chemokines is considered a potential mechanism for the development of age-related medical conditions such as frailty. However, evidence linking circulating chemokines with frailty remains lacking. MATERIALS AND METHODS: We performed a case-control study including 48 cases and 48 controls aged 65-90 years, using the National Center for Geriatrics and Gerontology outpatient registry data. Cases were outpatients with physical frailty and low habitual daily activity. Controls were robust outpatients who performed habitual daily activities. The Japanese version of the Cardiovascular Health Study criteria was used to diagnose physical frailty, and the modified Baecke questionnaire was used to evaluate habitual daily activities. Serum CXCL9 and CXCL10 levels were measured using enzyme-linked immunosorbent assay. RESULTS: The median age (interquartile range) in cases and controls was 78 (73-83) and 76 (72-80) years, with the proportions of men were 47.9% and 43.8%, respectively. In the logistic regression model with adjustment for age, sex, and other confounding factors, the multivariable odds ratios (95% confidence intervals) for the highest versus lowest tertile of CXCL9 and CXCL10 levels were 7.90 (1.61-49.80) and 1.61 (0.42-6.30), respectively. However, we did not observe a linear association between CXCL9 levels and physical frailty components. DISCUSSION/CONCLUSION: Our preliminary data exhibit that circulating CXCL9 levels were positively associated with the odds of physical frailty. However, these findings lack evidence of a dose-response relationship between CXCL9 levels and physical frailty components. Further research with a larger sample size is required to confirm these findings.
Assuntos
Fragilidade , Geriatria , Idoso , Humanos , Masculino , Atividades Cotidianas , Estudos de Casos e Controles , Quimiocina CXCL10 , Quimiocina CXCL9 , Quimiocinas , Feminino , Idoso de 80 Anos ou maisRESUMO
The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.
Assuntos
Senescência Celular , Redes e Vias Metabólicas , Humanos , Senescência Celular/efeitos dos fármacos , Animais , Doença Crônica , Inflamação/metabolismo , Inflamação/imunologia , Pneumopatias/etiologia , Pneumopatias/tratamento farmacológico , Pneumopatias/metabolismo , Pneumopatias/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/imunologia , Envelhecimento/imunologia , Envelhecimento/metabolismoRESUMO
Vaccinations against infectious diseases are a highly effective preventive measure, especially in old age due to the higher susceptibility to infections. As the effectiveness of vaccinations decreases in old age due to immune senescence but also due to comorbidities, specific, more immunogenic vaccines have been developed for this target group. In Germany, the Standing Commission on Vaccination (STIKO) publishes annually updated vaccination recommendations also specifically for the 60+ years age group. Since 2018, standard vaccinations for this group have included herpes zoster vaccination with adjuvanted inactivated vaccine. Since 2021, the use of the quadrivalent influenza high-dose vaccine is recommended for this age group. Currently, the annual COVID-19 vaccination and the single pneumococcal vaccination with the new 20-valent conjugate vaccine have been added as standard vaccinations. The free STIKO app provides an always up to date overview of standard and indicated vaccinations for all age groups.
Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Vacinas contra COVID-19 , Vacinação , Vacinas contra Influenza/uso terapêutico , Alemanha , Influenza Humana/prevenção & controleRESUMO
Introduction: People with HIV (PWH) are known to have underlying inflammation and immune activation despite virologic control. Substance use including opioid dependence is common in this population and is associated with increased morbidity and reduced lifespan. The primary objective of the present study termed opioid immunity study (OPIS), was to investigate the impact of chronic opioids in PWH. Methods: The study recruited people with and without HIV who had opioid use disorder (OUD). Study participants (n=221) were categorized into four groups: HIV+OP+, n=34; HIV-OP+, n=66; HIV+OP-, n=55 and HIV-OP-, n=62 as controls. PWH were virally suppressed on ART and those with OUD were followed in a syringe exchange program with confirmation of OP use by urine drug screening. A composite cytokine score was developed for 20 plasma cytokines that are linked to inflammation. Cellular markers of immune activation (IA), exhaustion, and senescence were determined in CD4 and CD8 T cells. Regression models were constructed to examine the relationships of HIV status and opioid use, controlling for other confounding factors. Results: HIV+OP+ participants exhibited highest inflammatory cytokines and cellular IA, followed by HIV-OP+ for inflammation and HIV+OP- for IA. Inflammation was found to be driven more by opioid use than HIV positivity while IA was driven more by HIV than opioid use. In people with OUD, expression of CD38 on CD28-CD57+ senescent-like T cells was elevated and correlated positively with inflammation. Discussion: Given the association of inflammation with a multitude of adverse health outcomes, our findings merit further investigations to understand the mechanistic pathways involved.
Assuntos
Infecções por HIV , Transtornos Relacionados ao Uso de Opioides , Humanos , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/metabolismo , Infecções por HIV/complicações , Linfócitos T CD8-Positivos , Inflamação/metabolismo , Citocinas/metabolismo , Transtornos Relacionados ao Uso de Opioides/complicaçõesRESUMO
Telomere, the biological chronometer, and its effect on the immune system considerably varies among individuals. During pregnancy, multiple risk factors affect telomere reprogramming during fetal life which can lead to health disparities in newborns. These changes may cause a long-term impact on the telomere genetics of the newborn and become a reason for lifelong health implications and immune senescence. Therefore, telomere shortening in parents due to genetic variation may act as a hallmark of immune senescence and aging in their newborns.
RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19) that presents with varied clinical manifestations ranging from asymptomatic or mild infections and pneumonia to severe cases associated with cytokine storm, acute respiratory distress syndrome (ARDS), and even death. The underlying mechanisms contributing to these differences are unclear, although exacerbated inflammatory sequelae resulting from infection have been implicated. While advanced aging is a known risk factor, the precise immune parameters that determine the outcome of SARS-CoV-2 infection in elderly individuals are not understood. Here, we found aging-associated (age ≥61) intrinsic changes in T cell responses when compared to those from individuals aged ≤ 60, even among COVID-positive patients with mild symptoms. Specifically, when stimulated with SARS-CoV-2 peptides in vitro, peripheral blood mononuclear cell (PBMC) CD4+ and CD8+ T cells from individuals aged ≥61 showed a diminished capacity to produce IFN-γ and IL-1ß. Although they did not have severe disease, aged individuals also showed a higher frequency of PD-1+ cells and significantly diminished IFN-γ/PD-1 ratios among T lymphocytes upon SARS-CoV-2 peptide stimulation. Impaired T cell IL-1ß expression coincided with reduced NLRP3 levels in T lymphocytes. However, the expression of these molecules was not affected in the monocytes of individuals aged ≥61. Together, these data reveal SARS-CoV-2-specific CD4+ and CD8+ T-cell intrinsic cytokine alterations in the individuals older than 61 and may provide new insights into dysregulated COVID-directed immune responses in the elderly.
Assuntos
Envelhecimento , COVID-19 , Idoso , Humanos , Envelhecimento/genética , Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/genética , COVID-19/imunologia , Leucócitos Mononucleares/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptor de Morte Celular Programada 1/imunologia , SARS-CoV-2 , Pessoa de Meia-Idade , Linfócitos T CD4-Positivos/imunologiaRESUMO
Individuals born preterm have shorter lifespans and elevated rates of chronic illness that contribute to mortality risk when compared to individuals born at term. Emerging evidence suggests that individuals born preterm or of low birthweight also exhibit physiologic and cellular biomarkers of accelerated aging. It is unclear whether, and to what extent, accelerated aging contributes to a higher risk of chronic illness and mortality among individuals born preterm. Here, we review accelerated aging phenotypes in adults born preterm and biological pathways that appear to contribute to accelerated aging. We highlight biomarkers of accelerated aging and various resiliency factors, including both pharmacologic and non-pharmacologic factors, that might buffer the propensity for accelerated aging among individuals born preterm.
RESUMO
Immunosenescence is an age-related change in the immune system characterized by a reduction in naïve T-cells and an impaired proliferative capacity of CD8+ T-cells in older individuals. Recent research revealed the crucial impact of immunosenescence on the development and control of cancer, and aging is one of the causes that diminish the therapeutic efficacy of cancer immunotherapies targeting CD8+ T-cell activation. Despite dog cancer being defined as an age-related disease, there are few fundamental understandings regarding the relationship between aging and the canine immune system. Therefore, we aimed to elucidate the characteristics of immunosenescence in dogs and analyzed the effects of aging on the differentiation status and proliferation of canine CD8+ T cells using T-cell specific stimulation with anti-canine CD3/CD28 antibody-coated beads and interleukin-2. As a result, we found that older dogs have a lower proliferative capacity of CD8+ T-cells and a reduction in the naïve subset in their peripheral blood. Further analysis showed that older dogs had attenuated proliferation of the effector and central memory subsets. These results indicate the importance of maintaining less differentiated subsets to expand CD8+ T-cells in dogs and provide helpful insight into the development of dog immune therapies that require T-cell expansion ex vivo.
RESUMO
Aging of the organism is associated diminished response to external stimuli including weakened immune function, resulting in diseases that impair health and lifespan. Several dietary restriction modalities have been reported to improve health and lifespan in different animal models, but it is unknown whether any of the lifespan-extending dietary treatments could be combined to achieve an additive effect. Here, we investigated the effects of halving amino acids components in the HUNTaa diet, a synthetic medium known to extend lifespan in Drosophila. We found that dietary restriction by halving the entire amino acid components (DR group) could further extend lifespan and improve resistance to oxidative stress, desiccation stress, and starvation than flies on HUNTaa diet alone (wt group). Transcriptome analysis of Drosophila at 40, 60, and 80 days of age revealed that genes related to cell proliferation and metabolism decreased with age in the wt group, whereas background stimulus response and amino acid metabolism increased with age. However, these trends differed in the DR group, that is, the DR flies had downregulated stress response genes, including reduced background immune activation. Infection experiments demonstrated that these flies survived longer after feeding infection with Serratia marcescens and Enterococcus faecalis, suggesting that these flies had stronger immune function, and therefore reduced immune senescence. These results demonstrated that halving the entire amino acid components in the HUNTaa diet further extended health and lifespan and suggested that lifespan-extending diet and dietary restriction treatment could be combined to achieve additive beneficial results.
Assuntos
Drosophila melanogaster , Longevidade , Animais , Longevidade/fisiologia , Drosophila melanogaster/genética , Dieta com Restrição de Proteínas , Drosophila , Aminoácidos , Restrição CalóricaRESUMO
We present an integrated analysis of the clinical measurements, immune cells, and plasma lipidomics of 2000 individuals representing different age stages. In the study, we explore the interplay of systemic lipids metabolism and circulating immune cells through in-depth analysis of immune cell phenotype and function in peripheral dynamic lipids environment. The population makeup of circulation lymphocytes and lipid metabolites changes dynamically with age. We identified a major shift between young group and middle age group, at which point elevated, immune response is accompanied by the elevation of specific classes of peripheral phospholipids. We tested the effects in mouse model and found that 10-month-dietary added phospholipids induced T-cell senescence. However, the chronic malignant disease, the crosstalk between systemic metabolism and immunity, is completely changed. In cancer patients, the unusual plasma cholesteryl esters emerged, and free fatty acids decreased. The study reveals how immune cell classes and peripheral metabolism coordinate during age acceleration and suggests immune senescence is not isolated, and thus, system effect is the critical point for cell- and function-specific immune-metabolic targeting. ⢠The study identifies a major shift of immune phenotype between young group and middle age group, and the immune response is accompanied by the elevation of specific classes of peripheral phospholipids; ⢠The study suggests potential implications for translational studies such as using metabolic drug to regulate immune activity.
Assuntos
Fosfolipídeos , Exaustão das Células T , Pessoa de Meia-Idade , Camundongos , Animais , Humanos , Fosfolipídeos/análise , Fosfolipídeos/metabolismo , Ácidos Graxos/metabolismo , Ésteres do ColesterolRESUMO
BACKGROUND: Patients with acute alcohol-associated hepatitis (AH) have immune dysfunction. Mitochondrial function is critical for immune cell responses and regulates senescence. Clinical translational studies using complementary bioinformatics-experimental validation of mitochondrial responses were performed in peripheral blood mononuclear cells (PBMC) from patients with AH, healthy controls (HC), and heavy drinkers without evidence of liver disease (HD). METHODS: Feature extraction for differentially expressed genes (DEG) in mitochondrial components and telomere regulatory pathways from single-cell RNAseq (scRNAseq) and integrated 'pseudobulk' transcriptomics from PBMC from AH and HC (n = 4 each) were performed. After optimising isolation and processing protocols for functional studies in PBMC, mitochondrial oxidative responses to substrates, uncoupler, and inhibitors were quantified in independent discovery (AH n = 12; HD n = 6; HC n = 12) and validation cohorts (AH n = 10; HC n = 7). Intermediary metabolites (gas-chromatography/mass-spectrometry) and telomere length (real-time PCR) were quantified in subsets of subjects (PBMC/plasma AH n = 69/59; HD n = 8/8; HC n = 14/27 for metabolites; HC n = 13; HD n = 8; AH n = 72 for telomere length). RESULTS: Mitochondrial, intermediary metabolite, and senescence-regulatory genes were differentially expressed in PBMC from AH and HC in a cell type-specific manner at baseline and with lipopolysaccharide (LPS). Fresh PBMC isolated using the cell preparation tube generated optimum mitochondrial responses. Intact cell and maximal respiration were lower (p ≤ .05) in AH than HC/HD in the discovery and validation cohorts. In permeabilised PBMC, maximum respiration, complex I and II function were lower in AH than HC. Most tricarboxylic acid (TCA) cycle intermediates in plasma were higher while those in PBMC were lower in patients with AH than those from HC. Lower telomere length, a measure of cellular senescence, was associated with higher mortality in AH. CONCLUSION: Patients with AH have lower mitochondrial oxidative function, higher plasma TCA cycle intermediates, with telomere shortening in nonsurvivors.
Assuntos
Hepatite , Leucócitos Mononucleares , Humanos , Leucócitos Mononucleares/metabolismo , Mitocôndrias/genéticaRESUMO
Background: The response to vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies depending on comorbidities. This study evaluated the clinical and immunological factors affecting the humoral response of patients with end-stage renal disease (ESRD) to the BNT162b2 vaccine. Methods: Humoral immunity was evaluated in 54 ESRD patients using serum levels of anti-receptor-binding domain (RBD) and neutralizing antibodies (NAbs), measured by a chemiluminescent immunoassay 30 (T1), 60 (T2), and 120 (T3) days after the second vaccine dose. The results were correlated to baseline patient T- and B-lymphocyte subpopulations determined by flow cytometry. Results: The proportion of seroconverted patients based on the NAb titer decreased from 83.3% at T1 to 53.7% at T3. Age was negatively correlated to the NAb titer at T1 and T2. Patients receiving hemodiafiltration had higher NAb titers at T3. Diabetes was associated with a lower response rate at T3. Univariate analysis revealed a positive correlation between the naïve CD4 T-lymphocyte population and RBD titer at T1 and the NAb titer at T3, with no association observed with naïve CD8 T lymphocytes. NAb titers at T3 were significantly correlated with late-differentiated CD4 T lymphocytes and terminally differentiated effector memory cells re-expressing CD45RA (TEMRA) CD8 T lymphocytes. RBD levels were positively correlated with naïve and memory B-lymphocyte counts at T3. Conclusions: Age, diabetes, and hemodialysis prescription had significant impacts on the response to vaccination. T- and B-lymphocyte phenotypes are major determinants of the humoral response potency to SARS-CoV-2 vaccination with BNT162b2 in patients with ESRD.