CD4
T-cell surface glycoprotein CD4 precursor (T-cell surface antigen T4/Leu-3) (CD4 antigen)
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Ovarian aging leads to reproductive and endocrine dysfunction, causing the disorder of multiple organs in the body and even declined quality of offspring's health. However, few studies have investigated the changes in gene expression profile in the ovarian aging process. Here, we applied integrated bioinformatics to screen, identify, and validate the critical pathogenic genes involved in ovarian aging and uncover potential molecular mechanisms. The expression profiles of GSE84078 were downloaded from the Gene Expression Omnibus (GEO) database, which included the data from ovarian samples of 10 normal C57BL/6 mice, including old (21-22 months old, ovarian failure period) and young (5-6 months old, reproductive bloom period) ovaries. First, we filtered 931 differentially expressed genes (DEGs), including 876 upregulated and 55 downregulated genes through comparison between ovarian expression data from old and young mice. Functional enrichment analysis showed that biological functions of DEGs were primarily immune response regulation, cell-cell adhesion, and phagosome pathway. The most closely related genes among DEGs ([i]Tyrobp[/i], [i]Rac2[/i], [i]Cd14[/i], [i]Zap70[/i], [i]Lcp2[/i], [i]Itgb2[/i], [i]H2-Ab1[/i], and [i]Fcer1g[/i]) were identified by constructing a protein-protein interaction (PPI) network and consequently verified using mRNA and protein quantitative detection. Finally, the immune cell infiltration in the ovarian aging process was also evaluated by applying CIBERSORT, and a correlation analysis between hub genes and immune cell type was also performed. The results suggested that plasma cells and naïve CD4 T cells may participate in ovarian aging. The hub genes were positively correlated with memory B cells, plasma cells, M1 macrophages, Th17 cells, and immature dendritic cells. In conclusion, this study indicates that screening for DEGs and pathways in ovarian aging using bioinformatic analysis could provide potential clues for researchers to unveil the molecular mechanism underlying ovarian aging. These results could be of clinical significance and provide effective molecular targets for the treatment of ovarian aging.
Keywords
- GEO database
- bioinformatics
- biomarker
- immune cell infiltration
- ovarian aging
Acquired immune responses mediated by CD4 T cells contribute to the initiation and progression of acute coronary syndrome (ACS). ACS patients show acquired immune system abnormalities that resemble the characteristics of autoimmune dysfunction described in the elderly. This study aimed to investigate the role of premature CD4 T cells senescence in ACS and the underlying mechanism. We compared the immunological status of 25 ACS patients, 15 young healthy individuals (C1), and 20 elderly individuals with absence of ACS (C2). The percentages of CD4 T lymphocyte subsets (including naïve, regulatory, memory and effector T cells) in peripheral blood were analyzed. In ACS patients, a significant expansion of CD4 CD28 effector T cells and a decline of CD4 CD25 CD62L Treg cells were observed. In addition, patients with ACS showed an accelerated loss of CD4 CD45RA CD62L naïve T cells and a compensatory increase in the number of CD4 CD45RO memory T cells. ACS patients demonstrated no significant difference in frequency of T cell receptor excision circles (TRECs) compared to age-matched healthy volunteers. The expression of p16 was increased while CD62L was decreased in CD4 CD28 T cells of ACS patients. Compared to healthy donors, ACS patients demonstrated the lowest telomerase activity in both CD4 CD28 and CD4 CD28 T cells. The serum levels of C-reactive protein, Cytomegalovirus IgG, [i]Helicobactor pylori[/i] IgG and [i]Chlamydia pneumonia[/i] IgG were significantly higher in ACS patients. The results suggested that the percentage of CD4 T cell subpopulations correlated with chronic infection, which contributes to immunosenescence. In conclusion, chronic infection induced senescence of premature CD4 T cells, which may be responsible for the development of ACS.
Keywords
- CD28null T cells
- CD4 T cells
- acute coronary syndrome
- immunosenescence
- infection
Healthy immune aging is in part determined by how well the sizes of naïve T cell compartments are being maintained with advancing age. Throughout adult life, replenishment largely derives from homeostatic proliferation of existing naïve and memory T cell populations. However, while the subpopulation composition of CD4 T cells is relatively stable, the CD8 T cell compartment undergoes more drastic changes with loss of naïve CD8 T cells and accumulation of effector T cells, suggesting that CD4 T cells are more resilient to resist age-associated changes. To determine the epigenetic basis for these differences in behaviors, we compared chromatin accessibility maps of CD4 and CD8 T cell subsets from young and old individuals and related the results to the expressed transcriptome. The dominant age-associated signatures resembled hallmarks of differentiation, which were more pronounced for CD8 naïve and memory than the corresponding CD4 T cell subsets, indicating that CD8 T cells are less able to keep cellular quiescence upon homeostatic proliferation. In parallel, CD8 T cells from old adults, irrespective of their differentiation state, displayed greater reduced accessibility to genes of basic cell biological function, including genes encoding ribosomal proteins. One possible mechanism is the reduced expression of the transcription factors YY1 and NRF1. Our data suggest that chromatin accessibility signatures can be identified that distinguish CD4 and CD8 T cells from old adults and that may confer the higher resilience of CD4 T cells to aging.
Keywords
- T-cell
- T-cell homeostasis
- aging
- chromatin accessibility
- epigenetics
- ribosomal proteins
CD4 Foxp3 T maintain immune homeostasis, but distinct mechanisms underlying their functional heterogeneity during infections are driven by specific cytokine milieu. Here we show that MyD88 deletion in Foxp3 cells altered their function and resulted in increased fungal burden and immunopathology during oral [i]Candida albicans[/i] (CA) challenge. Excessive inflammation due to the absence of MyD88 in T coincided with a reduction of the unique population of IL-17A expressing Foxp3 cells (T 17) and an increase in dysfunctional IFN-γ /Foxp3 cells (T IFN-γ) in infected mice. Failure of MyD88 T to regulate effector CD4 T cell functions correlated with heightened levels of IFN-γ in CD4 T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa [i]in vivo[/i]. Mechanistically, IL-1β/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of T 17 cells. In the absence of IL-1 receptor signaling, T 17 cells were reduced, but IL-6-driven expansion of T IFN-γ cells was increased. This mechanism was physiologically relevant during [i]Candida[/i] infection in aged mice, as they exhibited IL-1 receptor/MyD88 defect in Foxp3 cells, loss of p-mTOR T 17 cells and reduced levels of IL-1β in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with T dysfunction, aging was associated with increased CD4 T cell hyperactivation and heightened levels of IL-6 in mice and humans in oral mucosa [i]in vivo[/i]. Taken together, our data identify IL-1β/MyD88/T axis as a new component that modulates inflammatory responses in oral mucosa. Also, dysregulation of this axis in an aging immune system may skew host defense towards an immunopathological response in mucosal compartments.
Keywords
- Candida
- Foxp3
- IL-1β
- Treg
- Treg17
- aging
- fungal infection
- senescence
Aging is generally characterized as a gradual increase in tissue damage, which is associated with senescence and chronic systemic inflammation and is evident in a variety of age-related diseases. The extent to which such tissue damage is a result of a gradual decline in immune regulation, which consequently compromises the capacity of the body to repair damages, has not been fully explored. Whereas CD4 T lymphocytes play a critical role in the orchestration of immunity, thymus involution initiates gradual changes in the CD4 T-cell landscape, which may significantly compromise tissue repair. In this review, we describe the lifespan accumulation of specific dysregulated CD4 T-cell subsets and their coevolution with systemic inflammation in the process of declined immunity and tissue repair capacity with age. Then, we discuss the process of thymus involution-which appears to be most pronounced around puberty-as a possible driver of the aging T-cell landscape. Finally, we identify individualized T cell-based early diagnostic biomarkers and therapeutic strategies for age-related diseases.
Keywords
- Aging
- Chronic systemic inflammation
- Dysregulated CD4 T cells
- Immune-mediated repair
- Thymus
Food insecurity is associated with increased morbidity and mortality in people living with HIV on antiretroviral therapy, but its relationship with immune dysregulation, a hallmark of HIV infection and comorbidity, is unknown. In 241 women participating in the Women's Interagency HIV Study, peripheral blood mononuclear cells were characterized by flow cytometry to identify cell subsets, comprising surface markers of activation (�38 HLADR ), senescence (�57 CD28-), exhaustion (%PD-1 ), and co-stimulation (�57- CD28 ) on CD4 and CD8 T-cells. Mixed-effects linear regression models were used to assess the relationships of food insecurity with immune outcomes, accounting for repeated measures at up to three study visits and adjusting for sociodemographic and clinical factors. At the baseline study visit, 71% of participants identified as non-Hispanic Black, 75% were virally suppressed, and 43% experienced food insecurity. Food insecurity was associated with increased activation of CD4 and CD8 T-cells, increased senescence of CD8 T-cells, and decreased co-stimulation of CD4 and CD8 T-cells (all p<0.05), adjusting for age, race/ethnicity, income, education, substance use, smoking, HIV viral load, and CD4 cell count. In stratified analyses, the association of food insecurity with CD4 T-cell activation was more pronounced in women with uncontrolled HIV (viral load >40 copies/mL and CD4 <500 cells/mm 3), but remained statistically significant in those with controlled HIV. Food insecurity may contribute to the persistent immune activation and senescence in women living with HIV on antiretroviral therapy, independently of HIV control. Reducing food insecurity may be important for decreasing non-AIDS-related disease risk in this population.
Keywords
- HIV
- exhaustion
- food insecurity
- immune activation
- senescence
Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-γ in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident ([i]IFN-γ[/i], [i]IL-12[/i], [i]CIITA[/i] and [i]Ctss[/i]); this was accompanied by slightly diminished [i]Unc-51 Like Autophagy Activating Kinase 1[/i] ([i]ULK1[/i]) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the CD45 CD4 Foxp3 cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye.
Keywords
- aging
- dry eye
- goblet cell
- inflammation
- lacrimal gland
- ocular surface
- rapamycin
Aging is characterized by reduced immune responses, a process known as immunosenescence. Shortly after their generation, antigen-experienced adaptive immune cells, such as CD8 and CD4 T cells, migrate into the bone marrow (BM), in which they can be maintained for long periods of time within survival niches. Interestingly, we recently observed how oxidative stress may negatively support the maintenance of immunological memory in the BM in old age. To assess whether the generation and maintenance of immunological memory could be improved by scavenging oxygen radicals, we vaccinated 18-months (old) and 3-weeks (young) mice with alum-OVA, in the presence/absence of antioxidants vitamin C (Vc) and/or N-acetylcysteine (NAC). To monitor the phenotype of the immune cell population, blood was withdrawn at several time-points, and BM and spleen were harvested 91 days after the first alum-OVA dose. Only in old mice, memory T cell commitment was boosted with some antioxidant treatments. In addition, oxidative stress and the expression of pro-inflammatory molecules decreased in old mice. Finally, changes in the phenotype of dendritic cells, important regulators of T cell activation, were additionally observed. Taken together, our data show that the generation and maintenance of memory T cells in old age may be improved by targeting oxidative stress.
Keywords
- NAC
- T cells
- aging
- antioxidants
- immunosenescence
- vaccination
- vitamin C
Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells. The effects of the aging on these abilities of MSCs have not been adequately clarified. In this study, alterations in immunomodulatory abilities of MSCs caused by aging were investigated. For this, dental pulp (DP) MSCs and peripheral blood mononuclear cells (PBMCs) of elderly and young donors were co-cultured age-matched and cross. We detected that the effects of DP-MSCs on Th1 and Th2 cells and their specific cytokines IFN-γ and IL-4 are not affected by aging. However, we observed that young and elderly DP-MSCs have different effects on Th17 and Treg cells. Th17 frequencies of young and elderly PBMCs were significantly increased only by young DP-MSCs, in contrast, Treg frequencies were significantly increased by elderly DP-MSCs. IL-6, IL-17a and HGF levels of both young and elderly PBMCs showed a significant increase only by young DP-MSCs, but TGF-β levels were significantly increased only by elderly DP-MSCs. The oral cavity is home to a rich microflora. The interactions of dental tissues with this microflora can lead them to acquire different epigenetic modifications. Aging can affect the microflora composition of the oral cavity and change this process in different directions. According to our findings, DP-MSCs are effective cells in the regulation of CD4 T cells, and their effects on Th1 and Th2 cells were not affected by aging. However, pleiotropic molecules IL-6 and HGF expressions, which are important in dental and bone tissue regeneration, decreased significantly in elderly DP-MSCs. This situation may have indirectly made a difference in the modulation effects of young and elderly DP-MSCs on the Th17 and Treg cells.
Keywords
- Aging
- CD4 T cell
- Dental pulp
- Immunomodulation
- Mesenchymal stem cell
The objective of the study was to describe the evolution of chronic non-AIDS related diseases and their risk factors, in patients living with HIV (PLHIV) in the French ANRS CO3 Aquitaine prospective cohort, observed both in 2004 and in 2014 in order to improve long-term healthcare management. The ANRS CO3 Aquitaine cohort prospectively collects epidemiological, clinical, biological and therapeutic data on PLHIV in the French Aquitaine region. Two cross sectional analyses were performed in 2004 and 2014, to investigate the patient characteristics, HIV RNA, CD4 counts and prevalence of some common comorbidities and treatment. 2138 PLHIV (71% male, median age 52.2 years in 2014) were identified for inclusion in the study, including participants who were registered in the cohort with at least one hospital visit recorded in both 2004 and 2014. Significant increases in the prevalence of diagnosed chronic kidney disease (CKD), bone fractures, cardiovascular events (CVE), hypertension, diabetes and dyslipidaemia, as well as an increase in treatment or prevention for these conditions (statins, clopidogrel, aspirin) were observed. It was also reflected in the increase in the proportion of patients in the "high" or "very high" risk groups of the disease risk scores for CKD, CVE and bone fracture score. Between 2004 and 2014, the aging PLHIV population identified in the French ANRS CO3 Aquitaine prospective cohort experienced an overall higher prevalence of non-HIV related comorbidities, including CKD and CVD. Long-term healthcare management and long-term health outcomes could be improved for PLHIV by: careful HIV management according to current recommendations with optimal selection of antiretrovirals, and early management of comorbidities through recommended lifestyle improvements and preventative measures.
Keywords
- Aging
- Cardiovascular events
- Chronic kidney disease
- Comorbidities
- HIV
With increased use of antiretroviral therapy (ART), HIV mortality rates are declining and people living with HIV (PLWH) are surviving longer. We characterized CD4 recovery and viral suppression among adults aged < 50 and ≥ 50 years living with HIV who initiated ART in the African Cohort Study (AFRICOS). Beginning in January 2013, PLWH at twelve clinics in Kenya, Uganda, Tanzania and Nigeria underwent medical history review, CD4 and viral load testing as part of the ongoing African Cohort Study (AFRICOS). ART-naïve PLWH who initiated ART within 30 days of enrollment and had at least one year of follow-up were included in these analyses. To compare ART response in participants < 50 years and ≥ 50 years old, changes in CD4 count and viral load suppression after ART initiation were examined at different time points using linear and binomial regression with generalized estimating equations. Variables for time since ART initiation and the interaction between age group and time on ART were included in the model to evaluate longitudinal changes in CD4 recovery and viral suppression by age. Between January 2013 and September 2019, 2918 PLHV were enrolled in the cohort. Of these, 443 were ART naïve and initiated on ART within 30 days of enrollment, with 90% (n = 399) aged < 50 years old at ART initiation. At ART initiation, participants aged 50 and older had a higher median CD4 count compared to participants younger than 50 years of age although it did not reach statistical significance (306 cells/mm , IQR:130-547 vs. 277cells/mm , IQR: 132-437). In adjusted models examining CD4 recovery and viral suppression there were no significant differences by age group over time. By the end of follow-up viral suppression was high among both groups of adults (96% of adults ≥ 50 years old and 92% of adults < 50 years old). This study found no difference in long-term CD4 recovery or viral suppression by age at ART initiation. We found that particularly among younger adults participants had lower median CD4 counts at ART initiation, suggesting the importance of identifying and putting this population on treatment earlier in the disease course.
Keywords
- Elders on antiretroviral drugs
- HIV and aging
- HIV treatment outcomes
- Sub-saharan Africa
Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4 T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4 T cell senescence and identified the underlying mechanisms using a D-gal-induced mouse aging model. In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, D-gal group, hPMSC group, and PBS group. In in vitro experiment, human naive CD4 T (CD4CD45RA) cells were prepared using a naive CD4 T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4 T cell were co-cultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging-related proteins was detected by Western blotting, RT-PCR, and confocal microscopy. We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent CD4 T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent CD4 T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4 T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4 T cells. Our results indicate that hPMSCs attenuate D-gal-induced CD4 T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.
Keywords
- Aging
- CD4 T cells
- Nrf2
- Oxidative stress
- Senescence-associated secretoryphenotype
- hPMSC
Late diagnosis of human immunodeficiency virus (HIV) is associated with increased morbidity and mortality, and represents a serious public health concern. A retrospective medical record review was conducted on 188 patients with newly diagnosed HIV at a large academic center's HIV clinic from 1/2010 to 12/2019. Patient demographic data, HIV staging, and response to combination antiretroviral therapy (cART) as measured by HIV viral suppression at 12 weeks (HIV RNA < 50 copies) were collected. Bivariate analyses were applied to compare patients ≥50 years old to those < 50 years old. Over two-thirds of the older patients with a new diagnosis of HIV presented with a CD4 count < 200, or an AIDS-defining illness. Though not statistically significant, this same group also had a delay to viral suppression with only 59% achieving viral suppression after 12-weeks of cART initiation. This study suggests that older patients are presenting to care with advanced stages of HIV, and may also have a delay in achieving viral suppression after cART initiation. Future studies should aim to target HIV testing and treatment strategies for this at-risk older adult group.
Keywords
- Aging population
- HIV
- Older adults
- Risk
- Stigma
- Testing
- Motor and cognitive deficits were compared in aging, chronically treated human immunodeficiency virus (HIV) people, people with mild-to-moderate stage Parkinson's disease (PD), and healthy controls. : Groups consisted of 36 people with PD, 28 with HIV infection, and 28 healthy controls. Motor function was assessed with the Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) and a rapid alternating finger tapping (RAFT) task on an engineered keyboard known as Quantitative Digitography (QDG). Executive function, verbal memory, and visuospatial processing were assessed using standard neuropsychological tests. : HIV demonstrated RAFT deficits similar to PD such as reduced amplitude ([i]P[/i] = 0.023) and greater amplitude variability ([i]P[/i] = 0.019) in the index finger when compared to controls. This fine motor disturbance correlated with HIV's immune health, measured by their CD4 T cell count ([i]P[/i] < 0.01). The UPDRS did not yield motor differences between HIV and controls. Executive function and verbal memory were impaired in HIV ([i]P[/i] = 0.006, [i]P[/i] = 0.016, respectively), but not in PD; visuospatial processing was similarly impaired in HIV and PD ([i]P[/i] < 0.05) although motor deficits predominated in PD. : Fine motor bradykinesia measured quantitatively by QDG RAFT holds promise as a marker of motor decline related to current immune health in aging HIV patients and may be useful in longitudinal studies regarding mechanisms of immunosenescence vs. potential toxicity of combination antiretroviral therapy (cART) in this population. Additionally, motor and cognitive networks in HIV may be affected differently as the disease progresses as observed in the differential patterns of impairment between HIV and PD, providing insight into the mechanisms of brain deterioration in HIV.
Keywords
- HIV—human immunodeficiency virus
- Parkinson’s disease
- aging
- fine motor activities
- motor control
People with HIV on successful antiretroviral therapy show signs of premature aging and are reported to have higher rates of age-associated comorbidities. HIV-associated immune dysfunction and inflammation have been suggested to contribute to this age advancement and increased risk of comorbidities. Partial least squares regression (PLSR) was used to explore associations between biological age advancement and immunological changes in the T cell and monocyte compartment in people with HIV (n=40), comparable HIV-negative individuals (n=40) participating in the Comorbidity in Relation to AIDS (COBRA) cohort, and blood donors (n=35). We observed that age advancement in all three groups combined was associated with a monocyte immune phenotypic profile related to inflammation and a T cell immune phenotypic associated with immune senescence and chronic antigen exposure. Interestingly, a unique monocyte and T cell immune phenotypic profile predictive for age advancement was found within each group. An inflammatory monocyte immune phenotypic profile associated with age advancement in HIV-negative individuals, while the monocyte profile in blood donors and people with HIV was more reflective of loss of function. The T cell immune phenotypic profile in blood donors was related to loss of T cell function, whereas the same set of markers were related to chronic antigen stimulation and immune senescence in HIV-negative individuals. In people with HIV, age advancement was related to changes in the CD4 T cell compartment and more reflective of immune recovery after cART treatment. The identified monocyte and T cell immune phenotypic profiles that were associated with age advancement, were strongly related to inflammation, chronic antigen exposure and immune senescence. While the monocyte and T cell immune phenotypic profile within the HIV-negative individuals reflected those observed in the combined three groups, a distinct profile related to immune dysfunction, was observed within blood donors and people with HIV. These data suggest that varying exposures to lifestyle and infection-related factors may be associated with specific changes in the innate and adaptive immune system, that all contribute to age advancement.
Keywords
- HIV
- T cell
- aging
- immune activation
- immune dysfunction
- inflammation
- monocyte
Wisdom is a unique human personality trait with cognitive, affective or compassionate, and reflective dimensions. We evaluated relationships of three specific dimensions of wisdom with cognitive function and physical and mental well-being in people with HIV (PWH) and HIV-negative (HIV-) participants. Subjects included 138 adults (61 PWH, 77 HIV-) from the San Diego community. Validated measures were used to assess wisdom and well-being. Cognitive function was assessed via the Montreal Cognitive Assessment. We conducted multivariate linear regressions to evaluate the associations of wisdom dimensions with cognitive function and physical and mental well-being. Compared to the HIV- group, PWH had lower mean scores on cognitive function, and physical and mental well-being, and cognitive and reflective dimensions of wisdom, but similar scores on affective or compassionate wisdom. Among PWH, higher total wisdom scores were associated with older age, lower likelihood of substance dependence, greater mental well-being, better cognitive function, higher resilience, social support, and optimism scores, as well as lower levels of perceived stress and nadir CD4 count. Our findings of an association of different dimensions of wisdom with physical and/or mental well-being in PWH would point to a possibility that enhancing these dimensions of wisdom might improve health outcomes in PWH.
Keywords
- Affective
- Aging
- Aids
- Compassion
- Reflective
Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease (ESRD) in developed countries. It is known that patients with ESRD and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. 523 adult patients with type 2 diabetes were recruited for this study. Demographic data and clinical information were obtained from medical chart review. Immunosenescence, or aging of the immune system was assessed by staining freshly-obtained peripheral blood with immunophenotyping panels and analyzing cells using multicolor flow cytometry. Consistent with previously observed in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. When compared to diabetic patients with preserved renal function (estimated glomerular filtration rate > 60 ml/min), patients with impaired renal function exhibit a significant decrease of total CD3 and CD4 T cells, but not CD8 T cell and monocyte numbers. Immunosenescence was observed in patients with CKD stage 3 and in patients with more severe renal failure, especially of CD8 T cells. However, immunosenescence was not associated with level of proteinuria level or glucose control. In age, sex and glucose level-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28 , CD127 , and CD57 cells among CD8 T cells when compared to patients with preserved renal function. In contrast, no change was detected in monocyte subpopulations as renal function declined. In addition, higher body mass index (BMI) is associated with enhanced immunosenescence irrespective of CKD status. The extent of immunosenescence is not significantly associated with proteinuria or glucose control in type 2 diabetic patients. T cells, especially the CD8 subsets, exhibit aggravated characteristics of immunosenescence during renal function decline as early as stage 3 CKD. In addition, inflammation increases since stage 3 CKD and higher BMI drives the accumulation of CD8 CD57 T cells. Our study indicates that therapeutic approaches such as weight loss may be used to prevent the emergence of immunosenescence in diabetes before stage 3 CKD.
Keywords
- BMI
- CKD
- Diabetes
- Immunosenescence
- T cell
The presence and functional role of T cell infiltration in human brain parenchyma with normal aging and neurodegeneration is still under intense debate. Recently, CD8 cells have been shown to infiltrate the subventricular zone in humans and mice with a deleterious effect on neural stem cells. However, to which extent T cell infiltration in humans also occurs in other regions such as cortical areas and, especially, white matter (WM) has not yet been addressed. In this work, we report a low-grade infiltration of T cells (CD3 , CD4 and CD8 ) in the WM of aged individuals that is also observed at similar levels in patients with neurodegenerative disorders (Alzheimer´s disease). In particular, CD3 and CD8 cells were increased in perivascular and parenchymal WM and cortical regions (enthorinal cortex). These results reveal that T cell infiltration in brain parenchyma occurs with physiological and pathological aging in several regions, but it seems to be lower than in the subventricular zone neurogenic niche.
Keywords
- aging
- neuroscience
- pathology
Ageing implicates a remodeling of our immune system, which is a consequence of the physiological senescence of our cells and tissues coupled with environmental factors and chronic antigen exposure. An immune system that senesces includes more differentiated cells with accumulation of highly differentiated CD4 and CD8 T cells. The pool of naive T cells decreases with the exponential thymic involution induced by age. Differentiated T cells have similar, if not higher, functional capacities but scarce studies are looking at the impact of senescence among specific T cells. After a stimulation, other immune cells (monocytes, dendritic cells and NK) are functionally altered during ageing. It is as if the immune system was more efficient at the basal level, but less efficient after a stimulation in the old compared to young people, likely due to less reserve. Concerning the clinical impact, older people are more prone to certain pathogens and their clinical manifestations differ from the younger people. Severe flu and VZV reactivation are more frequent with an altered cellular response to vaccination. Vaccination failure can have detrimental consequences in people presenting frailty criteria. Old people frailty is majored by their comorbidities and diseases like cancer. Thus, chemotherapies are employed with circumspection in older patients. The use of anti-PD-1/PD-L1 immunotherapies is therefore attractive, because of less side effects with a better response compared to chemotherapy. Old persons inclusion is lacking in current studies and clinical trials. Some subgroups or pooled analyses confirm the gain in response without increased toxicities in older patients but their inclusion criteria differ from the real-life practice. Specific studies focusing on this population are needed because of the increasing cancer incidence with age and the overall ageing of the population.
Keywords
- Ageing
- Cancer
- Elderly
- Immunosenescence
- Immunotherapy
- Old people
- Oncogeriatry
While memory T-cells represent a hallmark of adaptive immunity, little is known about the genetic mechanisms regulating the longevity of memory CD4 T cells. Here, we studied the dynamics of gene expression in antigen specific CD4 T cells during infection, memory differentiation, and long-term survival up to nearly a year in mice. We observed that differentiation into long lived memory cells is associated with increased expression of genes inhibiting cell proliferation and apoptosis as well as genes promoting DNA repair response, lipid metabolism, and insulin resistance. We identified several transmembrane proteins in long-lived murine memory CD4 T cells, which co-localized exclusively within the responding antigen-specific memory CD4 T cells in human. The unique gene signatures of long-lived memory CD4 T cells, along with the new markers that we have defined, will enable a deeper understanding of memory CD4 T cell biology and allow for designing novel vaccines and therapeutics.
Keywords
- CD4 T cell
- Cell longevity
- Gene
- Genetic programs
- Memory T cell
- Memory cell markers
New diagnoses of multiple myeloma (MM) tend to occur after the age of 60, by which time thymic output is severely reduced. As a consequence, lymphocyte recovery after lymphopenia-inducing anti-MM therapies relies on homeostatic proliferation of peripheral T cells rather than replenishment by new thymic emigrants. To assess lymphocyte recovery and phenotype in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), we tracked CD4 and CD8 T cell populations at serial time points throughout treatment and compared them to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in the CD4:8 ratio, a decrease in naïve CD4 T cells, and an increase in effector memory T cells and PD1-expressing CD4 T cells. Transcriptional profiling highlighted that genes associated with fatty acid β-oxidation were upregulated in T cells in RRMM, suggesting increased reliance on mitochondrial respiration. High mitochondrial mass was seen in all T cell subsets in RRMM but with relatively suppressed reactive oxygen species and mitochondrial membrane potential, indicating mitochondrial dysfunction. These findings highlight that anti-MM and ASCT therapies perturb the composition of the T cell compartment and drive substantial metabolic remodeling, which may affect the fitness of T cells for immunotherapies. This is particularly pertinent to chimeric antigen receptor (CAR)-T therapy, which might be more efficacious if T cells were stored prior to ASCT rather than at relapse.
Keywords
- T cell
- aging
- autologous stem cell transplant
- metabolism
- myeloma
The number of elderly people with multiple sclerosis (MS) has increased in line with population ageing. As the immune system presents profound changes over an individual's lifetime, it is important to understand the differences between these patients and younger patients. Immunosenescence, defined as age-related alterations naturally occurring in the immune system, particularly influences tolerance, response, and adverse effects of disease-modifying treatments for MS. Thymic involution is the most noteworthy characteristic of this phenomenon. This process leads to a reduction in the number of virgin T cells. Other effects include an inverted CD4 /CD8 cell ratio, severe alterations in NK cell functioning, and reduced tissue repair capacity in the brain. The number of older people with MS is increasing due to population ageing, advances in disease-modifying treatments, and improved health and social care of these patients. Ageing of the immune system increases the risk of infections, tumours, and autoimmune diseases in elderly individuals. Furthermore, neurodegeneration is accelerated in patients with MS due to the nervous system's loss of remyelination capacity. Understanding of the changes affecting the immune system in the elderly population is essential to improving the care provided to this ever-growing patient group.
Keywords
- Ageing
- Envejecimiento
- Esclerosis múltiple
- Esclerosis múltiple de comienzo tardío
- Immunosenescence
- Inmunosenescencia
- Late-onset multiple sclerosis
- Multiple sclerosis
Whether accelerated aging develops over the course of chronic HIV infection or can be observed prior to significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) prior to the initiation of antiretroviral therapy. 378 antiretroviral therapy-naïve PLWH with CD4 T cell counts >500 cells/mm 3 enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared to 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and regions (DMRs) in PLWH compared to controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. There were a total of 56,639 DMPs and 6,103 DMRs at a false discovery rate<0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age compared to HIV-negative controls (p=0.001), with black race, low CD4, high CD8 T cell counts, and duration of HIV being risk factors for age acceleration. PLWH prior to the initiation of antiretroviral therapy and with preserved immune status show evidence of advanced methylation aging.
Keywords
- HIV
- aging
- epigenetics
- methylation
To study the effect of allogeneic umbilical cord mesenchymal stem cell transplantation on the structure and function of the thymus in aged C57 mice and provide a new method for the treatment of senile thymic atrophy. The changes in the thymus cortex and medulla volume and the lymphocyte ratio were analyzed by immunofluorescence. For thymus tissue sections, immunohistochemical staining was performed to detect p16, p53, SOD, becline1, LC3b, p62, sirt1, and sirt3. Changes in CK5, CK8, CD4 and CD8 expression were observed. Treatment with mUCMSCs could promote hair regeneration in aging mice and regenerate the thymus structure. mUCMSCs inhibited senescence of the thymus and promoted structural and functional thymus regeneration by downregulating the senescence genes p53 and p16 and upregulating the SOD, Sirt1 and Sirt3 genes, but the mechanism requires further research. C57 mice were obtained and met the requirements of thymic aging. mUCMSCs were infused via the tail vein at a dose of 1×10 cells/kg twice per week for 3 weeks. Six weeks after the last transplantation, the thymus was weighed, and the thymus-to-body weight ratio was calculated. The thymus tissue was stained with HE.
Keywords
- aged
- senescence
- thymus
- transplantation
- umbilical cord mesenchymal stem cells
Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks. Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38 CD8 T cells and an increase in the frequency of CD28-CD57 in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. NCT02577042.
MeSH Terms
- Adult
- Anti-HIV Agents
- Anticholesteremic Agents
- Atorvastatin
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Female
- HIV Infections
- HIV Protease Inhibitors
- Humans
- Immunosenescence
- Inflammation
- Lymphocyte Activation
- Male
- Middle Aged
- Pilot Projects
- Raltegravir Potassium
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8 T cells, but not CD4 T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8 T cell subsets. PD-1-expressing CD8 T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8 cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development. Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8 T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8 T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8 T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.
MeSH Terms
- Aged, 80 and over
- Antigens, CD
- Betacoronavirus
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- COVID-19
- Coronavirus Infections
- Cytotoxins
- Female
- Humans
- Immunity, Cellular
- Male
- Middle Aged
- Pandemics
- Pneumonia, Viral
- SARS-CoV-2
- T-Lymphocyte Subsets
- T-Lymphocytes, Cytotoxic
Keywords
- CD4
- CD8
- COVID-19
- PD-1
- SARS-CoV-2
- aging
- cytotoxic T cells
- granzyme
- perforin
The first SARS-CoV-2 vaccine(s) will likely be licensed based on neutralizing antibodies in Phase 2 trials, but there are significant concerns about using antibody response in coronavirus infections as a sole metric of protective immunity. Antibody response is often a poor marker of prior coronavirus infection, particularly in mild infections, and is shorter-lived than virus-reactive T-cells; strong antibody response correlates with more severe clinical disease while T-cell response is correlated with less severe disease; and antibody-dependent enhancement of pathology and clinical severity has been described. Indeed, it is unclear whether antibody production is protective or pathogenic in coronavirus infections. Early data with SARS-CoV-2 support these findings. Data from coronavirus infections in animals and humans emphasize the generation of a high-quality T cell response in protective immunity. Yellow Fever and smallpox vaccines are excellent benchmarks for primary immune response to viral vaccination and induce long-lived virus-reactive CD8 T-cells, which are present and measurable within 1-4 months of vaccination. Progress in laboratory markers for SARS-CoV2 has been made with identification of epitopes on CD4 and CD8 T-cells in convalescent blood. These are much less dominated by spike protein than in previous coronavirus infections. Although most vaccine candidates are focusing on spike protein as antigen, natural infection by SARS-CoV-2 induces broad epitope coverage, cross-reactive with other betacoronviruses. It will be important to understand the relation between breadth, functionality and durability of T-cell responses and resulting protective immunity. It would be a public health and general trust-in-medicine nightmare - including a boost to anti-vaccine forces - if immune protection wears off or new disease patterns develop among the immunized. Data correlating clinical outcomes with laboratory markers of cell-mediated immunity, not only with antibody response, after SARS-CoV-2 natural infection and vaccines may prove critically valuable if protective immunity fades or if new patterns of disease emerge.
Keywords
- Antibodies
- Antibody-dependent enhancement
- CD8 T-cells
- COVID-19
- Durable immunity
- Protective immunity
- SARS
- SARS-CoV-2
- T cell lifespan
- T-cell epitopes
- T-cells
- Vaccines
- Yellow Fever Vaccine
Chronic HIV infection accelerates immune aging and is associated with abnormal hemato-lymphopoiesis, but the relationship between HIV-induced aging and Hematopoietic Progenitor Cells (HPC) function is not well-defined. In the context of aging, it has been demonstrated using a murine model that Per2 (Period circadian clock 2) is a negative regulator of HPC survival and lineage potential. A possible involvement of Per2 modulation on hematopoietic failure during HIV infection has not yet been investigated. The aim of this study was to analyze whether Per2 is differently expressed and regulated on HPC during HIV infection, possibly providing a therapeutic target to restore lymphoid potential in the HPC compartment. To this purpose, Per2 expression in circulating HPC was compared in 69 chronic HIV infected patients under successful ART and in matched 30 uninfected healthy donors (HD). HPC aging was assessed by measuring relative telomere length (RTL), and HPC functionality was evaluated by Colony Forming Cell (CFC) assay from both [i]ex vivo[/i] HIV patients and [i]in vitro[/i] Per2 overexpressing donors. Our results showed a lower RTL in HPC and a decrease of white progenitor colonies from HIV patients with lower CD4 respect to those with higher CD4 T cell count (<500 respect to >500 CD4 T cell/mmc). Interestingly, we found that the frequency of Per2-expressing HPC is higher in HIV patients than in HD and correlated to RTL of CFC derived cells, highlighting a relationship between low proliferative rate and Per2 expression. Indeed, the [i]in vitro[/i] overexpression of Per2 resulted in a significant decrease of white progenitor colonies respect to control cells. Finally, we showed that the deacetylase Sirtuin 1, a negative regulator of Per2, was downregulated in HPC from HIV patients, and the peripheral blood treatment with resveratrol (Sirtuin 1 inducer) determined a decrease of Per2 expressing HPC. Altogether, these results suggest that during HIV infection, Per2 is involved in the regulation of HPC expansion and differentiation and its overexpression may impair the immune reconstitution. These data support the rationale to explore the role of this regulatory mechanism during aged-associated hemato-lymphopoiesis impairment in HIV infection.
Keywords
- HIV
- Sirtuin 1
- hematopoietic progenitor cells
- period circadian clock 2
- senescence
- telomere length
The SARS-CoV-2 infection has widely spread to become the greatest public health challenge to date, the COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. The Spanish case-fatality rate is 11.22%, far higher than those reported in Asia or by other European countries. A multicentre retrospective study of demographic, clinical, laboratory and immunological features of 584 Spanish COVID-19 hospitalized patients and their outcomes was performed. The use of renin-angiotensin system blockers was also analysed as a risk factor. In this study, 27.4% of cases presented a mild course, 42.1% a moderate one and for 30.5% of cases, the course was severe. Ages ranged from 18 to 98 (average 63). Almost 60 % (59.8%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19, and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of angiotensin-converting enzyme inhibitors was associated with a better prognosis. The angiotensin II receptor blocker use was associated with a more severe course. Age and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and the clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for the hampering of immune system effectors. The adaptive immunity would become exhausted and a strong but ineffective and almost deleterious innate response would account for COVID-19 severity. Angiotensin-converting enzyme inhibitors used by hypertensive patients have a protective effect in regards to COVID-19 severity in our series. Conversely, patients on angiotensin II receptor blockers showed a severer disease.
Keywords
- ACE2
- C-reactive protein
- COVID-19
- Immunity
- Immunosenescence
- Interleukin-6
- Lymphocytes
- Renin-angiotensin system
- Severe acute respiratory syndrome coronavirus 2
- Spain
Thymocyte differentiation is dependent on the availability and transport of metabolites in the thymus niche. As expression of metabolite transporters is a rate-limiting step in nutrient utilization, cell surface transporter levels generally reflect the cell's metabolic state. The GLUT1 glucose transporter is upregulated on actively dividing thymocytes, identifying thymocytes with an increased metabolism. However, it is not clear whether transporters of essential elements such as phosphate are modulated during thymocyte differentiation. While PiT1 and PiT2 are both phosphate transporters in the SLC20 family, we show here that they exhibit distinct expression profiles on both murine and human thymocytes. PiT2 expression distinguishes thymocytes with high metabolic activity, identifying immature murine double negative (CD4 CD8 ) DN3b and DN4 thymocyte blasts as well as immature single positive (ISP) CD8 thymocytes. Notably, the absence of PiT2 expression on RAG2-deficient thymocytes, blocked at the DN3a stage, strongly suggests that high PiT2 expression is restricted to thymocytes having undergone a productive TCRβ rearrangement at the DN3a/DN3b transition. Similarly, in the human thymus, PiT2 was upregulated on early post-β selection CD4 ISP and TCRαβ CD4 DP thymocytes co-expressing the CD71 transferrin receptor, a marker of metabolic activity. In marked contrast, expression of the PiT1 phosphate importer was detected on mature CD3 murine and human thymocytes. Notably, PiT1 expression on CD3 DN thymocytes was identified as a biomarker of an aging thymus, increasing from 8.4 ± 1.5% to 42.4 ± 9.4% by 1 year of age ([i]p[/i] < 0.0001). We identified these cells as TCRγδ and, most significantly, NKT, representing 77 ± 9% of PiT1 DN thymocytes by 1 year of age ([i]p[/i] < 0.001). Thus, metabolic activity and thymic aging are associated with distinct expression profiles of the PiT1 and PiT2 phosphate transporters.
Keywords
- aging
- glucose transporters
- human
- metabolism
- mice
- phosphate transporters
- thymus
Decline in immune system function (immunosenescence) has been implicated in several age-related disorders. However, little is known about whether alteration in T-cell senescence, a process underlying immunological ageing, is related to muscle health in very old adults (aged ≥85 years). Utilising data from the Newcastle 85 Study, we aimed to (a) derive and characterise immunosenescence profiles by clustering 13 baseline immunosenescence-related biomarkers of lymphocyte compartments in 657 participants; (b) explore the association between the profiles and 5-year change in muscle strength (grip strength) and physical performance (Timed Up-and-Go test), and (c) determine whether immunosenescence profiles predict 3-year incident sarcopenia. Two distinct clusters were identified; Cluster 1 ('Senescent-like phenotype', n = 421), and Cluster 2 ('Less senescent-like phenotype', n = 236) in individuals with complete biomarker data. Although Cluster 1 was characterised by T-cell senescence (e.g., higher frequency of CD4 and CD8 senescence-like effector memory cells), and elements of the immune risk profile (lower CD4/CD8 ratio, CMV ), it was not associated with change in muscle function over time, or with prevalent or incident sarcopenia. Future studies will determine whether more in-depth characterisation or change in T-cell phenotypes predict the decline in muscle health in late adulthood.
Keywords
- immunosenescence
- lymphocyte compartments
- physical performance
- sarcopenia
- very old adults
An upward trend in life expectancy has been observed in a majority of developed countries and leading to increasing in aging-related diseases. Aging is a risk factor for the development of widespread clinical conditions such as cardiovascular and autoimmune diseases, cancer, infections. Although studies have been very active, the problem of aging still remains one of the most obscure aspects of human biology. Regulatory T (Treg) cells with immunosuppressive properties have a pivotal role in the maintenance of immune homeostasis. Alterations in Treg cell functionality appear to be of great importance in the development of immune senescence and contribute to increased susceptibility to immune-mediated diseases with age. This review highlights recent findings regarding the age-related changes in the numbers and functional activity of human Tregs. Some of the mechanisms that maintain the balance of Tregs during human aging are discussed. The possible roles of Tregs in the pathogenesis of diseases associated with advanced age are also considered. Age-related systemic changes, such as thymic involution, hormonal status, and epigenetic modifications, may affect the state of the Treg population and trigger various diseases. These changes involve decline or amplification in the functional activity of Tregs, an increase in the memory Treg subset and shifting of a Th17/Treg balance. Taken together, the reviewed data suggest equal or even increased Treg functionality with age. Thus, age-mediated Treg expansion and higher Treg activity may contribute to elevated immune suppression and increased risk of infections and cancer.
Keywords
- Aging
- Autoimmunity
- Cancer
- FOXP3
- Immune senescence
- Immune suppression
- Inflammaging
- Regulatory T cells
- T helper 17
- Treg
The prevalence of age-related comorbidities is increased in people living with HIV, even in those well-controlled on combination antiretroviral therapy (ART). Persistent immune activation and inflammation may play pivotal roles in the pathogenesis; however, the burden of morbidities in the older HIV infected population may be exacerbated and driven by distinct mechanisms. In a cross sectional study of 45 HIV-infected participants 60 years or older, we examined the relationships between 14 immunomodulatory and inflammatory factors and the Veterans Aging Cohort Study (VACS) Index, a metric of multimorbidity and mortality comprised of age, CD4 count, hemoglobin, Fibrosis-4 [FIB-4], and estimated glomerular filtration rate [eGFR], by linear regression analysis. All participants were virally suppressed (<50 HIV RNA copies/mL), on ART, and primarily Caucasian (86.7%), and male (91.1%). Plasma levels of monocyte/macrophage-associated (neopterin, IP-10, sCD163, sCD14, and MCP-1) and glycan-binding immunomodulatory factors (galectin (Gal)-1, Gal-3, and Gal-9) were assessed, as well as inflammatory biomarkers previously linked to the VACS Index (i.e., CRP, cystatin C, TNF-α, TNFRI, IL-6, and D-dimer) for comparison. In regression analysis, higher VACS index scores were associated with higher levels of neopterin, cystatin C, TNFRI, and Gal-9 (all [i]p[/i] < 0.05), potentially driven by correlations found with individual VACS components, including age, CD4 count, FIB-4, and eGFR. Gal-9, cystatin C, and TNFRI directly correlated with the extent of multimorbidity. Multiple correlations among markers were observed, suggesting an interplay of overlapping, but distinct, pathways. Collectively, in addition to cystatin C and TNFRI, both galectin-9 and neopterin, independently emerged as novel fluid markers of the VACS Index and burden of comorbidity and may further guide in understanding pathogenic mechanisms of age-related disorders in older HIV-infected individuals on suppressive ART.
Keywords
- HIV
- aging
- anti-retroviral therapy
- inflammation
- morbidity
Ageing is often characterised by nutritional deficiencies and functional alterations of the digestive and immune system. The aim of the present study was to analyse the impact of consumption of conventional milk with A1/A2 beta-casein, compared to milk containing only the A2 beta-casein variant, characterised by a protein profile favouring gut health. Twenty-four ageing Balb-c mice (20 months old) were fed for 4 weeks, with either a control diet (CTRL), a diet supplemented with bovine milk containing A1/A2 beta-casein (A1A2) or a diet containing A2/A2 beta-casein (A2A2). Lymphocyte subpopulations, enzymatic activities, cytokine secretion, gut morphology and histopathological alterations were measured in different gut segments, while short-chain fatty acids (SCFAs) content and microbiota composition were evaluated in faecal samples. The A2A2 group showed higher content of faecal SCFAs (in particular, isobutyrate) of intestinal CD4 and CD19 lymphocytes in the intraepithelial compartment and improved villi tropism. The A1A2 group showed higher percentages of intestinal TCRγδ lymphocytes. Faecal microbiota identified [i]Deferribacteriaceae[/i] and [i]Desulfovibrionaceae[/i] as the most discriminant families for the A2A2 group, while [i]Ruminococcaceae[/i] were associated to the A1A2 group. Taken together, these results suggest a positive role of milk, in particular when containing exclusively A2 beta-casein, on gut immunology and morphology of an ageing mice model.
Keywords
- A2 beta-casein
- SCFAs
- elderly
- gut inflammation
- gut microbiota
- gut morphology
- immunosenescence
Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of immune system, which is recently concerned as a significant factor for increased risk of various morbidities. Nevertheless, there are few dates explicating the relevancy of T cell senescence to mortality. In this study, we prospectively studied the predictive value of T cell senescence for mortality in hemodialysis patients. Patients who had been on hemodialysis treatment for at least 6 months were enrolled. T cell senescence determined by differentiation status was evaluated by flow cytometry. Survival outcomes were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to evaluate the prognostic impact of T cell premature aging and other clinical factors on all-cause mortality. A total of 466 patients (277 man and 169 women) were enrolled in this study. Decreased number of naïve T cell, as the most prominent feature of T cell senescence, did not change in parallel with age in these patients. Decreased absolute count of T cell, naïve T cell, CD4 naïve T cell were independently associated with all-cause mortality. Decreased percentage of T cell and increased percentage of CD8 central-memory T cell were also independently associated with all-cause mortality. After including all the T cell parameters in one regression model, only decreased count of naïve T cell was significantly associated with increased mortality in these patients. Aging-associated T cell changes are aggravated in ESRD patients. For the first time, our study demonstrates that naïve T cell depletion is a strong predictor of all-cause mortality in HD patients.
Keywords
- Hemodialysis
- Inflammation
- Mortality
- T cell aging
- naïve T cells
With advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant's frailty score based on enumeration of immune cell subpopulations. In the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16 monocytes, and lower numbers of both CD56 T cells and late differentiated CD4 TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty. In-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.
Keywords
- Frailty
- Healthy aging
- Immune cellular profiling
- Immune homeostasis
- Immunosenescence
- Sex-specific immune profile
Aging is associated with immune dysregulation, especially T cell disorders, which result in increased susceptibility to various diseases. Previous studies have shown that loss of co-stimulatory receptors or accumulation of co-inhibitory molecules play important roles in T cell aging. In the present study, CD70, which was generally regarded as a costimulatory molecule, was found to be upregulated on CD4 and CD8 T cells of elderly individuals. Aged CD70 T cells displayed a phenotype of over-activation, and expressed enhanced levels of numerous inhibitory receptors including PD-1, 2B4 and LAG-3. CD70 T cells from elderly individuals exhibited increased susceptibility to apoptosis and high levels of inflammatory cytokines. Importantly, the functional dysregulation of CD70 T cells associated with aging was reversed by blocking CD70. Collectively, this study demonstrated CD70 as a prominent regulator involved in immunosenescence, which led to defects and overwhelming inflammatory responses of T cells during aging. These findings provide a strong rationale for targeting CD70 to prevent dysregulation related to immunosenescence.
Keywords
- CD70
- T cell aging
- co-inhibitory molecules
- immunosenescence
- overwhelming inflammatory responses
Antiretroviral therapy (ART) has improved life expectancy for individuals with HIV infection, but recent data comparing life span and comorbidity-free years by HIV status are lacking. To quantify the gap in life span and comorbidity-free years by HIV status among adults with access to care. This matched cohort study used data from insured adults with and without HIV infection (aged ≥21 years) matched 1:10 at medical centers of Kaiser Permanente in northern and southern California and the mid-Atlantic states of Washington DC, Maryland, and Virginia from January 1, 2000, through December 31, 2016. Data were analyzed from September 1, 2019, through March 31, 2020. HIV status and, for individuals with HIV infection, ART initiation at a CD4 cell count of 500/μL or greater. Overall life expectancy and expected years free of major chronic comorbidities, including chronic liver disease, chronic kidney disease, chronic lung disease, diabetes, cancer, and cardiovascular disease. Of 39 000 individuals with HIV infection and 387 785 matched uninfected adults, 374 421 (87.7%) were male, with a mean (SD) age of 41.4 (10.8) years. Among 359 244 individuals with known race/ethnicity, 90 177 (25.1%) were non-Hispanic black and 87 191 (24.3%) were Hispanic. From 2000 to 2003, overall life expectancy at age 21 years of age was 37.6 years among individuals with HIV infection and 59.7 years among uninfected adults, (difference, 22.1 years; 95% CI, 20.2-24.0 years). From 2014 to 2016, overall life expectancy at 21 years of age among individuals with HIV infection increased to 56.0 years compared with 65.1 years among uninfected adults (difference, 9.1 years; 95% CI, 7.9-10.2 years). During 2011 to 2016, individuals with HIV infection who initiated ART with a CD4 cell count of 500/μL or greater had a life expectancy at 21 years of age of 57.4 years compared with 64.2 years among uninfected adults (difference, 6.8 years; 95% CI, 5.0-8.5 years). From 2000 to 2003, the expected number of comorbidity-free years remaining at 21 years of age was 11.3 for individuals with HIV infection and 26.6 years for uninfected adults (difference, 15.3 years; 95% CI, 13.9-16.6 years). This difference in comorbidity-free years persisted over time but decreased to 9.5 years (95% CI, 7.7-11.2 years) for individuals with HIV infection who initiated ART at a CD4 cell count of 500/μL or greater. The results suggest that life expectancy of adults with HIV infection may be near that of life expectancy of individuals without HIV infection, but greater attention is needed to prevention of comorbidities among individuals with HIV infection.
MeSH Terms
- Adult
- Chronic Disease
- Cohort Studies
- Comorbidity
- Female
- HIV Infections
- Humans
- Insurance, Health
- Life Expectancy
- Male
- Middle Aged
It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45 , 8-OHdG , Ki-67 , and BrdU cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4 interferon (IFN)-γ cells in LGs were found in both aged mice. An increase in 8-OHdG cells in both glands was evident in 2Y-old mice. Reduced Ki-67 cells, but no change in CD45 cells, was observed in the MGs of 1Y-old mice. Increased BrdU cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.
Keywords
- aging
- dry eye
- inflammation
- lacrimal glands
- meibomian glands
- oxidative stress
- senescence
Elderly individuals are highly susceptible to influenza virus (IAV) infection and respond poorly to influenza vaccines. Although the generally accepted correlate of protection following influenza vaccination is neutralizing antibody titers, cytotoxic T cell activity has been found to be a better correlate in the elderly. This suggests that vaccines designed to protect against influenza in the elderly should induce both humoral and cellular immunity. The co-induction of T cell immunity is additionally advantageous, as virus-specific T cells are frequently cross-reactive against different strains of IAV. Here, we tested the capacity of a synthetic TLR-4 adjuvant, SLA-SE (second-generation lipid adjuvant formulated in a squalene-based oil-in-water emulsion) to elicit T cell immunity to a recombinant influenza nucleoprotein (rNP), in both young and aged mice. IAV challenge of vaccinated mice resulted in a modest increase in the numbers of NP-specific CD4 and CD8 effector T cells in the spleen, but did not increase numbers of memory phenotype CD8 T cells generated following viral clearance (compared to control vaccinated mice). Cytotoxic activity of CD8, but not CD4 T cells was increased. In addition, SLA-SE adjuvanted vaccination specifically enhanced the production of NP-specific IgG2c antibodies in both young and aged mice. Although NP-specific antibodies are not neutralizing, they can cooperate with CD8 T cells and antigen-presenting cells to enhance protective immunity. Importantly, SLA-SE adjuvanted rNP-vaccination of aged mice resulted in significantly enhanced viral clearance. In addition, vaccination of aged mice resulted in enhanced survival after lethal challenge compared to control vaccination, that approached statistical significance. These data demonstrate the potential of SLA-SE adjuvanted rNP vaccines to (i) generate both cellular and humoral immunity to relatively conserved IAV proteins and (ii) elicit protective immunity to IAV in aged mice.
Keywords
- Adjuvant
- Aging
- Influenza
- Mouse
- Nucleoprotein
- Vaccination
The epithelial microenvironment is involved in thymus aging, but the possible role of EphB receptors that govern the thymic epithelium development has not been investigated. Herein, we study the changes undergone by the thymus of EphB-deficient mice throughout their life. Immune alterations occurring throughout life were more severe in mutant than in wild-type (WT) mice. Mutant thymuses exhibit lower cellularity than WT ones, as well as lower proportions of early thymic progenitors cells and double-positive (CD4 CD8 ) thymocytes, but higher of double-negative (CD4 CD8 ) and single-positive (CD4 CD8 , CD4 CD8 ) cells. Throughout life, CD4 naïve cells decreased particularly in mutant mice. In correlation, memory T cells, largely CD8 cells, increased. Aged thymic epithelium undergoes changes including appearance of big epithelial free areas, decrease of K8 K5 areas, which, however, contain higher proportions of Ly51 UEA1 cortical epithelial cells, in correlation with reduced Aire medullary epithelial cells. Also, aged thymuses particularly those derived from mutant mice exhibited increased collagen IV, fat-storing cells, and connective cells. The absence of EphB accelerates the alterations undergone throughout life by both thymic epithelium and thymocytes, and the proportions of peripheral naïve and memory T cells, all of which are hallmarks of immune aging.
Keywords
- senescence
- thymic epithelial cells
- thymocytes
Aging is a natural biological process associated with cognitive decline and neuroendocrine-immune system changes; the neuroendocrine-immune system plays crucial role in brain aging and neurodegeneration, and it is essential to discern beneficial attempts to delay the aging progress based on immunological aging. In this study, we have investigated the effects of Traditional Chinese Medicine (TCM)-Liuwei Dihuang decoction (LW)-and donepezil, memantine, and melatonin on cognitive decline in aging mice. The aged SAMR1 mice received oral administration of donepezil (1mg/kg), memantine (10 mg/kg), melatonin (10 mg/kg), and LW (10 g/kg) for 3 months. A shuttle box, Morris water maze, and elevated-zero maze were performed to assess cognitive function, and flowcytometry, Luminex, and radioimmunoassay were performed to measure the lymphocyte subsets, inflammatory factors, and hormones. We observed that survival days of mice was increased with melatonin and LW, the anxiety behavior was significantly improved by memantine, melatonin, and LW treatment, active avoidance responses significantly improved by LW, donepezil, and memantine, the spatial learning ability was significantly improved by donepezil, and LW and melatonin were beneficial to the spatial memory of old mice. For immune function, LW increased CD4 and CD4 CD28 cells and reduced TNF-α, IL-1β, and G-CSF in plasma, and it also promoted the secretion of anti-inflammatory factors IL-4, IL-5, and IL-10 by regulating the active of Th2 cells in spleen. Donepezil and memantine exerted protective effects against CD4 CD28 cell decrease caused by aging and reduced the pro-inflammatory factors TNF-α, IL-1β, and G-CSF in plasma. Melatonin could reverse CD8 CD28 cell imbalances and increased B cells. For endocrine factors, LW increased TSH levels in the pituitary, and melatonin increased the GH level in blood. Our findings indicated that LW improved the cognitive decline in aging mice, and this might be associated with modulation of the active T cells and HPG axis hormones as well as increasing anti-inflammatory factors. Meanwhile, donepezil and memantine have advantages in regulating adaptive immunity, melatonin has advantages in the regulation of B cells and pituitary hormones, and LW exhibits a better effect on neuroendocrine immune function compared with the others from a holistic point of view. LW might be a potential therapeutic strategy for anti-aging-related syndromes, and it can also provide a value on medication guidance about drug combinations or treatment in clinic.
Keywords
- Liuwei Dihuang decoction
- aging
- cognition
- immune response
- inflammation
Dyskeratosis congenita (DC) is a syndrome resulting from defective telomere maintenance. Immunodeficiency associated with DC can cause significant morbidity and lead to premature mortality, but the immunological characteristics and molecular hallmark of DC patients, especially young patients, have not been described in detail. We summarize the clinical data of two juvenile patients with DC. Gene mutations were identified by whole-exome and direct sequencing. Swiss-PdbViewer was used to predict the pathogenicity of identified mutations. The relative telomere length was determined by QPCR, and a comprehensive analysis of lymphocyte subsets and CD57 expression was performed by flow cytometry. Both patients showed typical features of DC without severe infection. In addition, patient 1 (P1) was diagnosed with Hoyeraal-Hreidarsson syndrome due to cerebellar hypoplasia. Gene sequencing showed P1 had a compound heterozygous mutation (c.204G > T and c.178-245del) in PARN and P2 had a novel hemizygous mutation in DKC1 (c.1051A > G). Lymphocyte subset analysis showed B and NK cytopenia, an inverted CD4:CD8 ratio, and decreased naïve CD4 and CD8 cells. A significant increase in CD21 B cells and skewed numbers of helper T cells (Th), regulatory T cells (Treg), follicular regulatory T cells (Tfr), and follicular helper T cells (Tfh) were also detected. Short telomere lengths, increased CD57 expression, and an expansion of CD8 effector memory T cells re-expressing CD45RA (TEMRA) were also found in both patients. Unique immunologic abnormalities, CD8 T-cell senescence, and shortened telomere together as a hallmark occur in young DC patients before progression to severe disease.
Keywords
DKC1
PARN
- Dyskeratosis Congenita
- primary immunodeficiency
- senescence
- telomere
Physical exercise (PE) and environmental enrichment (EE) can modulate immunity. However, the differential effects of short-term PE, EE, and PE EE on neuroimmune mechanisms during normal aging has not been elucidated. Hence, a cohort of 3-, 8-, and 13-month-old immunologically unchallenged C57BL/6 wild-type mice were randomly assigned to either Control, PE, EE, or PE EE groups and provided with either no treatment, a running wheel, a variety of plastic and wooden objects alone or in combination with a running wheel for seven weeks, respectively. Immunohistochemistry and 8-color flow cytometry were used to determine the numbers of dentate gyrus glial cells, and the proportions of CD4 and CD8 T cell numbers and their subsets from cervical lymph nodes, respectively. An increase in the number of IBA1 microglia in the dentate gyrus at 5 and 10 months was observed after EE, while PE and PE EE increased it only at 10 months. No change in astroglia number in comparison to controls were observed in any of the treatment groups. Also, all treatments induced significant differences in the proportion of specific T cell subsets, i.e., CD4 and CD8 T naïve (T ), central memory (T ), and effector memory (T ) cells. Our results suggest that in the short-term, EE is a stronger modulator of microglial and peripheral T cell subset numbers than PE and PE EE, and the combination of short-term PE and EE has no additive effects.
Keywords
- Aging
- Astrocytes
- Environmental enrichment
- Microglia
- Physical exercise
- T cells
In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China) ; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4 and CD8 T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Asymptomatic Infections
- Betacoronavirus
- COVID-19
- China
- Cohort Studies
- Coronavirus Infections
- Critical Illness
- Disease Progression
- Evolution, Molecular
- Female
- Genetic Variation
- Genome, Viral
- Hospitalization
- Host-Pathogen Interactions
- Humans
- Inflammation Mediators
- Interleukin-6
- Interleukin-8
- Lymphocyte Count
- Lymphopenia
- Male
- Middle Aged
- Pandemics
- Phylogeny
- Pneumonia, Viral
- Respiratory Distress Syndrome
- SARS-CoV-2
- T-Lymphocytes
- Time Factors
- Treatment Outcome
- Virulence
- Virus Shedding
- Young Adult
- Zoonoses
Because people living with HIV (PLWH) are ageing, they will inevitably develop non-communicable diseases (NCDs) and the number of non-HIV medications will increase. Drug-drug interactions(DDIs) will become an ever-increasing issue. However, little is known about this important issue in Chinese PLWH. This study aimed to investigate the prevalence and risk factors of DDIs among PLWH in China. Chinese PLWH aged ≥18 years were enrolled prospectively from October 2018 to April 2019 and after informed consent was obtained, they were ask to fill out a questionnaire about comorbidity and co-medications. Potential DDIs were identified using the University of Liverpool HIV Drug Interaction Checker. A total of 1804 questionnaires were included. Antiretroviral drugs (ARVs) that most frequently were prescribed were lamivudine (96.18%), efavirenz(64.64%) and tenofovir(60.62%). 16.96% of the participations reported current co-infection with HIV and14.69% reported NCDs. 263(14.57%) participations reported they had used co-medications in the past six months while 186(10.31%) reported they were taking co-medications. Age≥50 years (p < 0.001), living in developed areas(p < 0.001) and lower CD4 cell count(p = 0.045) were independently associated with the use of co-medications. Potential DDIs were identified in 54 (19.15%) persons using co-medications. Age≥50 [OR = 2.272(1.241-4.158)], PLWH with NCDs[OR = 2.889(1.509-5.532)] and usage of protease inhibitors[OR = 2.538(1.250-5.156)] were independently associated with the potential DDIs. The prevalence of the use of co-medications and potential DDIs among Chinese PLWH are low. Older age, NCDs and use of PIs were risk factors for the potential of developing DDIs. With the aging of PLWH, co-medications and DDIs in China warrants more attention.
Keywords
- Aging
- China
- Co-medication
- Drug-drug interaction
- HIV
Aging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion. C57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4 T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling. Aged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve CD4 T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4 T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4 T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice. These results indicate that age-related CD4 T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cell Line, Tumor
- Cell Movement
- Humans
- Inflammation
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Animal
- NF-kappa B
- Neoplasm Invasiveness
- PC-3 Cells
- Prostatic Neoplasms
- Th17 Cells
Keywords
- CD4 T cell-secreted factors
- PCa cells
- Th17 cytokines
- aging
- inflammation
The processes governing lymphocyte fate (division, differentiation, and death), are typically assumed to be independent of cell age. This assumption has been challenged by a series of elegant studies which clearly show that, for murine cells [i]in vitro[/i], lymphocyte fate is age-dependent and that younger cells (i.e., cells which have recently divided) are less likely to divide or die. Here we investigate whether the same rules determine human T cell fate [i]in vivo[/i]. We combined data from [i]in vivo[/i] stable isotope labeling in healthy humans with stochastic, agent-based mathematical modeling. We show firstly that the choice of model paradigm has a large impact on parameter estimates obtained using stable isotope labeling i.e., different models fitted to the same data can yield very different estimates of T cell lifespan. Secondly, we found no evidence in humans [i]in vivo[/i] to support the model in which younger T cells are less likely to divide or die. This age-dependent model never provided the best description of isotope labeling; this was true for naïve and memory, CD4 and CD8 T cells. Furthermore, this age-dependent model also failed to predict an independent data set in which the link between division and death was explored using Annexin V and deuterated glucose. In contrast, the age-independent model provided the best description of both naïve and memory T cell dynamics and was also able to predict the independent dataset.
Keywords
- decision
- fate
- half-life
- labeling
- lifespan
- lymphocyte
- mathematical model
- proliferation
The progression of the human immunodeficiency virus (HIV) infection to acquired immunodeficiency syndrome (AIDS) can be efficiently interrupted by antiretroviral therapy (ART). However, even successfully treated HIV-infected individuals are prone to develop non-AIDS-related diseases that affect the metabolism and several organs and systems. Biomarkers that predict the occurrence of comorbidities may help develop preventive measures. Current research shows that CD4 T cell counts and viral load do not predict the development of non-AIDS-related diseases. The CD4/CD8 ratio has been indicated as a suitable marker of persistent immune dysfunction and the occurrence of non-AIDS-related events in treated HIV-positive patients. In this study, we explored the relationship between CD4/CD8 ratios, comorbidities, and aging in ART-treated HIV patients on viral suppression. We collected and evaluated data from 352 HIV-positive adults who were virologically suppressed (<40 copies/mL) on ART and with CD4 counts above 350 cells/mm . The median age for participants was 46 years, 218 individuals had at least one comorbidity, and 239 had inverted CD4/CD8 ratios (<1). Current CD4/CD8 ratios were predicted by baseline CD4/CD8 ratios and nadir CD4 counts. Despite the high rates of inverted CD4/CD8 ratios and prevalence of comorbidities, no association between them was observed. The prevalence of comorbidities was significantly higher in older individuals, though aging alone did not explain the rate of all individual comorbidities. Low CD4/CD8 ratios were linked to neurocognitive disorders, suggesting that persistent T cell dysfunction contributes to neurocognitive decline.
Keywords
- CD4/CD8 ratio
- HIV
- aging
- comorbidities
Although HAART cannot eradicate HIV, it suppresses viral replication, resulting in a progressive reduction in HIV-related morbidity and mortality. The increase in life expectancy for HIV-infected patients has turned this disease into a chronic disease and, therefore, to the appearance of comorbidities. At the same time there is an increase in the use of concomitant medication, making HIV-infected patient a polymedicated patient. To determine the degree of polypharmacy and to describe clinically relevant drug interactions, as well as the comorbidities and adherence to HAART in HIV patients over 50 years. Observational, transversal study. Patients ≥50 years on HAART ambulatory were included. The variables were collected: aged, sex, VL, CD4, comorbidities, ARV, concomitant medication, herbal products and adherence. Patients who did not sign informed consent were excluded. Were included 154 patients ≥50 years on HAART. The presence of polypharmacy, defined as the use of 5 or more medications including HAART, was 40.3%. 73.4% of the patients had concomitant medication: lipid-lowering agents (33.8%), anxiolytics / sedatives (28.6%), proton-pump inhibitors (26.0%) antihypertensive agents (23.4%). 102 relevant interactions were recorded, finding statistically significant differences in relation to the presence of polypharmacy and pharmacologic drugs classes ([i]p[/i] <0.001). The prevalence of polypharmacy among HIV patients ≥50 years is high. Comorbidities, interactions and drugs associated were similar to those described in the literature. It is necessary to establish priorities in relation to drug interactions with polypharmacy and a correct approach to the pathologies that may develop.
MeSH Terms
- Aged
- Anti-HIV Agents
- Antiretroviral Therapy, Highly Active
- Cross-Sectional Studies
- Drug Interactions
- Female
- HIV Infections
- Humans
- Male
- Medication Adherence
- Middle Aged
- Polypharmacy
- Prevalence
Keywords
- aging
- comorbidities
- drug interactions
- highly active antiretroviral therapy
- polypharmacy
Paediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients. In this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry-based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T-cell sets from parental donors and children who received T-cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy). Senescent T cells, CD28 or CD57 cells, were significantly expanded in patients. Further, not only CD4 CD28 T cells, but also CD4 CD28 T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR-mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4 and CD8 T cells in patients were influenced by donor age and the frequency of CD28 cells, respectively. Our data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long-term immune monitoring should be conducted.
Keywords
- CD28− T cells
- HaploSCT
- immune monitoring
- immunosenescence
- telomere length
Women who conceive at 35 years of age or older, commonly known as advanced maternal age, have a higher risk of facing parturition complications and their children have an increased risk of developing diseases later in life. However, the immunological mechanisms underlying these pathological processes have yet to be established. To fill this gap in knowledge, using a murine model and immunophenotyping, we determined the effect of advanced maternal age on the main cellular branch of adaptive immunity, T cells, at the maternal-fetal interface and in the offspring. We report that advanced maternal age impaired the process of labor at term, inducing dystocia and delaying the timing of delivery. Advanced maternal age diminished the number of specific proinflammatory T-cell subsets [T helper type 1 (Th1): CD4 IFN-γ , CD8 IFN-γ and Th9: CD4 IL-9 ], as well as CD4 regulatory T cells (CD4 CD25 FoxP3 T cells), at the maternal-fetal interface prior to term labor. Advanced maternal age also altered fetal growth and survival of the offspring in early life. In addition, infants born to advanced-age mothers had alterations in the T-cell repertoire but not in CD71 erythroid cells (CD3 CD71 TER119 cells). This study provides insight into the immune alterations observed at the maternal-fetal interface of advanced-age mothers and their offspring.
MeSH Terms
- Adult
- Aging
- Animals
- Female
- Humans
- Live Birth
- Mice
- Mice, Transgenic
- Placenta
- Pregnancy
- T-Lymphocyte Subsets
Keywords
- birth weight
- neonate
- offspring
- pregnancy
- preterm labor
Morphometric analysis of structural and functional changes in the human mesenteric lymph nodes during aging revealed the development of fibrous connective tissue, fragmentation of the lymphoid parenchyma, the absence of follicles with germinal centers, and a decrease in the level of lymphocyte proliferation, which was confirmed by the absence of Ki-67 cells. The paracortical zone lacked CD4 T helpers that regulate both cellular and humoral immunity. High content of plasma cells and eosinophilic granulocytes in the medullary cords and sinuses reflects the development of autoimmune processes associated with a decrease in the number of regulatory T lymphocytes. The development of fibrous connective tissue in the sinus system complicates lymph flow through the lymph node and impairs lymph filtration.
Keywords
- age-related involution
- aging
- immune system
- immunomorphology
- mesenteric lymph nodes
Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n = 98, mean age(SD) = 36(10) years, 74.5% female, 57.1% CMV ) and comparison controls (n = 98, mean age(SD) = 34(10) years, 68.4% female, 51.0% CMV ) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27 CD28 ) cells within CD4 and CD8 T-cell subsets, i.e. naive (CCR7 CD45RA ), effector memory (EM, CCR7 CD45RA ), central memory (CM, CCR7 CD45RA ) and effector memory cells re-expressing CD45RA (EMRA, CCR7 CD45RA ). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27 CD28 cells within CD4 and CD8 memory T-cell subsets (p's < 0.004), but there was no significant effect of MDD, nor any significant interaction between CMV and diagnosis. Unexpectedly, depressed men were less likely to be CMV and depressed women were more likely to be CMV than sex-matched controls suggesting a possible interaction between sex and MDD on CMV susceptibility, but this three-way interaction did not significantly affect the T-cell subtypes. Our findings suggest that depression in young and middle-aged adults does not prematurely advance aging of the T-cell compartment independently of CMV, but there may be significant sex-specific effects on adaptive immunity that warrant further investigation.
Keywords
- Biological aging
- Cytomegalovirus
- Depression
- Immunosenescence
- Major depressive disorder
- Sex differences
- T-cells
ageing is accompanied by impairments in immune responses due to remodelling of the immune system (immunesenescence). Additionally, a decline in habitual physical activity has been reported in older adults. We have recently published that specific features of immunesenescence, such as thymic involution and naïve/memory T-cell ratio, are prevented by maintenance of a high level of physical activity. This study compares immune ageing between sedentary and physically active older adults. a cross-sectional study recruited 211 healthy older adults (60-79 years) and assessed their physical activity levels using an actigraph. We compared T- and B-cell immune parameters between relatively sedentary (n = 25) taking 2,000-4,500 steps/day and more physically active older adults (n = 25) taking 10,500-15,000 steps/day. we found a higher frequency of naïve CD4 (P = 0.01) and CD8 (P = 0.02) and a lower frequency of memory CD4 cells (P = 0.01) and CD8 (P = 0.04) T cells in the physically active group compared with the sedentary group. Elevated serum IL7 (P = 0.03) and IL15 (P = 0.003), cytokines that play an essential role in T-cell survival, were seen in the physically active group. Interestingly, a positive association was observed between IL15 levels and peripheral CD4 naïve T-cell frequency (P = 0.023). we conclude that a moderate level of physical activity may be required to give a very broad suppression of immune ageing, though 10,500-15,000 steps/day has a beneficial effect on the naïve T-cell pool.
Keywords
- T cells
- ageing
- immune senescence
- older people
- physical activity
Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57 or loss of CD28 expression), of naïve T cells (CD4 CD45RA and CD8 CD45RA ), memory T cells (CD4 CD45RO and CD8 CD45RO ), and antigen-experienced T cells (CD4 KLRG1 and CD8 KLRG1 ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P = .005 and P = .000) and MOCA (P = .017 and P = .000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P = .046). There was a negative correlation between memory CD4 CD45RO T cells with recall and visuospatial domain (R = -0.204, P = .039 and R = -0.250, P = .033; respectively), and negative correlation between CD8 CD28 T cells with recall and attention domain (R = -0.249, P = .027 and R = -0.145, P = .048, respectively). Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.
Keywords
- immunosenescence
- lupus-associated brain fog
- systemic lupus erythematosus
People living with HIV (PLWH) are at higher risk for poorer neurocognitive functioning and health literacy than uninfected persons, which are associated with worse medical outcomes. Aging research suggests that the effect of neurocognitive functioning on health outcomes may be more pronounced in those with low health literacy. We aimed to determine whether low health literacy might amplify the adverse effects of neurocognitive functioning on treatment management outcomes in 171 PLWH aged 40 . In this cross-sectional, observational study, participants completed a well-validated battery of neurocognitive, health literacy, and treatment management measures. A binary health literacy variable (low vs. adequate) was determined via established cut points on the well-validated health literacy tests. Treatment management outcomes included biomarkers of HIV (i.e., CD4 counts and viral load), self-management of HIV disease (i.e., self-reported medication adherence and self-efficacy for HIV disease management), and performance-based health-related decision-making. Forty-seven percent of the sample met the criteria for low health literacy. Multivariable regressions adjusting for clinicodemographic (e.g., race, socioeconomic status) covariates revealed significant interactions for self-efficacy for HIV disease management and health-related decision-making, such that neurocognitive functioning was associated with these outcomes among those with low, but not adequate health literacy. Findings suggest that low health literacy may increase the vulnerability of PLWH to the adverse effects of neurocognitive impairment on health outcomes, or conversely that adequate health literacy may provide a buffer against the health risks associated neurocognitive impairment. Interventions targeting health literacy in PLWH may mitigate the effects of neurocognitive impairment on health outcomes.
MeSH Terms
- Adult
- Cognition
- Cross-Sectional Studies
- HIV Infections
- Health Literacy
- Humans
- Neuropsychological Tests
- Self Report
Keywords
- Adherence
- Aging
- Cognitive impairment
- HIV/AIDS
- Health illiteracy
- Observational study
Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triple-negative breast cancer and melanoma growth associated with activation of CD4 T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3-blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors.
Keywords
- Stat3
- immune checkpoint blockade
- immunotherapy
- oncogene addiction
- senescence
The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers ([i]n[/i] = 48, 21-84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40-69 yrs.; blood: [i]n[/i] = 13; TIL: [i]n[/i] = 17) and elderly cancer patients (70-90 yrs.; blood: [i]n[/i] = 20; TIL: [i]n[/i] = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4 and CD8 T cells as well as regulatory T cells (T ) were assessed by flow cytometry. We observed lower frequencies of CD8 cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients.
Keywords
- Aging
- Head and neck cancer
- Immune escape
- Immunosenescence
- T cells
The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (T ) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that T heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 T and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 T . Our data thus hint that reversing T defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- CD4-Positive T-Lymphocytes
- Gene Expression Profiling
- HIV Infections
- Humans
- Immunologic Memory
- Intercellular Signaling Peptides and Proteins
- Mice
- Precursor Cells, T-Lymphoid
- Thymus Gland
- Wnt Signaling Pathway
- beta Catenin
Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1 [[CD44]] CD4 T cells as well as CD95 GL7 germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.
MeSH Terms
- Animals
- B-Lymphocytes
- Cellular Senescence
- Circadian Rhythm
- Disease Models, Animal
- Humans
- Hyaluronan Receptors
- Inflammation
- Jet Lag Syndrome
- Longevity
- Mice
- Programmed Cell Death 1 Receptor
- Sequence Analysis, RNA
- T-Lymphocytes
As life expectancy of patients infected with human immunodeficiency virus (HIV) approaches that of the general population, the composition of HIV management costs is likely to change. To (a) review treatment and disease management costs in HIV, including costs of adverse events (AEs) related to antiretroviral therapy (ART) and long-term toxicities, and (b) explore the evolving cost drivers. A targeted literature review between January 2012 and November 2017 was conducted using PubMed and major conferences. Articles reporting U.S. costs of HIV management, acquired immunodeficiency syndrome (AIDS)-defining events, end of life care, and ART-associated comorbidities such as cardiovascular disease (CVD), chronic kidney disease (CKD), and osteoporosis were included. All costs were inflated to 2017 U.S. dollars. A Markov model-based analysis was conducted to estimate the effect of increased life expectancy on costs associated with HIV treatment and management. 22 studies describing HIV costs in the United States were identified, comprising 16 cost-effectiveness analysis studies, 5 retrospective analyses of health care utilization, and 1 cost analysis in a resource-limited setting. Management costs per patient per month, including routine care costs (on/off ART), non-HIV medication, opportunistic infection prophylaxis, inpatient utilization, outpatient utilization, and emergency department utilization were reported as CD4 cell-based health state costs ranging from $1,192 for patients with CD4 > 500 cells/mm to $2,873 for patients with CD4 < 50 cells/mm . Event costs for AEs ranged from $0 for headache, pain, vomiting, and lipodystrophy to $31,545 for myocardial infarction. The mean monthly per-patient costs for CVD management, CKD management, and osteoporosis were $5,898, $6,108, and $4,365, respectively. Improvements in life expectancy, approaching that of the general population in 2018, are projected to increase ART-related and AE costs by 35.4% and comorbidity costs by 175.8% compared with estimated costs with HIV life expectancy observed in 1996. This study identified and summarized holistic cost estimates appropriate for use within U.S. HIV cost-effectiveness analyses and demonstrates an increasing contribution of comorbidity outcomes, primarily associated with aging in addition to long-term treatment with ART, not typically evaluated in contemporary HIV cost-effectiveness analyses. This analysis was sponsored by ViiV Healthcare, which had no role in the analyses and interpretation of study results. Ward, Sugrue, Hayward, and McEwan are employees of HEOR Ltd, which received funding from ViiV Healthcare to conduct this study. Anderson is an employee of GlaxoSmithKline and holds shares in the company. Punekar and Oglesby are employees of ViiV Healthcare and hold shares in GlaxoSmithKline. Lopes was employed by ViiV Healthcare at the time of the study and holds shares in GlaxoSmithKline.
MeSH Terms
- Anti-HIV Agents
- CD4 Lymphocyte Count
- Comorbidity
- Cost-Benefit Analysis
- HIV Infections
- Health Care Costs
- Humans
- Life Expectancy
- United States
To evaluate differences between older women and men with HIV regarding HIV variables, comorbidity, physical function, and quality of life (QOL). The Modena HIV clinic. Prospective cohort study. Cross-sectional analysis. Patients >50 years were included, stratified by sex. We recorded sociodemographic data, comorbidities, variables related to HIV infection, frailty, data on body composition, physical function, physical activity, and QOL. We evaluated 1126 older adults with HIV, of which 284 (25.2%) were women. Median age was 55 (IQR 6) years. There were significant differences between women and men in the median current CD4 T-cell and the mean CD4/CD8 ratio. There were differences regarding alcohol consumption, cardiovascular (CV) disease, hypertension, diabetes mellitus, and renal failure. Sarcopenia and slower gait speed were found more prevalent among men, but without significant differences. Significant differences were found regarding lower extremity strength measured by the chair stand test and in the short physical performance battery score. Short physical performance battery <9 was detected for 11.1% women vs. 5.6% men (P = 0.002). EQ5D5L score was 0.87 in women vs. 0.89 in men (P = 0.002). In our cohort, older women represented one in 4 of the total patients. Despite the fact that women have better immunological recovery measured by CD4 T-cell count and CD4/CD8 ratio, and fewer CV disease and CV risk factors than men, their physical function and their QOL are worse. Therefore, older HIV-infected women have special characteristics, and the assessment of physical function in this group seems to be crucial.
MeSH Terms
- Aged
- Aging
- Alcohol Drinking
- Body Composition
- CD4 Lymphocyte Count
- CD4-CD8 Ratio
- CD4-Positive T-Lymphocytes
- Cohort Studies
- Cross-Sectional Studies
- Female
- Frailty
- HIV Infections
- Humans
- Male
- Middle Aged
- Muscle Strength
- Prospective Studies
Immunological aging impairs immune system protection in the body and is associated with high morbidity and mortality in aged people. Electroacupuncture (EA) has been proven to boost immunity. The purpose of this study was to identify the effect of EA on miRNA expression in the immune system of senescence-accelerated mouse P8 (SAMP8) mice. We utilized SAMP8 mice as an aging model and detected the altered expression of miRNAs in CD4 T cells after EA stimulation by deep sequencing. Differentially expressed miRNAs in different groups were identified using Venn diagrams and functional analysis was performed. The effect of EA on the expression of the identified miRNAs was investigated in natural-aged C57BL/6J mice and the biological functions of miR-301a-3p and miR-181a-1-3p in CD4 T cells were identified. Four upregulated and two downregulated miRNAs were identified in group I (EA-SAMP8 vs. shEA-SAMP8); 41 upregulated and nine downregulated miRNAs were identified in group II (EA-SAMP8 vs. SAMP8); 42 upregulated and eight downregulated miRNAs were identified in group III (shEA-SAMP8 vs. SAMP8). The three groups shared four overlapping differentially expressed miRNAs, and 10 miRNAs were only found in group II. Gene Ontology enrichment analysis of these 14 miRNAs revealed that their target genes were enriched in 229 "biological process" categories. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the targets were significantly mapped in 76 pathways. Furthermore, five significant pathways were involved in T cell differentiation. MiRNA-gene-net showed that miR-582-5p, miR-17-5p, miR-144-3p, miR-451a, and miR-301a-3p regulated the most important target genes in these pathways. The expression of these miRNAs was also regulated by EA in aged C57BL/6J mice. In addition, miR-301a-3p was involved in regulating the expression of inflammatory factors by mediating the differentiation of CD4 T cells in C57BL/6J mice. Analysis of miRNAs indicated that EA contributes to maintaining the balance of CD4 T cell differentiation in the aging immune system. These results provide novel insights into the effect of EA in immunological aging.
MeSH Terms
- Aging
- Animals
- Antagomirs
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cytokines
- Down-Regulation
- Electroacupuncture
- Female
- Gene Regulatory Networks
- High-Throughput Nucleotide Sequencing
- Male
- Mice
- Mice, Inbred C57BL
- MicroRNAs
- Sequence Analysis, RNA
- Spleen
- Up-Regulation
Keywords
- CD4 T cell
- Deep sequencing
- Electroacupuncture
- Immunological aging
- miRNA
Thymus glands from 283 autopsy cases were sampled and evaluated with histochemical and immunohistochemical methods. A subpopulation of 41 intravenous drug addicts were compared with age-matched control cases.It was found that an accelerated involution of the thymus occurred in the 20- to 25-year interval and thereafter with a steady pace of 5% per year. Also the size of Hassall bodies declined successively.In drug addicts, an increased dystrophic calcification of the Hassall bodies and a significant difference in thymus size (atrophy) compared with controls were seen. Moreover, a difference was seen in the relative numbers of CD4 and CD8 lymphocytes where CD4 cells were reduced in drug addicts.It is hypothesized that signs of hepatitis C virus infection that was found in the majority of drug addicts and the reduced number of functionally intact Hassall corpuscles could explain the reduction of CD4 lymphocytes and thymic hypotrophy in this population.
MeSH Terms
- Adolescent
- Adult
- Aging
- Atrophy
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Calcinosis
- Case-Control Studies
- Drug Users
- Female
- Forensic Pathology
- Hepatitis C, Chronic
- Humans
- Male
- Middle Aged
- Substance Abuse, Intravenous
- Thymus Gland
- Young Adult
T-lymphocytes have a multifaceted role in ischemic stroke, but the majority of studies have been conducted in young mice, which may limit the translational value of these findings. Previous studies have shown that aging results in T cell dysfunction, leading to enhanced production of pro-inflammatory cytokines and chemokines, including interferon gamma (IFN-γ) and interferon-gamma-inducible protein (IP-10). This study assessed the role of T cells and pro-inflammatory factors on histologic and functional outcomes in an aged mouse model. Levels of IP-10 were measured in the brain and serum of young and aged male mice following middle cerebral artery occlusion (MCAo) or sham surgery. Additionally, IP-10 levels were evaluated in stroke patients. To directly determine the role of brain-infiltrating T cells after stroke, a separate cohort of aged male and female animals received either an anti-CD4 depletion antibody or IgG isotype control at 72 and 96 h following experimental stroke. Behavioral assessments were performed on day 7 post-MCAo. CD4 T cell depletion resulted in improved behavioral outcomes, despite the lack of differences in infarct size between the isotype control and anti-CD4 antibody treated stroke groups. Circulating IP-10 levels were increased in both humans and mice with age and stroke, and depletion of CD4 T cells led to a reduction in IFN-γ and IP-10 levels in mice. Since anti-CD4 treatment was administered three days after stroke onset, targeting this inflammatory pathway may be beneficial to aged stroke patients who present outside of the current time window for thrombolysis and thrombectomy.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Brain Chemistry
- Brain Ischemia
- CD4-Positive T-Lymphocytes
- Chemokines
- Cytokines
- Female
- Infarction, Middle Cerebral Artery
- Inflammation
- Male
- Mice
- Mice, Inbred C57BL
- Stroke
- Treatment Outcome
Keywords
- Age
- CD4 T cells
- CXCL10
- Inflammation
- Stroke
Millions of people living with the HIV have received antiretroviral therapy (ART). Older adults make up a significant portion of these individuals; however, the immunological and virological responses to ART for older patients still need to be clarified. Meta-analysis. In this article, we systematically reviewed research articles published between 2001 and 2018 that reported immunological and virological responses and AIDS-related mortality among HIV- infected adults (including individuals aged 50 years and older) receiving ART, using meta-analysis. ART efficiency was measured using 3 outcomes: (1) immunological response, (2) virological response, and (3) mortality. We identified 4937 citations, and 40 studies were eventually selected to investigate ART efficiency in older HIV-infected patients, comprising more than 888,151 patients initiating ART. We report that older patients showed poor immunological responses, with CD4 counts and the restoration of CD4 counts after ART initiation being significantly lower than seen in younger patients. However, older patients exhibited better viral suppression rates (risk ratio: 1.04; 95% confidence intervals: 1.01 to 1.08) after 36 months following ART initiation. In addition, older adults had a higher risk of AIDS-related death (adjusted hazard ratio: 1.44, 95% confidence interval: 1.30 to 1.60). Older age after ART initiation was associated with a poorer immunological response and a higher risk of mortality, suggesting the need to increase early diagnosis and treatment among older HIV patients.
MeSH Terms
- Aged
- Aging
- Anti-HIV Agents
- HIV Infections
- Humans
- Middle Aged
Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with human immunodeficiency virus (HIV; PLWH), but remains unexplored in populations with African ancestry. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and the homeostatic model assessments of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), as well as incident diabetes mellitus (DM), among Black women living with or at risk for HIV. Women without DM who had fasting glucose (FG) and insulin (FI) data for ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI data. Incident DM was defined by a combination of FG ≥ 126 mg/dL, the use of DM medication, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the associations between HOMA-B and HOMA-IR and DM by haplogroup. Of 1288 women (933 living with HIV and 355 living without HIV), PLWH had higher initial HOMA-B and HOMA-IR than people living without HIV. PLWH with haplogroup L2 had a slower decline in HOMA-B per year (Pinteraction = .02) and a lower risk of incident DM (hazard ratio [HR], 0.51; 95% confidence interval [CI], .32-.82) than PLWH with other haplogroups after adjustments for age, body mass index, combination antiretroviral therapy use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2, compared to non-L2 (HR, 1.28 [95% CI, .70-2.38] vs 4.13 [95% CI, 3.28-5.22], respectively; Pinteraction < .01), among PLWH. Mitochondrial genetic variation is associated with β-cell functions and incident DM in non-Hispanic, Black women with HIV and alters the relationship between insulin resistance and DM.
Keywords
- HIV
- aging
- diabetes mellitus
- mitochondrial genetics
Blood pressure often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of proinflammatory cytokines increases in T lymphocytes. Prostaglandin D , a proresolution mediator, suppresses Type 1 T helper (Th1) cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of the prostaglandin D /DP1 axis in T cells on age-related hypertension. To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants, and CD4 T cells were sorted for gene expression, prostaglandin production, and Western blot assays. Mice blood pressure was quantified by invasive telemetric monitor. The prostaglandin D /DP1 axis was downregulated in CD4 T cells from older humans and aged mice. DP1 deletion in CD4 T cells augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling, CD4 T cells infiltration, and superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. Tumor necrosis factor α neutralization or interferon γ deletion ameliorated the age-related hypertension in DP1 deletion in CD4 T cells mice. Mechanistically, DP1 inhibited Th1 activity via the PKA (protein kinase A)/p-Sp1 (phosphorylated specificity protein 1)/neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) pathway-mediated T-box-expressed-in-T-cells (T-bet) ubiquitination. T-bet deletion or forced NEDD4L expression in CD4 T cells attenuated age-related hypertension in CD4 T cell-specific DP1-deficient mice. DP1 receptor activation by BW245C prevented age-associated blood pressure elevation and reduced vascular/renal superoxide production in male mice. The prostaglandin D /DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension.
MeSH Terms
- Aged
- Aging
- Animals
- Antihypertensive Agents
- CD4-Positive T-Lymphocytes
- Cyclic AMP-Dependent Protein Kinases
- Cytokines
- Humans
- Hypertension
- Mice
- Mice, Inbred C57BL
- Nedd4 Ubiquitin Protein Ligases
- Prostaglandin D2
- Receptors, Prostaglandin
- Signal Transduction
- Sp1 Transcription Factor
- Superoxides
- T-Box Domain Proteins
- Th1 Cells
- Ubiquitination
Keywords
- D-prostanoid receptor 1
- aging
- hypertension
- lymphocyte
- prostaglandin (PG) D2
The aim of the present study was to calculate a frailty index (FI) in older adults (≥50) living with HIV, search for cross-sectional associations with the FI, and investigate the association between the FI score and two-year mortality. Cross-sectional study with a short-term prospective component for the determination of two-year mortality was performed. The study took place in an HIV outpatient clinic in Calgary, Canada between November 1, 2016 and December 31, 2018. Over 700 patients 50 years of age or older took part. We calculated a FI for each patient, examined associations between FI and select patient characteristics, and evaluated the association between FI value and two-year mortality. The mean FI was 0.303 (± 0.128). Mean FI did not differ between males and females, nor was it associated with either nadir or current CD4 cell count. It did increase with age, duration of ART, and duration of diagnosed HIV infection. Mean FI was higher among those who died compared to survivors (0.351 vs. 0.301; [i]p[/i]=.033). Frailty is highly prevalent in persons living with HIV and associated with a higher mortality rate. Health-care providers should be aware of the earlier occurrence of frailty in adults living with HIV.
Keywords
- accelerated aging
- anti-retroviral therapy
- frailty
- frailty index
- geriatric syndrome
- human immunodeficiency virus (HIV)
- multimorbidity
- vulnerability
Adolescents and young adults (AYA) with HIV experience poorer health outcomes compared with adults. To improve care for AYA with HIV, information about patterns of costly health care resource utilization is needed. Among 13-30 year olds in the US HIV Research Network, we stratified outpatient visits, emergency department (ED) visits, and inpatient days/person-year (PY) by HIV acquisition model [perinatal (PHIVY) and nonperinatal (NPHIVY)], age (13-17, 18-23, and 24-30 years), CD4 strata (<200, 200-499, and ≥500 cells/µL), and viral load (VL) suppression (<, ≥400 copies/mL [c/mL]) combined with antiretroviral (ARV) use. Among 4540 AYA (PHIVY: 15%; NPHIVY: 85%), mean follow-up was 2.8 years. Among PHIVY, most person-time (PT) was spent between ages 13 and 23 years (13-17 years: 43%; 18-23 years: 45%), CD4 ≥500/µL (61%), and VL <400 c/mL (69%). Among NPHIVY, most PT was spent between ages 24 and 30 years (56%), with CD4 ≥500/µL (54%), and with VL <400 c/mL (67%). PT spent while prescribed ARVs and with VL ≥400 c/mL was 29% (PHIVY) and 24% (NPHIVY). For PHIVY and NPHIVY, outpatient visit rates were higher at younger ages (13-17 years and 18-23 years), lower CD4 (<200 and 200-499/µL), and among those prescribed ARVs. Rates of ED visits and inpatient days were higher during PT spent at older ages (18-23 years and 24-30 years), lower CD4 (<200 and 200-499/µL), and VL ≥400 c/mL. Utilization was higher among PHIVY than NPHIVY (outpatient: 12.1 vs. 6.0/PY; ED: 0.4 vs. 0.3/PY; inpatient: 1.5 vs. 0.8/PY). More ED visits and inpatient days were observed during time spent at older ages, lower CD4 count, and VL ≥400 c/mL. Interventions to improve virologic suppression and immune response may improve outcomes, and thus decrease costly resource utilization, for AYA with HIV.
MeSH Terms
- Adolescent
- Adult
- Aging
- Anti-Retroviral Agents
- CD4 Lymphocyte Count
- Drug Administration Schedule
- Female
- HIV Infections
- HIV-1
- Humans
- Male
- Medication Adherence
- Viral Load
- Young Adult
Age-related reductions in vaccine-induced B cells in aging indicate that germinal centers (GCs), the anatomical site where the development of humoral responses takes place, may lose efficacy with age. We have investigated the baseline follicular and GC composition in nonhuman primates (NHPs) with respect to their age. There was a marked reduction in follicular area in old animals. We found significantly lower normalized numbers of follicular PD1 CD4 T (Tfh) and proliferating (Ki67 ) GC B cells with aging, a profile associated with significantly higher numbers of potential follicular suppressor FoxP3 Lag3 CD4 T cells. Furthermore, a positive correlation was found between Tfh and follicular CD8 T cells (fCD8) only in young animals. Despite the increased levels of circulating preinflammatory factors in aging, young animals had higher numbers of monocytes and granulocytes in the follicles, a profile negatively associated with numbers of Tfh cells. Multiple regression analysis showed an altered association between GC B cells and other GC immune cell populations in old animals suggesting a differential mechanistic regulation of GC activity in aging. Our data demonstrate defective baseline GC composition in old NHPs and provide an immunological base for further understanding the adaptive humoral responses with respect to aging.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- B-Lymphocytes
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Forkhead Transcription Factors
- Germinal Center
- Granulocytes
- Immunity, Humoral
- Inflammation
- Lymph Nodes
- Macaca mulatta
- Monocytes
Keywords
- B cells
- Tfh cells
- aging
- follicles
Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine whether haplogroup is associated with frailty and its components among older PWH. A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, gender, education, smoking, hepatitis C, and prior use of didanosine/stavudine. Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (standard deviation 7.5) years and median nadir CD4 count was 212 (interquartile range 72, 324) cells/μL; 6% were frail, 7% had slow gait, and 21% weak grip. H haplogroup participants were more likely to be frail/prefrail ([i]p[/i] = .064), have slow gait ([i]p[/i] = .09), or weak grip ([i]p[/i] = .017) compared with non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail versus nonfrail [odds ratio (OR) 4.0 (95% confidence interval 1.0-15.4)] and having weak grip [OR 2.1 (1.1, 4.1)], but not slow gait [OR 1.6 (0.5, 5.0)] compared with non-H haplogroup. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. Among antiretroviral therapy (ART)-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.
Keywords
- HIV
- aging
- frailty
- haplotypes
- mitochondria
- sarcopenia
Senescence is an inevitable and complicated phenomenon. Age-associated thymic involution increases the risk of infectious diseases, which results in the immunosenescence and leads to a poor immune function. d-galactose (d-gal) can cause damages that resemble accelerated aging in mice. Gallic acid (GA), as one of the natural phenolic compounds, has been demonstrated to act in antioxidant and anti-tumor effects. In this study, we explored the effects of GA in preventing the age-related thymic involution and the alterations of the forkhead box protein N1 (FoxN1) in d-gal induced accelerated aging mice. The accelerated aging mice model was established by intraperitoneal injection d-gal for eight weeks and given GA with 200, 250, 500 mg/kg body weight per day, respectively, for six weeks. It showed that the d-gal-treated mice developed structural changes in the thymi compared to normal control mice. With supplement of GA, the mice restored the normal thymic anatomy, including the thickening cortex compartment and clearer cortico-medullary junction. The d-gal-treated mice showed a severe reduction in the number of thymocytes, GA mice also displayed the increased numbers of CD4 T cells through flow cytometric analysis. GA treatment increased the proliferative cells by BrdU incorporation assay and reduced the numbers of apoptotic cells with FITC-12-dUTP labeling (TUNEL). The expression of FoxN1 was also found increased in GA treated mice by immunohistochemistry and quantitative reverse transcriptase PCR (qRT-PCR). Taken together, our results suggested that the administration of GA opposed the involution of thymus via stimulation of FoxN1 expression and proliferation of cells in a dose-dependent manner.
Keywords
- Aging
- FoxN1
- Gallic acid
- Thymus
- d-galactose
The susceptibility of human CD4 and CD8 T cells to senesce differs, with CD8 T cells acquiring an immunosenescent phenotype faster than the CD4 T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4 T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8 T cells has knock-on consequences for nutrient usage, metabolism and function. Senescent CD4 T cells uptake more lipid and glucose than their CD8 counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4 T cells allows for more proliferation and migration than observed in the senescent CD8 subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4 T cells, through the addition of low-dose rotenone, causes the generation of a CD4 T cell with a CD8 -like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.
MeSH Terms
- Adenosine Triphosphate
- Adult
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Movement
- Cell Proliferation
- Cellular Senescence
- Glucose
- Glycolysis
- Humans
- Immunosenescence
- Leukocyte Common Antigens
- Microscopy, Electron, Transmission
- Middle Aged
- Mitochondria
- Rotenone
Keywords
- T cell
- aging
- metabolism
- mitochondria
- senescence
Aging is a universal and complex process that affects all tissues and cells types, including immune cells, in a process known as immunosenescence. However, many aspects of immunosenescence are not completely understood, as the characteristics of the immune cells of nonagenarians and centenarians or the features and implications of extracellular vesicles (EVs). In this study, we analyzed blood samples from 51 individuals aged 20-49 and 70-104 years. We found that senescent CD8 cells accumulate with age, while there is a partial reduction of senescent CD4 cells in nonagenarians and centenarians. Moreover, plasma EVs carry T cell specific markers, but no accumulation of "senescent-like EVs" was found within any of analyzed age groups. Our functional studies of cocultures of peripheral blood mononuclear cells and EVs showed that EVs enhance T cell viability and, under phytohemagglutinin stimulation, they influence cytokine secretion and cell activation in an age-dependent manner. These results underline the importance of EVs on the immune system functioning, and open new perspectives to further study their implication in human aging.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Extracellular Vesicles
- Female
- Humans
- Immunosenescence
- Lymphocyte Activation
- Male
- Middle Aged
- T-Lymphocytes
Keywords
- T cells
- aging
- centenarians
- extracellular vesicles (EVs)
- immunosenescence
HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends-telomeres, leading to accelerated telomere erosion-a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN complex) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following ATM knockdown or exposure to the ATM inhibitor KU60019 [i]in vitro[/i], recapitulating the biological effects observed in HIV-derived CD4 T cells [i]in vivo[/i]. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to ATM deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection.
MeSH Terms
- Anti-Retroviral Agents
- Ataxia Telangiectasia Mutated Proteins
- Cellular Senescence
- DNA Damage
- HIV Infections
- Humans
- T-Lymphocytes
- Telomere
Keywords
- ATM
- DNA damage repair
- HIV
- T cell homeostasis
- apoptosis
- immune aging
Generation of protective immunity to infections and vaccinations declines with age. Studies in healthy individuals have implicated reduced miR-181a expression in T cells as contributing to this defect. To understand the impact of miR-181a expression on antiviral responses, we examined LCMV infection in mice with miR-181ab1-deficient T cells. We found that miR-181a deficiency delays viral clearance, thereby biasing the immune response in favor of CD4 over CD8 T cells. Antigen-specific CD4 T cells in mice with miR-181a-deficient T cells expand more and have a broader TCR repertoire with preferential expansion of high-affinity T cells than in wild-type mice. Importantly, generation of antigen-specific miR-181a-deficient CD8 effector T cells is particularly impaired, resulting in lower frequencies of CD8 T cells in the liver even at time points when the infection has been cleared. Consistent with the mouse model, CD4 memory T cells in individuals infected with West Nile virus at older ages tend to be more frequent and of higher affinity.
MeSH Terms
- Aging
- Animals
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Disease Models, Animal
- Lymphocytic Choriomeningitis
- Lymphocytic choriomeningitis virus
- Mice
- MicroRNAs
Keywords
- CD8 effector T cell
- T cell repertoire
- antiviral response
- immune aging
- immunosenescence
- microRNA
There are limited data on the comparative prevalence of neurocognitive impairment (NCI) in aging people living with human immunodeficiency virus (PLHIV) and people not living with HIV. This was a cross-sectional study of PLHIV randomly matched by age (±4 years), gender, and education with 5 HIV-uninfected individuals from the CONSTANCES cohort. PLHIV were fluent in French and sequentially included during routine outpatient visits if aged 55-70 years, with HIV viral load <50 copies/mL, and lymphocyte T-CD4 level ≥200 cells/µL in the past 24 and 12 months, respectively. The primary outcome was NCI as defined by the Frascati criteria. Multivariate normative comparison (MNC) and -1.5 standard deviations in ≥2 neurocognitive domains were secondary outcomes of NCI. Two hundred PLHIV were matched with 1000 controls. Median age was 62 years, and 85% were men. In PLHIV, the median T-CD4 lymphocyte level was 650 cells/µL, and median nadir T-CD4 lymphocyte level was 176 cells/µL. NCI was found in 71 (35.5%) PLHIV and in 242 (24.2%) controls (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.25, 2.41). After adjusting for confounders, HIV remained significantly associated with NCI (OR, 1.50; 95% CI, 1.04, 2.16). Adjusted results were similar with NCI defined by MNC (ORMNC, 2.95; 95% CI, 1.13, 3.50) or -1.5 SD (OR-1.5, 2.24; 95% CI, 1.39, 3.62). In this matched study of aging individuals, HIV was significantly associated with an increased risk of NCI after adjusting for major confounders. Results were confirmed with more stringent NCI classifications. NCT02592174.
Keywords
- Frascati criteria
- HAND
- HIV
- aging
- neurocognitive impairment
To gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4 T cells obtained from younger (20-39 years-old) and older (70 years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in CD4 T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in CD4 T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4 T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.
MeSH Terms
- Adult
- Aged
- CD4-Positive T-Lymphocytes
- Cell Respiration
- Humans
- Immunosenescence
- Longitudinal Studies
- Mitochondria
- Mitophagy
- Young Adult
Keywords
- CD4 T cells
- aging
- autophagy
- mitochondria
- proteomics
Sex differences in autoimmunity and infection suggest that a better understanding of molecular sex differences will improve the diagnosis and treatment of immune-related disease. We identified 144 differentially expressed genes, referred to as immune sex expression signature (iSEXS), between human males and females using an integrated multi-cohort analysis of blood transcriptome profiles from six discovery cohorts from five continents with 458 healthy individuals. We validated iSEXS in 11 additional cohorts of 524 peripheral blood samples. When we separated iSEXS into genes located on sex chromosomes (XY-iSEXS) or autosomes (autosomal-iSEXS), both modules distinguished males and females. iSEXS reflects sex differences in immune cell proportions, with female-associated genes showing higher expression by CD4 T cells and male-associated genes showing higher expression by myeloid cells. Autosomal-iSEXS detected an increase in monocytes with age in females, reflected sex-differential immune cell dynamics during influenza infection, and predicted antibody response in males, but not females.
MeSH Terms
- Aging
- CD4-Positive T-Lymphocytes
- Female
- Humans
- Influenza, Human
- Male
- Monocytes
- Sex Characteristics
- Transcriptome
Keywords
- CD4( ) T cells
- aging
- immune system
- immunology
- influenza
- meta-analysis
- monocytes
- multi-cohort analysis
- sex differences
- transcriptome
"Graying of HIV epidemic" is observed globally, as people living with HIV (PLWH) are aging, due to effectiveness of antiretrovirals. The normal aging processes and HIV-induced immune dysfunction, are potential mechanisms, driving multimorbidity (MM) in PLWH. MM is the concurrent presence of two or more diseases in a single individual. Aging PLWH, are at increased risk of acute and chronic morbidities compared with counterpart without HIV. Despite increasing concern in Nigeria, research on correlates of MM in aging PLWH is lagging. This was a comparative study, of ≥60 years of age, age-matched (±5 years) HIV-positive and HIV-negative patients. Patients were recruited, from the Infectious Disease Institute and Geriatric clinics of the University College Hospital, Ibadan, Nigeria, between April and June 2018. MM was defined as the occurrence of more than two morbidities in an individual, and it was considered acute, when within 30 days and chronic, when above 3-months duration. Data analysis was done using SPSS 23. We studied 186 individuals (62 HIV-positive and 124 HIV-negative). The PLWH had lower mean age (63.9 vs. 68.1 years, [i]p[/i] = .00, [i]t[/i] = 5.68), more chronic MM (2.0 vs. 1.3, [i]p[/i] = .004, [i]t[/i] = 2.970), which occurred earlier (4.7 vs. 9.6 years, [i]p[/i] = .003, [i]t[/i] = 3.05), more overall MM (3.6 vs. 2.8, [i]p[/i] = .015, [i]t[/i] = 2.448), and lower quality of life (82.7 vs. 86.2, [i]p[/i] = .002, [i]t[/i] = 3.130). Risk estimates for "any" MM revealed the odds are in favor of the older PLWH [69.4% vs. 46.8%, [i]p[/i] = .004, odds ratio = 0.388 (95% confidence interval = 0.204-0.740)]. Logistic regression revealed, age >64 years, higher total body fat, lower nadir CD4 counts, and longer duration of HIV infection, were significantly associated with MM in aging PLWH ([i]p[/i] = .019). Older individuals with HIV on antiretrovirals in Ibadan, had a significantly greater burden of MM compared with those without HIV. HIV treatment programs in Nigeria will need to adapt a comprehensive health care plan for aging PLWH.
Keywords
- ART
- PLWH
- aging
- multimorbidity
- quality of life
Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTLs]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-γ and TNF-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- B-Lymphocytes
- CD4-Positive T-Lymphocytes
- Case-Control Studies
- Cell Differentiation
- Cells, Cultured
- Clonal Evolution
- Gene Expression Profiling
- Humans
- Interferon-gamma
- Leukocytes, Mononuclear
- Middle Aged
- Single-Cell Analysis
- Tumor Necrosis Factor-alpha
Keywords
- CD4 CTL
- aging
- centenarian
- single-cell transcriptome
Aging has been suggested to be associated with immune dysregulation. An understanding of alterations in the host immunity with advancing age is, therefore, important for designing immune therapy for elderly cancer patients. In this context, not much is known about age-associated alterations in the immune system in oral cancer. To evaluate age-associated alterations in the immune system, which might affect anti-tumor immune responses in oral cancer, we performed a comparative analysis of the proportion of different immune cells, the proliferative capacity of T cell compartment, and the response against immune therapies targeting immune check point molecules between young and aged oral cancer-bearing mice. The proportion of immune regulatory cells, such as regulatory T cells and myeloid derived suppressor cells, was significantly increased in aged mice compared to that in young mice. Moreover, the expression of PD-1 and CTLA-4 on both CD4 and CD8 T cells was elevated in aged mice compared to that in young mice, and the proliferative abilities of CD4 and CD8 T cells derived from aged mice were significantly reduced following stimulation of T-cell receptors. Moreover, tumor growth was significantly enhanced in aged mice compared to that in young mice. However, immunotherapies targeting PD-1, CTLA-4, and PD-L1 resulted in faster tumor regression in aged mice than in young mice. Together, our results indicate that age-associated alterations in the immune system are directly associated with the impairment of anti-tumor immunity in aged mice bearing oral cancer, and might facilitate the progression of the tumor.
MeSH Terms
- Aged
- Animals
- Cell Line, Tumor
- Cell Proliferation
- Female
- Humans
- Immunotherapy
- Mice
Keywords
- Aging
- Immune check-point molecules
- Immunosenescence
- Immunotherapy
- Myeloid derived suppressor cells
- Oral cancer
- Regulatory T cells
{{medline-entry |title=LTA1 is a safe, intranasal enterotoxin-based adjuvant that improves vaccine protection against influenza in young, old and B-cell-depleted (μMT) mice. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31641151 |abstract=Enterotoxin-based adjuvants including cholera toxin and heat-labile toxin (LT) are powerful manipulators of mucosal immunity; however, past clinical trials identified unacceptable neurological toxicity when LT or mutant AB adjuvant proteins were added to intranasal vaccines. Here, we examined the isolated enzymatic A1 domain of LT (LTA1) for intranasal safety and efficacy in combination with influenza (flu) vaccination. LTA1-treated mice exhibited no neurotoxicity, as measured by olfactory system testing and H