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1.
Front Immunol ; 13: 833531, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35651622

RESUMO

Aging leads to alterations in the immune system that result in ineffective responsiveness against pathogens. Features of this process, collectively known as immunosenescence, accumulate in CD8+ T cells with age and have been ascribed to differentiation of these cells during the course of life. Here we aimed to identify novel markers in CD8+ T cells associated with immunosenescence. Furthermore, we assessed how these markers relate to the aging-related accumulation of highly differentiated CD27-CD28- cells. We found that co-expression of the transcription factor Helios and the aging-related marker TIGIT identifies CD8+ T cells that fail to proliferate and show impaired induction of activation markers CD69 and CD25 in response to stimulation in vitro. Despite this, in blood of older adults we found TIGIT+Helios+ T cells to become highly activated during an influenza-A virus infection, but these higher frequencies of activated TIGIT+Helios+ T cells associate with longer duration of coughing. Moreover, in healthy individuals, we found that TIGIT+Helios+ CD8+ T cells accumulate with age in the highly differentiated CD27-CD28- population. Interestingly, TIGIT+Helios+ CD8+ T cells also accumulate with age among the less differentiated CD27+CD28- T cells before their transit into the highly differentiated CD27-CD28- stage. This finding suggests that T cells with immunosenescent features become prominent at old age also within the earlier differentiation states of these cells. Our findings show that co-expression of TIGIT and Helios refines the definition of immunosenescent CD8+ T cells and challenge the current dogma of late differentiation stage as proxy for T-cell immunosenescence.


Assuntos
Imunossenescência , Idoso , Envelhecimento , Antígenos CD28 , Linfócitos T CD8-Positivos , Humanos , Fator de Transcrição Ikaros/genética , Receptores Imunológicos/genética
2.
Front Immunol ; 13: 864929, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720307

RESUMO

The problem of aging is mainly the increase of age-related diseases, and elderly patients have longer hospitalization and worse prognosis. Poorer nutritional status and immunosenescence may be predisposing and severe factors. The mechanism of the high incidence of diseases and poor prognosis behind aging is complex. Finding suitable aging models is of great significance to find strategies to prevent aging related events. In this study, the relationship between thyrotoxicosis and aging was investigated in mice. The results of routine blood tests and flow cytometry showed that immunosenescence occurred in thyrotoxicosis mice, which was characterized by a significant decrease in neutrophils, lymphocytes, CD4+/CD8+ and CD4+IFN-γ+ lymphocytes. Biochemical examination results showed that there were hypocholesterolemia, hypolipoproteinemia, and hyperlipidemia in thyrotoxicosis mice. Serum proteomics analysis showed that the downregulation of complement and coagulation proteins was another manifestation of declined immunity. Moreover, proteomics analysis showed that many downregulated proteins were related to homeostasis, mainly transport proteins. Their downregulation led to the disturbance of osmotic pressure, ion homeostasis, vitamin utilization, lipid transport, hyaluronic acid processing, and pH maintenance. Serum metabolomics analysis provided more detailed evidence of homeostasis disturbance, especially lipid metabolism disorder, including the downregulation of cholesterol, vitamin D, bile acids, docosanoids, and the upregulation of glucocorticoids, triglycerides, sphingolipids, and free fatty acids. The upregulated lipid metabolites were related to lipotoxicity, which might be one cause of immunosenescence and many aging related syndromes. This study provides evidence for the aging model of thyrotoxicosis mice, which can be used for exploring anti-aging drugs and strategies.


Assuntos
Imunossenescência , Desnutrição , Tireotoxicose , Idoso , Envelhecimento , Animais , Humanos , Lipídeos , Camundongos
3.
Artigo em Inglês | MEDLINE | ID: mdl-35588939

RESUMO

Immunosenescence is a term used to describe the age-related changes in the immune system. Immunosenescence is associated with complex alterations and dysregulation of immune function and inflammatory processes. Age-related changes in innate immune responses including alterations in chemotactic, phagocytic, and natural killing functions, impaired antigen presenting capacity, and dysregulated inflammatory response have been described. The most striking and best characterized feature of immunosenescence is the decline in both number and function of T cells. With age there is decreased proliferation, decreased number of antigen-naïve T cells, and increased number of antigen-experienced memory T cells. This decline in naïve T cell population is associated with impaired immunity and reduced response to new or mutated pathogens. While the absolute number of peripheral B cells appears constant with age, changes in B cell functions including reduced antibody production and response and cell memory have been described. However, the main alteration in cell-mediated function that has been reported across all species with aging is those observed in in T cell. These T cell mediated changes have been shown to contribute to increased susceptibility to infection and cancer in older adults. In addition to functional and phenotype alterations in immune cells, studies demonstrate that circulating concentrations of inflammatory mediators in older adults are higher than those of young. This low grade, chronic inflammatory state that occurs in the context of aging has been termed "inflammaging". This review will focus on age-related changes in the immune system including immunosenescence and inflammation as well as the functional consequences of these age-related alterations for the aged.


Assuntos
Imunossenescência , Idoso , Humanos , Sistema Imunitário/fisiologia , Imunidade Inata , Imunossenescência/fisiologia , Inflamação
4.
Mech Ageing Dev ; 204: 111672, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35378106

RESUMO

Ageing is associated with modified function of both innate and adaptive immunity. It is believed that changes occurring in ageing immune system are responsible for increased severity and deadliness of COVID-19 in the elderly. Although supported by statistics and epidemiology, these finding do not compute at the mechanistic level as depending solely on chronological and biological ageing. The phenomena describing changes in the aging immune system are immunosenescence and inflammageing, which develop in time depending on challenges to the individual immune system (immunobiography). Thus, "richer" immunobiography (in addition to other factors, including genetic, epigenetics or metabolic) may adversely affect the reactivity to the SARS-CoV-2 not only at later decades of life, but also earlier, in young and middle-aged individuals. On the other hand, infection with SARS-CoV-2 is affecting the function of both innate and adaptive branches of the immune system, adding to the individual immunobiography. Summarizing, immunosenescence and inflammaging may aggravate, but also may be aggravated by SARS-CoV-2 infection.


Assuntos
COVID-19 , Imunossenescência , Imunidade Adaptativa , Idoso , Envelhecimento , Humanos , Pessoa de Meia-Idade , SARS-CoV-2
5.
Aging Cell ; 21(5): e13607, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35397197

RESUMO

Age-related changes in human T-cell populations are important contributors to immunosenescence. In particular, terminally differentiated CD8+ effector memory CD45RA+ TEMRA cells and their subsets have characteristics of cellular senescence, accumulate in older individuals, and are increased in age-related chronic inflammatory diseases. In a detailed T-cell profiling among individuals over 65 years of age, we found a high interindividual variation among CD8+ TEMRA populations. CD8+ TEMRA proportions correlated positively with cytomegalovirus (CMV) antibody levels, however, not with the chronological age. In the analysis of over 90 inflammation proteins, we identified plasma TRANCE/RANKL levels to associate with several differentiated T-cell populations, including CD8+ TEMRA and its CD28- subsets. Given the strong potential of CD8+ TEMRA cells as a biomarker for immunosenescence, we used deep-amplicon bisulfite sequencing to match their frequencies in flow cytometry with CpG site methylation levels and developed a computational model to predict CD8+ TEMRA cell proportions from whole blood genomic DNA. Our findings confirm the association of CD8+ TEMRA and its subsets with CMV infection and provide a novel tool for their high throughput epigenetic quantification as a biomarker of immunosenescence.


Assuntos
Infecções por Citomegalovirus , Imunossenescência , Idoso , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos , Infecções por Citomegalovirus/genética , Epigênese Genética , Humanos , Memória Imunológica , Subpopulações de Linfócitos T
6.
Int J STD AIDS ; 33(6): 597-603, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35377254

RESUMO

BACKGROUND: It has been hypothesized that HIV-1 infection prematurely "ages" individuals phenotypically and immunologically. We measured phenotypic frailty and immune "aging" markers on T-cells of people living with HIV on long term, suppressive anti-retroviral therapy (ART) to determine if there is an association between frailty and immunosenescence. METHODS: Thirty-seven (37) community-dwelling people living with HIV were measured for frailty using a sensor-based frailty meter that quantifies weakness, slowness, rigidity, and exhaustion. An immunological profile of the patients' CD4+ and CD8+ T-cell expression of cell surface proteins and cytokines was performed (n = 20). RESULTS: Phenotypic frailty prevalence was 19% (7/37) and correlated weakly with the number of past medical events accrued by the patient (r = 0.34, p = .04). There was no correlation of frailty with age, sex, prior AIDS diagnosis or HIV-1 viral load, or IFN-γ expression by CD4+ or CD8+ T-cells. There were more immune competent (CD28+ CD57-) cells than exhausted/senescent (CD28- CD57+) T cells. CONCLUSION: Frailty in people living with HIV on long term, suppressive ART did not correlate with aging or T cell markers of exhaustion or immunosenescence.


Assuntos
Fragilidade , Infecções por HIV , Imunossenescência , Biomarcadores , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Fragilidade/epidemiologia , Fragilidade/metabolismo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos
7.
J Mol Med (Berl) ; 100(5): 697-712, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35384505

RESUMO

The aging process is associated with a remodeling of the immune system involving chronic low-grade inflammation and a gradual decline in the function of the immune system. These processes are also called inflammaging and immunosenescence. The age-related immune remodeling is associated with many clinical changes, e.g., risk for cancers and chronic infections increases, whereas the efficiency of vaccination and immunotherapy declines with aging. On the other hand, there is convincing evidence that chronic inflammatory states promote the premature aging process. The inflammation associated with aging or chronic inflammatory conditions stimulates a counteracting immunosuppression which protects tissues from excessive inflammatory injuries but promotes immunosenescence. Immunosuppression is a driving force in tumors and chronic infections and it also induces the tolerance to vaccination and immunotherapies. Immunosuppressive cells, e.g., myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and type M2 macrophages, have a crucial role in tumorigenesis and chronic infections as well as in the tolerance to vaccination and immunotherapies. Interestingly, there is substantial evidence that inflammaging is also associated with an increased immunosuppressive activity, e.g., upregulation of immunosuppressive cells and anti-inflammatory cytokines. Given that both the aging and chronic inflammatory states involve the activation of immunosuppression and immunosenescence, this might explain why aging is a risk factor for tumorigenesis and chronic inflammatory states and conversely, chronic inflammatory insults promote the premature aging process in humans.


Assuntos
Senilidade Prematura , Imunossenescência , Neoplasias , Envelhecimento , Carcinogênese , Humanos , Imunossupressores/uso terapêutico , Inflamação , Neoplasias/etiologia
8.
Cells ; 11(6)2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35326467

RESUMO

Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer's and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging ("inflammaging"). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.


Assuntos
Imunossenescência , Humanos , Imunossenescência/fisiologia , Inflamação , Células Matadoras Naturais , Fenótipo
9.
Dis Markers ; 2022: 2143892, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35280438

RESUMO

Immunosenescence refers to the immune system undergoing a series of degenerative changes with advancing age and is tightly associated with the initiation and progression of cancers. However, the immunosenescence-related genes as critical biomarkers for bladder cancer (BLCA) have not been systematically analyzed. We retrieved the immunosenescence-related genes from the public database and verified their association with hallmarks of immunosenescence based on The Cancer Genome Atlas (TCGA) cohort. Through gene pairing, Lasso, and univariate Cox regression, an 8-gene pair model was constructed to evaluate the overall survival of BLCA, which was then validated in the training cohort (P < 0.001, n = 396), two external validation cohorts (P < 0.05, n = 165; P < 0.001, n = 224), and local samples (P < 0.05, n = 10). We also downloaded the clinical information and gene expression matrices of other 32 different cancers from TCGA. The established model showed significant predictive value for the prognosis in 15 cancers (P < 0.05). The risk model could also serve as a promising predictor for immunotherapeutic response, which has been verified by the TIDE algorithm (P < 0.05), IMvigor210 dataset (P < 0.01, n = 298), and other two datasets correlated with immunotherapy (P < 0.05, n = 56; P = 0.17, n = 27). The TCGA dataset, in vitro cell experiments, and pan-cancer analysis displayed that the gene signature was associated with cisplatin sensitivity (P < 0.05). Overall, we proposed a novel immunosenescence-related gene signature to predict prognosis, immunotherapeutic response, and cisplatin sensitivity of BLCA, which were validated in different independent cohorts, local samples, and pan-cancer analyses.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Imunossenescência/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transcriptoma , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade
10.
Exp Eye Res ; 219: 109035, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35307396

RESUMO

Ageing has been defined as a specific individual plasticity and remodeling capacity to the environment' insults and stimuli. The precise physiology of aging is not entirely understood. Several theories have been proposed and included programmed cell death, genetic mutations, the epigenetic clock, wear-and-tear and free radicals. Ocular surface represents a complex morpho-functional unit composed of different tissues that strictly interact to preserve homeostasis and function. Ageing severely disrupts this system by means of inflammaging and immunosenescence, leading to ocular surface failure in older population.


Assuntos
Imunossenescência , Inflamação , Idoso , Envelhecimento , Apoptose , Humanos
11.
Semin Immunopathol ; 44(3): 281-301, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35141865

RESUMO

Two vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are recognized as autoimmune and autoinflammatory diseases that manifest exclusively within the aorta and its large branches. In both entities, the age of the affected host is a critical risk factor. TAK manifests during the 2nd-4th decade of life, occurring while the immune system is at its height of performance. GCA is a disease of older individuals, with infrequent cases during the 6th decade and peak incidence during the 8th decade of life. In both vasculitides, macrophages and T cells infiltrate into the adventitia and media of affected vessels, induce granulomatous inflammation, cause vessel wall destruction, and reprogram vascular cells to drive adventitial and neointimal expansion. In GCA, abnormal immunity originates in an aged immune system and evolves within the aged vascular microenvironment. One hallmark of the aging immune system is the preferential loss of CD8+ T cell function. Accordingly, in GCA but not in TAK, CD8+ effector T cells play a negligible role and anti-inflammatory CD8+ T regulatory cells are selectively impaired. Here, we review current evidence of how the process of immunosenescence impacts the risk for GCA and how fundamental differences in the age of the immune system translate into differences in the granulomatous immunopathology of TAK versus GCA.


Assuntos
Imunossenescência , Vasculite , Idoso , Envelhecimento , Humanos , Macrófagos , Fatores de Risco
12.
Front Immunol ; 13: 807454, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35145520

RESUMO

Background: Innate immunity, armed with pattern recognition receptors including Toll-like receptors (TLR), is critical for immune cell activation and the connection to anti-microbial adaptive immunity. However, information regarding the impact of age on the innate immunity in response to SARS-CoV2 adenovirus vector vaccines and its association with specific immune responses remains scarce. Methods: Fifteen subjects between 25-35 years (the young group) and five subjects between 60-70 years (the older adult group) were enrolled before ChAdOx1 nCoV-19 (AZD1222) vaccination. We determined activation markers and cytokine production of monocyte, natural killer (NK) cells and B cells ex vivo stimulated with TLR agonist (poly (I:C) for TLR3; LPS for TLR4; imiquimod for TLR7; CpG for TLR9) before vaccination and 3-5 days after each jab with flow cytometry. Anti-SARS-CoV2 neutralization antibody titers (surrogate virus neutralization tests, sVNTs) were measured using serum collected 2 months after the first jab and one month after full vaccination. Results: The older adult vaccinees had weaker vaccine-induced sVNTs than young vaccinees after 1st jab (47.2±19.3% vs. 21.2±22.2%, p value<0.05), but this difference became insignificant after the 2nd jab. Imiquimod, LPS and CpG strongly induced CD86 expression in IgD+CD27- naïve and IgD-CD27+ memory B cells in the young group. In contrast, only the IgD+ CD27- naïve B cells responded to these TLR agonists in the older adult group. Imiquimode strongly induced the CD86 expression in CD14+ monocytes in the young group but not in the older adult group. After vaccination, the young group had significantly higher IFN-γ expression in CD3- CD56dim NK cells after the 1st jab, whilst the older adult group had significantly higher IFN-γ and granzyme B expression in CD56bright NK cells after the 2nd jab (all p value <0.05). The IFN-γ expression in CD56dim and CD56bright NK cells after the first vaccination and CD86 expression in CD14+ monocyte and IgD-CD27-double-negative B cells after LPS and imiquimod stimulation correlated with vaccine-induced antibody responses. Conclusions: The innate immune responses after the first vaccination correlated with the neutralizing antibody production. Older people may have defective innate immune responses by TLR stimulation and weak or delayed innate immune activation profile after vaccination compared with young people.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , COVID-19/prevenção & controle , Feminino , Humanos , Imiquimode/farmacologia , Imunidade Inata/imunologia , Imunossenescência/imunologia , Interferon gama/sangue , Masculino , Pessoa de Meia-Idade , Poli I-C/administração & dosagem , Poli I-C/imunologia , Receptores Toll-Like/imunologia , Vacinação
13.
Cells ; 11(3)2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35159168

RESUMO

Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, or the dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults, including centenarians, is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing-it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity, and mortality risk. While inflammageing was initially thought to be caused by "continuous antigenic load and stress", reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and the ageing of the immune system. In this review, we explore some of the main sources and consequences of inflammageing in the context of immunosenescence and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise, and pharmacological interventions can reduce inflammageing and thus, improve later life health.


Assuntos
Imunossenescência , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Biomarcadores/metabolismo , Senescência Celular/fisiologia , Humanos , Inflamação/metabolismo
14.
Immunol Lett ; 243: 19-27, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35108570

RESUMO

The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19.


Assuntos
Envelhecimento/fisiologia , Sistema Imunitário/imunologia , Inflamação/imunologia , SARS-CoV-2/fisiologia , Idoso , Animais , COVID-19 , Humanos , Imunossenescência
15.
Viruses ; 14(2)2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216002

RESUMO

Before the antiretroviral therapy (ART) era, people living with HIV (PLWH) experienced complications due to AIDS more so than aging. With ART and the extended lifespan of PLWH, HIV comorbidities also include aging-most likely due to accelerated aging-as well as a cardiovascular, neurocognitive disorders, lung and kidney disease, and malignancies. The broad evidence suggests that HIV with ART is associated with accentuated aging, and that the age-related comorbidities occur earlier, due in part to chronic immune activation, co-infections, and possibly the effects of ART alone. Normally the immune system undergoes alterations of lymphocyte and monocyte populations with aging, that include diminished naïve T- and B-lymphocyte numbers, a reliance on memory lymphocytes, and a skewed production of myeloid cells leading to age-related inflammation, termed "inflamm-aging". Specifically, absolute numbers and relative proportions of monocytes and monocyte subpopulations are skewed with age along with myeloid mitochondrial dysfunction, resulting in increased accumulation of reactive oxygen species (ROS). Additionally, an increase in biomarkers of myeloid activation (IL-6, sCD14, and sCD163) occurs with chronic HIV infection and with age, and may contribute to immunosenescence. Chronic HIV infection accelerates aging; meanwhile, ART treatment may slow age-related acceleration, but is not sufficient to stop aging or age-related comorbidities. Overall, a better understanding of the mechanisms behind accentuated aging with HIV and the effects of myeloid activation and turnover is needed for future therapies.


Assuntos
Infecções por HIV/imunologia , Imunossenescência , Monócitos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Animais , Biomarcadores , Infecções por HIV/patologia , HIV-1/imunologia , Humanos , Inflamação/imunologia , Monócitos/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/imunologia
16.
Elife ; 112022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35129436

RESUMO

Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.


Assuntos
Diversidade de Anticorpos/imunologia , Fundulidae/imunologia , Imunossenescência/imunologia , Imunidade Adaptativa/imunologia , Envelhecimento/imunologia , Animais , Linfócitos B/imunologia , Humanos , Longevidade/imunologia , Microbiota/imunologia , Modelos Animais
17.
mSphere ; 7(1): e0090821, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-34986317

RESUMO

A novel Enterocytozoon infection was identified in the intestines of sexually mature Chinook salmon. While microsporidian parasites are common across a diverse range of animal hosts, this novel species is remarkable because it demonstrates biological, pathological, and genetic similarity with Enterocytozoon bieneusi, the most common causative agent of microsporidiosis in AIDS patients. There are similarities in the immune and endocrine processes of sexually mature Pacific salmon and immunocompromised humans, suggesting possible common mechanisms of susceptibility in these two highly divergent host species. The discovery of Enterocytozoon schreckii n. sp. contributes to clarifying the phylogenetic relationships within family Enterocytozoonidae. The phylogenetic and morphological features of this species support the redescription of Enterocytozoon to include Enterospora as a junior synonym. Furthermore, the discovery of this novel parasite may have important implications for conservation, as it could be a sentinel of immune suppression, disease, and prespawning mortality in threatened populations of salmonids. IMPORTANCE In this work, we describe a new microsporidian species that infects the enterocytes of Chinook salmon. This novel pathogen is closely related to Enterocytozoon bieneusi, an opportunistic pathogen commonly found in AIDS patients and other severely immunocompromised humans. The discovery of this novel pathogen is of interest because it has only been found in sexually mature Chinook salmon, which have compromised immune systems due to the stresses of migration and maturation and which share similar pathological features with immunocompromised and senescent humans. The discovery of this novel pathogen could lead to new insights regarding how microsporidiosis relates to immunosuppression across animal hosts.


Assuntos
Síndrome de Imunodeficiência Adquirida , Enterocytozoon , Imunossenescência , Microsporídios , Microsporidiose , Animais , Enterócitos/patologia , Enterocytozoon/genética , Humanos , Microsporídios/genética , Microsporidiose/parasitologia , Microsporidiose/veterinária , Filogenia , Salmão/parasitologia
18.
Hum Cell ; 35(2): 572-582, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35032296

RESUMO

The underlying state of alterations in adipose tissue is hypothesized to be as a result of age-related changes. Young and aged mice have been documented to show distinct gene expression and distinct macrophage-specific adipose tissue regulation. However, more biological understanding is required to know the processes associated with these conditions in relation to the aging process. Transcriptional profiling with RNA-seq analysis was used to determine differentially expressed genes in young (2 months old) and aged (20 months old) mice macrophage-enriched phagocytic stromal vascular fractions of pooled epididymal white adipose tissue using data obtained from gene expression omnibus. Results showed distinct differentially expressed genes in young and aged mice with a p value cutoff of 0.05 and dissimilarities in the young and aged epididymal white adipose tissue phagocytic cells. Functional enrichment showed activation of cytokine-cytokine receptor interaction pathways, phosphorus metabolic processes and inflammatory pathways such as IL-17, TNF, NF-kappa B, and TGF-ß, while AMPK, PPAR and oxidative phosphorylation were suppressed. The analysis showed that aging is linked with phagocytic cell decline, accumulated cellular damages, inflammation, immunosenescence and increased phosphorus metabolism. Interventions that reduce phosphate-containing compound could improve phosphorus metabolism in old age to prolong lifespan and better health.


Assuntos
Imunossenescência , Tecido Adiposo , Tecido Adiposo Branco/metabolismo , Animais , Macrófagos/metabolismo , Camundongos , Fósforo/metabolismo , Análise de Sequência de RNA
19.
Glia ; 70(5): 913-934, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35061297

RESUMO

Microglia, the innate immune cells of the brain, develops a pro-inflammatory, "primed" profile with age. Using single-cell RNA-sequencing, we confirmed hippocampal microglia of aged mice (18 m.o.) had an amplified (4 h) and prolonged (24 h) neuroinflammatory response to peripheral lipopolysaccharide (LPS) challenge compared to adults (2 m.o.). Overall, there were several unique cell-, age-, and time-dependent differences in the clusters of microglia identified. Analysis of upstream regulators and canonical pathways revealed impaired regulation of an activated, neuroinflammatory state within microglia. Moreover, microglia in the aged hippocampus failed to turn over during the resolving phase of neuroinflammation. Concomitantly, astrocytes in the aged hippocampus were "immunosenescent" both 4 and 24 h after LPS challenge. For example, aged astrocytes had reduced anti-inflammatory signaling and cholesterol biosynthesis, two pathways by which astrocytes regulate the inflammatory profile of microglia. One of the pathways reduced in the aged hippocampus was interleukin (IL)-10 signaling. This pathway increases astrocytic expression of transforming growth factor (TGF)-ß, an anti-inflammatory cytokine with abundant receptor expression on microglia. Therefore, transgenic astrocytic Il10raKO mice were generated to determine if impaired IL-10R/TGFß signaling within astrocytes caused an amplified microglial neuroinflammatory response. Astrocytic Il10raKO caused exaggerated sickness behavior and a prolonged neuroinflammatory response to peripheral LPS, including increased social avoidance with amplified microglial Il1b and Tnf mRNA expression. In summary, astrocytes had an immunosenescent profile with age and, in response to peripheral LPS, had IL-10R signaling deficits and a lack of cholesterol biosynthesis, both leading to the inability to resolve microglial activation.


Assuntos
Imunossenescência , Microglia , Animais , Anti-Inflamatórios , Astrócitos/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Imunidade Inata , Inflamação/metabolismo , Interleucina-10/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Microglia/metabolismo , Fator de Crescimento Transformador beta/metabolismo
20.
Diabetes ; 71(1): 23-30, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34995348

RESUMO

Age-related immunosenescence, defined as an increase in inflammaging and the decline of the immune system, leads to tissue dysfunction and increased risk for metabolic disease. The elderly population is expanding, leading to a heightened need for therapeutics to improve health span. With age, many alterations of the immune system are observed, including shifts in the tissue-resident immune cells, increased expression of inflammatory factors, and the accumulation of senescent cells, all of which are responsible for a chronic inflammatory loop. Adipose tissue and the immune cell activation within are of particular interest for their well-known roles in metabolic disease. Recent literature reveals that adipose tissue is an organ in which signs of initial aging occur, including immune cell activation. Aged adipose tissue reveals changes in many innate and adaptive immune cell subsets, revealing a complex interaction that contributes to inflammation, increased senescence, impaired catecholamine-induced lipolysis, and impaired insulin sensitivity. Here, we will describe current knowledge surrounding age-related changes in immune cells while relating those findings to recent discoveries regarding immune cells in aged adipose tissue.


Assuntos
Tecido Adiposo/patologia , Microambiente Celular/fisiologia , Senescência Celular/fisiologia , Inflamação/patologia , Leucócitos/fisiologia , Tecido Adiposo/metabolismo , Idoso , Envelhecimento/sangue , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Microambiente Celular/imunologia , Feminino , Humanos , Imunossenescência/fisiologia , Inflamação/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos
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