Successful ageing of nonagenarians is related to the sensitivity of NK cells to activation.
Lucyna KaszubowskaAgnieszka Dettlaff‐PokoraŁukasz HakMagdalena SzaryńskaMonika Ryba‐StanisławowskaJolanta MyśliwskaAndrzej Myśliwski
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Abstract:
NK cells are a component of innate immunity which activity significantly correlates with health status. The aim of our study was to estimate a status of NK (natural killer) cells in the very old (mean age 92+/-2 ys) and old subjects (mean age 78+/-5 ys) as compared to a control group of young individuals (mean age 25+/-4 ys). NK cells were characterized by measurement of their cytotoxic activity, expression of intracellular interferon gamma, telomere length and telomerase activity in resting and activated cells. The results revealed that the oldest seniors did not differ from the other age groups in the number of NK cells and NK cytotoxic activity, however, they displayed the shortest telomeres and the lowest telomerase activity. Surprisingly, activated NK cells of the very old, similarly to the old subjects, were able to significantly increase intracellular level of IFNgamma. Moreover, activated with IL-2 NK cells of the old and oldest seniors showed increased telomerase activity. The results of our study suggest that the functional status of NK cells and their sensitivity to activation is well preserved until very advanced age and may contribute to longevity and successful ageing.Keywords:
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Immune involvement is well-described in Parkinson's disease (PD), including an adaptive T lymphocyte response. Given the increasing prevalence of Parkinson's disease in older age, age-related dysregulation of T lymphocytes may be relevant in this disorder, and we have previously observed changes in age-associated CD8+ T cell subsets in mid-stage PD. This study aimed to further characterise T cell immunosenescence in newly diagnosed PD patients, including shifts in CD4+ and CD8+ subpopulations, and changes in markers of cellular ageing in CD8+ T lymphocytes.Peripheral blood mononuclear cells were extracted from the blood of 61 newly diagnosed PD patients and 63 age- and sex-matched controls. Flow cytometric analysis was used for immunophenotyping of CD8+ and CD4+ lymphocyte subsets, and analysis of recent thymic emigrant cells. Telomere length within CD8+ T lymphocytes was assessed, as well as the expression of the telomerase reverse transcriptase enzyme (hTERT), and the cell-ageing markers p16INK4a and p21CIP1/Waf1.The number of CD8+ TEMRA T cells was found to be significantly reduced in PD patients compared to controls. The expression of p16INK4a in CD8+ lymphocytes was also lower in patients versus controls. Chronic latent CMV infection was associated with increased senescent CD8+ lymphocytes in healthy controls, but this shift was less apparent in PD patients.Taken together, our data demonstrate a reduction in CD8+ T cell replicative senescence which is present at the earliest stages of Parkinson's disease.
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The incidence of cancer increases with age and at the same time, normal individuals aged over 65 years, are characterized by an extremely reduced naive CD8+ T cell count and an increased number of memory cells, indicating an acceleration of the decay of the immune system from this age onwards. Several reports indicate that the immune system becomes overwhelmed with memory cells (both effector memory and terminally differentiated) and this appears to be directly related with an increase in age. The aim of this study was to investigate whether in patients with lung cancer and normal healthy individuals, the frequency and the qualitative features of circulating precursor cytotoxic T lymphocytes (pCTLs) specific for naturally processed and presented peptides of human telomerase reverse transcriptase (hTERT) and MAGE-A3 could be attributed to changes related to immunosenescence. An age-related decline of the frequency of anti-tumor specific pCTLs was observed for the first time in the literature2, despite the fact that, in the presence of tumours, this response is augmented. Our observation, questions how the application of various immunostimulating protocols could prove beneficial for aged cancer patients.
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NK cells are a component of innate immunity which activity significantly correlates with health status. The aim of our study was to estimate a status of NK (natural killer) cells in the very old (mean age 92+/-2 ys) and old subjects (mean age 78+/-5 ys) as compared to a control group of young individuals (mean age 25+/-4 ys). NK cells were characterized by measurement of their cytotoxic activity, expression of intracellular interferon gamma, telomere length and telomerase activity in resting and activated cells. The results revealed that the oldest seniors did not differ from the other age groups in the number of NK cells and NK cytotoxic activity, however, they displayed the shortest telomeres and the lowest telomerase activity. Surprisingly, activated NK cells of the very old, similarly to the old subjects, were able to significantly increase intracellular level of IFNgamma. Moreover, activated with IL-2 NK cells of the old and oldest seniors showed increased telomerase activity. The results of our study suggest that the functional status of NK cells and their sensitivity to activation is well preserved until very advanced age and may contribute to longevity and successful ageing.
Immunosenescence
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The role of the innate immunity during human ageing is not well understood. The aim of the study was to estimate reactivity of NK (natural killer) cells in the very old (mean age 91 years) and old subjects (mean age 78 years) compared to young individuals (mean age 26 years) in respect to the indices of the oxidative stress (telomere length of NK cells, serum content of -H groups), serum total antioxidant status and serum concentrations of interleukin 6 and tumor necrosis factor-α (TNF-α). The activation state of NK cells, reflected by telomerase activity and intracellular interferon γ (IFNγ) content, was also measured. We found that length of telomeres in NK cells and serum concentration of -SH groups decreased both in the old and the oldest subjects as compared to young individuals. The oldest seniors, on the contrary to the old ones, revealed similar level of serum antioxidant status as the young subjects. The serum level of IL-6, not detectable in the young subjects, did not differ in the oldest and old seniors. TNF-α serum concentrations progressively increased with age. After stimulation, NK cells of both old groups showed higher intracellular levels of IFNγ than young subjects. IL-2-activated NK cells of the oldest seniors showed the highest increase of telomerase activity as compared to the other age groups. Serum level of IL-6 correlated positively with activation markers of NK cells. Moreover, in seniors but not in young subjects, the number of active, IFNγ-expressing NK cells, correlated positively with the serum content of the -SH groups. These findings indicate that sensitivity of NK cells to activation is maintained during ageing and this phenomenon may be related to the oxidative and inflammatory status of the elderly.
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Senescence
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Senescence, the decline of physiological parameters with increasing age, is a quasi-ubiquitous phenomenon in the living world. However, the observed patterns of senescence can markedly differ between across species and populations, between sexes and even among individuals. To identify the drivers of this variation in senescence, experimental approaches are essential and involve the development of tools and new study models. In this context, we tested whether biomarkers of vertebrate ageing could be used to study senescence in a very promising invertebrate model of ageing: the common woodlouse Armadillidium vulgare. More specifically, we looked for the effect of age in woodlouse on three well established physiological biomarkers of ageing in vertebrates: immune cells (cell size, density and viability), β-galactosidase activity, and Telomerase Reverse Transcriptase (TERT) (essential subunit of the telomerase protein) gene expression. We found that the size of immune cells was higher in older individuals, whereas their density and viability decreased, and that the β-galactosidase activity increased with age, whereas the Telomerase Reverse Transcriptase (TERT) gene expression decreased. These findings demonstrate that woodlouse display age-related changes in biomarkers of vertebrate senescence, with different patterns depending on gender. Thus, the tools used in studies of vertebrate senescence can be successfully used in studies of senescence of invertebrates such as the woodlouse. The application of commonly used tools to new biological models offers a promising approach to assess the diversity of senescence patterns across the tree of life.
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Ageing is characterized by the impairment of the acute innate immune response and the upregulation of low-grade inflammation, i.e. inflammaging. At the cellular level, telomeres are considered as a marker of biological ageing as their length is progressively eroded in the absence of repair mechanisms. However, the link between telomeres and inflammaging remains underexplored. We aimed to identify proteins that are differentially expressed between age classes in response to an acute inflammatory challenge. We challenged young (two months) and old (12 months) C57BL/6 mice using bacterial lipopolysaccharide (LPS) and measured telomere length and proteomic profiles in splenocytes. In total, 233 out of the 1966 proteins we quantified differed among experimental groups. A hierarchical clustering analysis revealed that nine of those 233 proteins were differently expressed among the experimental groups. Young mice responded to LPS by increasing the expression of proteins involved in the innate immune response, and interestingly, in telomere length maintenance. However, this regulation was impaired at older ages. These results are in agreement with the assumption that the strength of selection declines with age, potentially explaining the maintenance of costly, dysregulated, immune responses at old age. We suggest that the immune response is competing with the telomere maintenance process, highlighting how telomeres reflect the ageing trade-off even in a species where telomere length is not related to lifespan.
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As humans age, their immune systems undergo a process known as immunosenescence. This global aging of the immune system is associated with increased susceptibility to infectious diseases and cancer, reduced effectiveness of vaccination, increased autoimmune phenomena, and tissue damage due to dysregulated inflammation. One hallmark feature of immunosenescence is the accumulation of late-differentiated memory CD8 T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, and enhanced secretion of inflammatory cytokines. The proportion of senescent CD8 T cells increases progressively with age, and often consists of oligoclonal populations that are specific for cytomegalovirus (CMV) antigens. In addition, there is evidence that senescent memory CD8 T cells acquire suppressive functions and may also contribute to carcinogenesis. Chronic HIV disease, even when controlled through antiretroviral therapy (ART), is associated with accelerated immunosenescence, as evidenced by the higher numbers of senescent memory CD8 T cells and increased inflammatory milieu. Interestingly, even in HIV disease, a high proportion of late-differentiated, putatively senescent, memory CD8 T cells are specific for CMV antigens. As in age-related immunosenescence, these HIV-associated changes result in dysregulated immunity, chronic diseases linked to inflammatory damage, and increased morbidity and mortality. This review explores the evidence for CD8 T cell replicative senescence in vitro and in vivo, in the context of both chronological aging and HIV-mediated immunosenescence. We also highlight an important gap in our understanding of human immunosenescence, since all the studies to date have focused on peripheral blood, which contains a minority of the total body lymphocyte population.
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Telomeres are protein-DNA complexes localized at the ends of linear chromosomes constituted by short, tandem G-rich hexanucleotide repeats and associated proteins. Their length shortens with each cell division and correlates inversely with age. It can be modified by genetic and epigenetic factors, sex hormones, reactive oxygen species and inflammatory reactions. A critical minimum length of telomeres triggers a cell cycle arrest or senescence of the cell. The immune system is highly sensitive to shortening of telomeres as its competence depends strictly on cell renewal and clonal expansion of T- and B-cell populations. Cells of the immune system are unique among normal somatic cells as they can up-regulate telomerase, the telomere extending enzyme, and limit telomere attrition in the process of cell proliferation undergoing in activated cells. Telomere length is highly variable among humans. Lineage-specific telomere shortening with different kinetics of telomere attrition was observed in CD4+, CD8+ T lymphocytes, B lymphocytes, granulocytes, monocytes and NK cell population. Immunosenescence is characterized by a special remodeling of the immune system induced by antigen exposure and oxidative stress. In ageing immune system adaptive immunity deteriorates because of a progressive decline of naive T and B cells and decrease of absolute numbers of T and B lymphocytes. The innate compartment of the immune system is relatively well preserved although some age-dependent alterations can be also observed. Nonagenarians or centenarians represent phenomenon of successful ageing of the immune system as most of their immune parameters are well preserved.
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