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BackgroundThe cellular mechanisms involved in the lack of protective antibody response after hepatitis B vaccination are still rather unclear. Regulatory B cells (Breg) known as modulators of B-and T-cell responses may contribute to poor vaccine responsiveness. The current study aimed to investigate the role of regulatory B cells (Breg) in hepatitis B vaccine non-responsiveness after immunization with second- or third-generation hepatitis B vaccines.MethodWe performed comparative phenotypic and frequency analysis of Breg subsets (CD24+CD27+ and CD24highCD38high Breg) in second-generation hepatitis B vaccine non-responders (2nd HBvac NR, n = 11) and responders (2nd HBvac R, n = 8) before (d0), on day 7 (d7), and 28 (d28) after booster vaccination. Cryopreserved peripheral blood mononuclear cells were stimulated ex vivo with a combination of CpG, PMA, and Ionomycin (CpG+P/I) and analyzed for numbers and IL-10 expression levels of Breg by flow cytometry-based analyses.ResultsFlow cytometry-based analyses revealed elevated frequencies of CD24+CD27+ Breg at all time points and significantly higher frequencies of CD24highCD38high Breg on d0 (p = 0.004) and 28 (p = 0.012) in 2nd HBvac NR compared to 2nd HBvac R. In parallel, we observed significantly lower levels of CpG+P/I-induced IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg (d0: p < 0.0001; d7: p = 0.0004; d28: p = 0.0003 and d0: p = 0.016; d7: p = 0.016, respectively) in 2nd HBvac NR compared to 2nd HBvac R before and after booster immunization. Frequencies of CD24+CD27+ and CD24highCD38high Breg significantly decreased after third-generation hepatitis B booster vaccination (d7: p = 0.014; d28: p = 0.032 and d7: p = 0.045, respectively), whereas IL-10 expression levels of both Breg subsets remained stable.ConclusionHere we report significantly higher frequencies of CD24highCD38high Breg in parallel with significantly lower IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg in 2nd HBvac NR compared to 2nd HBvac R. Anti-HBs seroconversion accompanied by a decrease of Breg numbers after booster immunization with a third-generation hepatitis B vaccine could indicate a positive effect of third-generation hepatitis B vaccines on Breg-mediated immunomodulation in hepatitis B vaccine non-responders.

The analysis of copper (Cu) and zinc (Zn) along with their major serum carriers, albumin (Alb) and ceruloplasmin (Cp), could provide information on the capacity of humans to maintain homeostasis of metals (metallostasis). However, their relationship with aging, sex, body mass index, as well as with nutritional and inflammatory markers was never investigated in a large-scale study. Here, we report results from the European large-scale cross-sectional study MARK-AGE in which Cu, Zn, Alb, Cp, as well as nutritional and inflammatory parameters were determined in 2424 age-stratified participants (35–75 years), including the general population (RASIG), nonagenarian offspring (GO), a well-studied genetic model of longevity, and spouses of GO (SGO). In RASIG, Cu to Zn ratio and Cp to Alb ratio were higher in women than in men. Both ratios increased with aging because Cu and Cp increased and Alb and Zn decreased. Cu, Zn, Alb, and Cp were found associated with several inflammatory as well as nutritional biomarkers. GO showed higher Zn levels and higher Zn to Alb ratio compared to RASIG, but we did not observe significant differences with SGO, likely as a consequence of the low sample size of SGO and the shared environment. Our results show that aging, sex, body mass index, and GO status are characterized by different levels of Cu, Zn, and their serum carrier proteins. These data and their relationship with inflammatory biomarkers support the concept that loss of metallostasis is a characteristic of inflammaging.

Torquetenovirus (TTV) viremia has been associated with increased mortality risk in the elderly population. This work aims to investigate TTV viremia as a potential biomarker of immunosenescence. We compared levels of circulating TTV in 1813 participants of the MARK-AGE project, including human models of delayed (offspring of centenarians [GO]) and premature (Down syndrome [DS]) immunosenescence. The TTV load was positively associated with age, cytomegalovirus (CMV) antibody levels, and the Cu/Zn ratio and negatively associated with platelets, total cholesterol, and total IgM. TTV viremia was highest in DS and lowest in GO, with intermediate levels in the SGO (spouses of GO) and RASIG (Randomly Recruited Age-Stratified Individuals From The General Population) populations. In the RASIG population, TTV DNA loads showed a slight negative association with CD3+T-cells and CD4+T-cells. Finally, males with ≥4log TTV copies/mL had a higher risk of having a CD4/CD8 ratio

The regular use of medication may interfere with micronutrient metabolism on several levels, such as absorption, turnover rate, and tissue distribution, and this might be amplified during aging. This study evaluates the impact of self-reported medication intake on plasma micronutrients in the MARK-AGE Project, a cross-sectional observational study in 2217 subjects (age- and sex-stratified) aged 35&ndash, 75 years from six European countries that were grouped according to age. Polypharmacy as possible determinant of micronutrient concentrations was assessed using multiple linear regression models adjusted for age-group, dietary fruit, vegetables, and juice intake, and other confounders. Younger participants reported taking fewer drugs than older participants. Inverse associations between medication intake and lutein (&minus, 3.31% difference per increase in medication group), &beta, carotene (&minus, 11.44%), &alpha, 8.50%) and positive associations with retinol (+2.26%), &alpha, tocopherol/cholesterol (+2.89%) and &gamma, tocopherol/cholesterol (+1.36%) occurred in multiple adjusted regression models. Combined usage of a higher number of medical drugs was associated with poorer status of carotenoids on the one hand and higher plasma concentrations of retinol, &alpha, and &gamma, tocopherol on the other hand. Our results raise concerns regarding the safety of drug combinations via the significant and surprisingly multifaceted disturbance of the concentrations of relevant micronutrients.

Frailty among elderly people leads to an increased risk for negative health outcomes. To prevent frailty, we need a better understanding of the underlying mechanisms and early detection of individuals at risk. Both may be served by identifying candidate (bio)markers, i.e. biomarkers and markers, for the physical, cognitive, and psychological frailty domains. We used univariate (Rank-ANOVA) and multivariate (elastic net) approaches on the RASIG study population (age range: 35–74 years, n = 2220) of the MARK-AGE study to study up to 331 (bio)markers between individuals with and without frailty for each domain. Biomarkers and markers identified by both approaches were studied further regarding their association with frailty using logistic regression. Univariately, we found lower levels of antioxidants, including β-cryptoxanthin and zeaxanthin, in those who were physically, cognitively or psychologically frail. Additionally, self-reported health was worse in these three frail groups. Multivariately, we observed lower levels of β-cryptoxanthin and zeaxanthin in the cognitively frail. Levels of these carotenoids were inversely associated with the risk of being cognitively frail after adjusting for confounders. Antioxidants and self-reported health are potential (bio)markers to detect persons at risk of becoming frail. The biomarkers identified may indicate the involvement of inflammation in frailty, especially for physical and cognitive frailty.

Many currently used vaccines are less immunogenic in the elderly compared to young adults. The impact of latent infection with Cytomegalovirus (CMV) on vaccine-induced antibody responses has been discussed controversially. We have demonstrated that recall responses to diphtheria vaccination are frequently insufficient in elderly persons and that antibody concentrations decline substantially within 5 years. In the current study we show that within a cohort of healthy elderly (n = 87; median age 71 years, range 66–92) antibody responses to a booster vaccination against diphtheria do not differ between CMV-negative and CMV-positive individuals 4 weeks after vaccination.. However, the goal of diphtheria-vaccination is long-term protection and this is achieved by circulating anti-toxin antibodies. Diphtheria-specific antibody concentrations decline faster in CMV-positive compared to CMV-negative older adults leading to an increased proportion of persons without protective antibody concentrations 5 years after booster vaccination and endangering long-term protection. This finding could be relevant for vaccination schedules. Electronic supplementary material The online version of this article (doi:10.1186/s12979-017-0099-y) contains supplementary material, which is available to authorized users.

Only 20–25% of healthy life expectancy is predetermined by genes; lifestyle and environment play a major role. In the past decades, biogerontological research has significantly contributed to a better understanding of the ageing process that now provides the basis for the development of efficient intervention strategies suitable to increase healthy life expectancy. Based on the most recent biogerontological findings, the authors summarise which interventions at which stage of life are needed to preserve health and prevent or ameliorate disease. Classical lifestyle interventions as well as novel pharmacological substances with mixed proof of efficacy and evidence are discussed. The authors conclude that novel communication strategies, incentives, and regulations need to be developed to promote and force the adoption of a healthy lifestyle in the general population.

Metallothionein (MT) family are cysteine-rich proteins that regulate zinc (Zn) homeostasis and protect against oxidative damage. Studies in transgenic mice have shown that MT favorably influence longevity, although their role in human aging is not completely understood. Within the European multicenter study MARK-AGE, we analyzed MT induction after Zn treatment in peripheral blood mononuclear cells (PBMCs) and its relation with redox biomarkers in 2,936 age-stratified subjects (35–75 years) including the general population (RASIG), centenarian offspring (GO), and their spouses (SGO). We found that the lymphocyte capability to induce MT in response to Zn is not affected by aging. However, GO participants showed lower Zn-induced MT and increased basal expression of MT1A, MT1X, and ZnT-1 genes than RASIG subjects. Moreover, Zn-induced MT levels were found to be inversely related with oxidative stress markers (plasma protein carbonyls, 3-nitrotyrosine, and malondialdehyde) in the whole population, but not in GO subjects. In conclusion, our results support the hypothesis that the response to Zn is attenuated in PBMCs of centenarian offspring compared to the general population as a consequence of a tighter control of Zn homeostasis which is likely to provide them constant protection against stress stimuli over the whole lifespan. published

Objectives Populations are aging worldwide. This paper summarizes some of the challenges and opportunities due to the increasing burden of infectious diseases in an aging population. Results Older adults typically suffer elevated morbidity from infectious disease, leading to increased demand for healthcare resources and higher healthcare costs. Preventive medicine, including vaccination can potentially play a major role in preserving the health and independence of older adults. However, this potential of widespread vaccination is rarely realized. Here, we give a brief overview of the problem, discuss concrete obstacles and the potential for expanded vaccination programs to promote healthy aging. Conclusion The increasing healthcare burden of infectious diseases expected in aging populations could, to a large extent, be reduced by achieving higher vaccination coverage among older adults. Vaccination can thus contribute to healthy aging, alongside healthy diet and physical exercise. The available evidence indicates that dedicated programs can achieve substantial improvements in vaccination coverage among older adults, but more research is required to assess the generalizability of the results achieved by specific interventions (see Additional file 1). Electronic supplementary material The online version of this article (10.1007/s41999-018-0040-8) contains supplementary material, which is available to authorized users.

Many current vaccines are less immunogenic and less effective in elderly compared to younger adults due to age-related changes of the immune system. Most vaccines utilized in the elderly contain antigens, which the target population has had previous contact with due to previous vaccination or infection. Therefore, most studies investigating vaccine-induced immune responses in the elderly do not analyze responses to neo-antigens but rather booster responses. However, age-related differences in the immune response could differentially affect primary versus recall responses. We therefore investigated the impact of age on primary and recall antibody responses following hepatitis B vaccination in young and older adults. Focused gene expression profiling was performed before and 1 day after the vaccination in order to identify gene signatures predicting antibody responses. Young (20-40 years;  = 24) and elderly (>60 years;  = 17) healthy volunteers received either a primary series (no prior vaccination) or a single booster shot (documented primary vaccination more than 10 years ago). Antibody titers were determined at days 0, 7, and 28, as well as 6 months after the vaccination. After primary vaccination, antibody responses were lower and delayed in the elderly compared to young adults. Non-responders after the three-dose primary series were only observed in the elderly group. Maximum antibody concentrations after booster vaccination were similar in both age groups. Focused gene expression profiling identified 29 transcripts that correlated with age at baseline and clustered in a network centered around type I interferons and pro-inflammatory cytokines. In addition, smaller 8- and 6-gene signatures were identified at baseline that associated with vaccine responsiveness during primary and booster vaccination, respectively. When evaluating the kinetic changes in gene expression profiles before and after primary vaccination, a 33-gene signature, dominated by IFN-signaling, pro-inflammatory cytokines, inflammasome components, and immune cell subset markers, was uncovered that was associated with vaccine responsiveness. By contrast, no such transcripts were identified during booster vaccination. Our results document that primary differs from booster vaccination in old age, in regard to antibody responses as well as at the level of gene signatures. Clinical Trial Registration: www.clinicaltrialsregister.eu, this trial was registered at the EU Clinical Trial Register (EU-CTR) with the EUDRACT-Nr. 2013-002589-38.

Background Formation of lamellar bone in non-osseus tissue is a pathological process called heterotopic ossification. It is the aim of this study to analyse the morphology and immunological status of patients with heterotopic ossification compared to individual healthy persons. Methods Human bone marrow and blood samples were obtained from 6 systemically healthy individuals and 4 patients during resection of heterotopic ossification from bone at hip arthroplasty. Bone was fragmented and treated with purified collagenase. Immunofluorescence surface staining was performed and analyzed with flow cytometry. Microcomputed tomography scanning was done performed at a resolution of 11 and 35 μm isometric voxel size respectively using a two different cone beam X-computer tomography systems and a microfocus X-ray tube. Subsequently the volume data was morphometrically analysed. Results The monocytes, stem cells, stroma cells and granulocytes progenitor cells were strongly reduced in the heterotopic ossification patient. Additionally a significant reduction of stromal stem cells cells and CD34 positive stem cells was observed. The frequency of NK-cells, B cells and T cells were not altered in the patients with heterotopic ossification compared to a healthy person. Micromorphometric parameters showed a lower content of mineralized bone tissue compared to normal bone. Mean trabecular thickness showed a high standard deviation, indicating a high variation in trabecular thickness, anisotropy and reducing bone strength. Conclusions This work shows altered immunological distribution that is accompanied by a low decrease in bone volume fraction and tissue mineral density in the heterotopic ossification sample compared to normal bone. Compared to healthy subjects, this might reflect an immunological participation in the development of this entity.

The progressive increase of the aged population worldwide mandates new strategies to ensure sustained health and well-being with age. The development of better and/or new vaccines against pathogens that affect older adults is one pivotal intervention in approaching this goal. However, the functional decline of various physiological systems, including the immune system, requires novel approaches to counteract immunosenescence. Although important progress has been made in understanding the mechanisms underlying the age-related decline of the immune response to infections and vaccinations, knowledge gaps remain, both in the areas of basic and translational research. In particular, it will be important to better understand how environmental factors, such as diet, physical activity, co-morbidities, and pharmacological treatments, delay or contribute to the decline of the capability of the aging immune system to appropriately respond to infectious diseases and vaccination. Recent findings suggest that successful approaches specifically targeted to the older population can be developed, such as the high-dose and adjuvanted vaccines against seasonal influenza, the adjuvanted subunit vaccine against herpes zoster, as well as experimental interventions with immune-potentiators or immunostimulants. Learning from these first successes may pave the way to developing novel and improved vaccines for the older adults and immunocompromised. With an integrated, holistic vaccination strategy, society will offer the opportunity for an improved quality of life to the segment of the population that is going to increase most significantly in numbers and proportion over future decades.

Due to the successful implementation of vaccination strategies early-life morbidity and mortality due to infectious disease has been reduced dramatically. Vaccines against tetanus and diphtheria are among the most frequently used vaccines worldwide, but various studies in different European countries have shown that protection against tetanus and particularly against diphtheria is unsatisfactory in adults and older persons. In this study we analyzed tetanus- and diphtheria-specific antibody concentrations in 2100 adults of different age from 6 selected European countries (Austria, Belgium, Germany, Greece, Italy, Poland) in order to investigate differences in the level of protection against tetanus and diphtheria across Europe. Our data reveal that tetanus- and diphtheria-specific antibody concentrations vary greatly between countries, which is also reflected in the percentage of persons with antibody concentrations below the protective level (0.1 IU/ml), which ranged from 2 to 31% percent for tetanus and 28–63% for diphtheria. In most countries, tetanus- and diphtheria-specific antibody concentrations decrease with age. This phenomenon is more pronounced in countries with generally low antibody levels, such as Italy, Poland and Greece. Interestingly, tetanus-specific antibody concentrations are generally higher in males than in females, which is probably due to vaccination during their military service or more frequent booster vaccinations after injuries, whereas no gender-related differences were found for diphtheria-specific antibodies. In conclusion, our study demonstrates that the European population is not fully protected against tetanus and diphtheria. Measures to improve protection should include a life-long perspective on vaccination, more education to increase awareness of and compliance with vaccination guidelines, and a harmonization of recommendations and incentives across Europe.

There is an increased susceptibility and mortality in the elderly due to pneumonia caused by Streptococcus pneumoniae. We aimed to assess the inflammatory cell composition with respect to age in pneumococcal pneumonia patients. Neutrophilic granulocytes and various lymphocyte and macrophage subpopulations were immunohistochemically quantified on lung tissue specimens of young (n = 5; mean age 8.4 years), middle-aged (n = 8; mean age 55.9 years) and elderly (n = 9; mean age 86.6 years) pneumonia patients with microbiologically proven S. pneumoniae pneumonia. We discovered a higher percentage of neutrophilic granulocytes in elderly as opposed to young patients (95 vs. 75%, p = 0.012). Conversely, young patients versus elderly patients had more alveolar macrophages (CD11c+: 20 vs. 9%, p = 0.029) and M1 macrophages (CD14+: 30 vs. 10%, p = 0.012 and HLA-DR+: 52 vs. 11%, p = 0.019). There was no significant difference concerning M2 macrophages and lymphocytes. Comparison of young patients with middle-aged patients showed similar significant results for alveolar macrophages (p = 0.019) and subsignificant results for M1 macrophages and neutrophilic granulocytes (p < 0.08). This is the first study characterizing the inflammatory infiltrate of pneumococcal pneumonia in situ. Our observations improve the understanding of the innate immune mechanisms of pneumococcal lung infection and point at the potential of therapies for restoring macrophage function and decreasing neutrophilic influx in order to help prevent or cure pneumonia.

Adaptive immune responses are severely affected by the aging process as reflected by an increased morbidity and mortality from infectious diseases and a low efficacy of vaccination in elderly persons. Age-related changes within the bone marrow and thymus lead to an impaired generation of new T and B cells severely compromising the maintenance of a diverse and balanced T and B cell repertoire in old age. The maintenance of a balanced T cell repertoire is further challenged by latent persistent infections, such as Cytomegalovirus. Understanding the mechanisms of age-related alterations of the adaptive immune response may help to facilitate the development of more efficient vaccines for elderly persons and to envisage strategies to overcome immunosenescence.

Since Looney at al. published their seminal paper a decade ago [1] it has become clear that many of the differences in T cell immunological parameters observed between young and old people are related to the age-associated increasing prevalence of infection with the persistent β-herpesvirus HHV-5 (Cytomegalovirus). Ten years later, studies suggest that hallmark age-associated changes in peripheral blood T cell subset distribution may not occur at all in people who are not infected with this virus [[2]; Derhovanessian et al., in press]. Whether the observed changes are actually caused by CMV is an open question, but very similar, rapid changes observed in uninfected patients receiving CMV-infected kidney grafts are consistent with a causative role [3]. This meeting intensively discussed these and other questions related to the impact of CMV on human immune status and its relevance for immune function in later life.

Among the greatest achievements of the 20th century, prolongation of life expectancy has been the result of improved health conditions, decreased childhood mortality, lower incidence of infectious diseases. The consequence is the rapid ageing of the world population, with the elderly representing over 25% of the entire population by the year 2030, of which 75% living in less developed countries. Ageing thus represents one of the major public health challenges of the 21st century. Indeed, unhealthy ageing and frailty of the aged population has an important impact on the economic development and social costs of a country, a problem even more acute in less developed countries. A better knowledge of immune senescence and the design of customised vaccination strategies for the elderly are the immediate challenges posed to scientists and physicians. The conference “Ageing and immunity”, recently held in Siena (Italy), has addressed these issues and defined the global strategic priorities for research and health policies aimed at ensuring healthy ageing.

Because of decreased immune functions of older people booster intervals of 3 years - instead of 5 - are recommended for tick-borne encephalitis (TBE) vaccinations for persons >or=60 years in Austria. So far, no comparative data on the immune-responsiveness of the age group 50-59 years are available. We therefore investigated the antibody titers and booster responses (in ELISA and neutralization assays) for the age groups 50-59, 60-69, and >69 years in comparison to a control group below 30 years. The age group 50-59 years displayed the same decreased antibody response, also characteristic for persons 60 years and older. Although antibody concentrations were lower after 5-7 years compared to 3-4 year intervals, antibodies were still detectable and could be sufficiently increased by booster shots in the vast majority of persons. Our results clearly indicate that the responsiveness of the immune system to vaccination is already impaired at the age of 50.

Successful vaccination of the elderly against important infectious pathogens which cause high morbidity and mortality represents a growing public health priority. Building upon the theme of aging and immunosenescence, we review mechanisms of human immunosenescence and the immune response to currently-licensed vaccines. We discuss the difficulties in identifying the risk factors that, in addition to aging, cause immunosenescence and address the relative paucity of vaccine studies in the elderly. We conclude that vaccine responses are blunted in the elderly when compared to that of healthy young adults. However, it is also clear that our understanding of the mechanisms underlying immunosenescence is limited and much remains to be learned in order to improve the effectiveness of next generation vaccines.

The study was aimed to assess indicators of immunosenescence, such as the total counts of peripheral blood CD4(+)CD45RA(+)CD62L(+) (naive) T cells, the numbers of T cell receptor excision circles (TRECs), and Ki67-expression as marker of peripheral replication in thymectomized patients (TP) (n=101) compared to age-matched healthy donors (HD) (n=81). In TP, there was an inverse correlation between naive T cells and chronological age (p

With increasing age, the human immune system undergoes characteristic changes, termed immunosenescence, which lead to increased incidence and severity of infectious diseases and to insufficient protection following vaccination. Functional defects and altered frequencies of innate and adaptive immune cells impair local responses at the site of vaccine injection, hamper the generation of primary responses to neoantigens, prevent the effective induction of memory lymphocytes, and decrease the effect of booster vaccination. As a result, antibody responses of elderly vaccinees are weaker and decline faster, and long-term protective effects of vaccination cannot be taken for granted in elderly persons. Improved vaccination strategies, new adjuvants, and new vaccines that specifically target the aged immune system will help to overcome the limitations of immunosenescence and ensure a better protection of the vulnerable elderly population.

Influenza-specific CD8+ T cells are important for the clearance of infection especially in high risk groups such as elderly persons. Activation of these cells by immunization might therefore be a useful tool for a better protection of this specific age group. We therefore analyzed the frequency, phenotype and function of CD8+ T cells with specificity to the influenza M1(58-66) peptide in young, middle-aged and elderly persons ex vivo and after in vitro stimulation. Significantly lower numbers of M1(58-66)-specific CD8+ T cells were detected in the middle-aged and elderly compared to young donors. M1(58-66)-specific CD8+ T cells were either CD45RA(low)CD45RO(low) or CD45RA-CD45RO+, expressed CD28 and CD62L and did not produce perforin. There was no difference in the phenotype of influenza-specific CD8+ T cells between the three age groups. Despite the initially low numbers of M1(58-66)-specific CD8+ T cells in the older age groups, these cells could be expanded in vitro following peptide stimulation. They also acquired a CD45RO+CD28+ CD62L(+/-) phenotype and produced perforin. Our results demonstrate that although initially low in number, M1(58-66)-specific CD8+ T cells from elderly persons can be propagated and differentiated into perforin producing effector cells upon appropriate stimulation. M1(58-66) peptide or other immunodominant peptides derived from conserved influenza proteins could therefore be useful in future influenza vaccines in order to render elderly persons better protected against disease, in particular in the case of an influenza pandemic.

Average life expectancy is continuously rising in all developed countries, leading to an ever-increasing elderly population. Of the many functions of the body affected by the complex process of ageing, the immune system in particular undergoes various changes, collectively termed immunosenescence. As a result, elderly people are more susceptible to infections and are frequently less protected by vaccines. This review summarises the effect of ageing on immunity, emphasising the age-associated changes within T and B cells at a molecular and cellular level. Furthermore, it discusses strategies, such as the addition of immunostimulatory adjuvants and the use of potent antigen-delivery systems, that may counteract age-related defects in immune responses to vaccination. A proper understanding of how immunological memory is affected by ageing, and the introduction of strategies to ameliorate vaccine efficacy in the elderly, might reduce the incidence and the severity of infectious disease within this fragile age group and have a strong impact on the quality of life of elderly individuals.

Summary In the 21st century, public health is not only challenged by newly emerging and re-emerging infectious diseases but also by demographic developments that are taking place in many countries. Importantly, infections in the elderly are more frequent, more severe and have distinct features with respect to clinical presentation and treatment. This is due to a decline in the functions of the immune system referred to as immunosenescence. The most important age-related changes affect the T cell system. Although this derogates the protective effect of some vaccines, vaccinations are still considered the most cost-effective medical procedure for preventing morbidity and mortality caused by infectious diseases. The present article aims at outlining the impact of infectious diseases on the elderly and summarizing the progress made in the field of vaccinations of the elderly and how age-related changes within the immune system contribute to the decreased efficacy of vaccines.

A wide range of age-related alterations in immune system function have been reported and are referred to as immunosenescence. Much of the decline in immunoresponsiveness seen in elderly persons is due to changes within the T cell compartment because of the involution of the thymus. For this reason, infectious diseases are more frequent and severe in elderly persons, and the efficacy of vaccinations is low. Recently, scientific evidence has accumulated that chronic cytomegalovirus (CMV) infection may accelerate the aging of the immune system and may lead to a high chronic-inflammatory background in elderly persons. This may exacerbate the functional pathology and disease course of age-related disorders, such as atherosclerosis, rheumatoid arthritis, and Alzheimer's disease. Therefore, the present article will summarize the changes that occur in the immune system of elderly persons with and without chronic CMV infection and will highlight the impact of CMV infection on the immune response and efficacy of vaccinations in old age. It will also elucidate the mechanisms CMV uses to escape immune surveillance, the basis for life-long persistence in the host. Finally, current and future immunotherapeutic strategies to fight or prevent CMV infection will be reviewed.

Neopterin is produced from human monocyte-derived macrophages and dendritic cells upon Stimulation with interferon-y, and increased neopterin concentrations thus indicate cell-mediated immune activation. In healthy individuals increasing neopterin concentrations are found with increasing age, which is also evident from the agedependency of reference values of serum neopterin concentrations. Increase of neopterin concentrations in the elderly may relate to, e.g., altered T lymphocyte differentiation with age. In this study, serum neopterin concentrations of 138 persons (median age: 34 years; interquartile range 29.0 - 67.8 years) were investigated and compared to age and to the percentage of CD28+CD45RA+ or CD28+CD45RO+ subsets among CD8+ T cells. With increasing age, the percentage of CD28+CD45RA+ in CD8+ T-cells decreased (Spearman's rank correlation coefficient: rs = -0.561; p < 0.0001) accompanied by an increase of the percentage of CD28+CD45RO+ in CD8+ T-cells (rs = +0.221; p < 0.01). Serum neopterin concentrations increased with age (rs = -+0.541; p < 0.0001). This increase of neopterin concentration was accompanied by a decreased percentage of CD28+CD45RA+ in CD8+ T-cells (r+ = -0.287; p < 0.001). Multivariate analyses revealed that the inverse relationship between the percentage of CD28+CD45RA+ in CD8+ T-cells and neopterin concentrations was at least partly independent from age. Thus, investigation allows to conclude that an increase of neopterin concentrations with older age is accompanied by a loss of naive CD28+CD45RA+ CD8+ T-cells. Data suggest that the subset of CD28+CD8+ T-cells, which is developing in states of sustained immune activation, is important for a chronic production of interferon-γ which in turn gives rise to increased neopterin concentrations.

Tetanus toxoid (TT) antibodies of 447 adult persons aged 27-69 years were investigated and analyzed in relationship with the time span since the last vaccination against tetanus as well as the serum concentration of neopterin. Neopterin is a pteridine, which is produced by monocytes/macrophages upon stimulation with the type 1 T cell-derived cytokine interferon-gamma. There was an inverse correlation between serum neopterin and TT antibody concentrations (Spearman's rank correlation coefficient: r(s)=-0.259; p0.0001) which was even stronger when persons with neopterin concentrations and TT antibodies below the third quartile of the study population were excluded (residual group: n=210; r(s)=-0.718; p0.0001). The study demonstrates that an immunoregulatory shift towards type 1 immunity as indicated by higher neopterin concentrations coincides with lower TT antibody concentrations in the elderly.

The dysregulation in the metabolism of beta-amyloid precursor protein and consequent deposition of amyloid-beta (Abeta) has been envisaged as crucial for the development of neurodegeneration in Alzheimer's disease (AD). Amyloid deposition begins 10-20 years before the appearance of clinical dementia. During this time, the brain is confronted with increasing amounts of toxic Abeta peptides and data from the last decade intriguingly suggest that both the innate and the adaptive immune systems may play an important role in the disorder. Innate immunity in the brain is mainly represented by microglial cells, which phagocytose and degrade Abeta. As the catabolism of Abeta decreases, glial cells become overstimulated and start to produce substances that are toxic to neurons, such as nitric oxide and inflammatory proteins. Pro-inflammatory cytokines can be directly toxic or stimulate Abeta production and increase its cytotoxicity. A therapeutic possibility arises from clinical studies, which demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD. Recent data show that in addition to the suppression of inflammatory processes in the brain NSAIDs may decrease the production of Abeta peptides. The role of adaptive immunity lies mainly in the fact that Abeta can be recognised as an antigen. Immunisation with Abeta peptides and peripheral administration of Abeta-specific antibodies both decrease senile plaques and cognitive dysfunction in murine models of AD. A recent trial in humans seems still to be hampered by adverse effects. As adaptive immunity decreases with aging while innate immunity remains intact, immunotherapy for AD will have to be adapted to this situation. Strategies that combine vaccination and inflammatory drug treatment could be considered.

The aging of the human population is posing serious challenges to research and to public health authorities in order to prevent diseases that more frequently affect the elderly, a portion of the population that will increase more and more in the coming years. While some vaccines exist and are used in the elderly to effectively fight against some infections (e.g. influenza, pneumococci, varicella-zoster virus, diphtheria, and tetanus), still a lot of work remains to be done to better adapt these vaccines and to develop new ones for this age group. The prevention of infectious diseases affecting the elderly can be successful only through a holistic approach. This approach will aim at the following: (1) a deeper understanding of the mechanisms leading to the senescence of the immune system, (2) a better and broader use of vaccines recommended for the elderly, (3) the use of vaccines currently considered only for other age groups and (4) actively priming the population when they are immunological competent, before the physiological waning of immune responsiveness may affect the beneficial effects of vaccination.

Trying to decrease the production of Amyloid beta (Abeta) has been envisaged as a promising approach to prevent neurodegeneration in Alzheimer's disease (AD). A chronic inflammatory reaction with activated microglia cells and astrocytes is a constant feature of AD. The participation of the immune system in the disease process is further documented in several retrospective clinical studies showing an inverse relationship between the prevalence of AD and nonsteroidal anti-inflammatory drug (NSAID) therapy. Previously, we demonstrated that the combination of the proinflammatory cytokines TNFalpha with IFNgamma induces the production of Abeta-42 and Abeta-40 in human neuronal cells. In the present study, the neuronal cell line Sk-n-sh was incubated for 12 h with the cyclooxygenase inhibitor ibuprofen and subsequently stimulated with the cytokines TNFalpha and IFNgamma. Ibuprofen treatment decreased the secretion of total Abeta in the conditioned media of cytokine stimulated cells by 50% and prevented the accumulation of Abeta-42 and Abeta-40 in detergent soluble cell extracts. Viability of neuronal cells measured by detection of apoptosis was neither influenced by ibuprofen nor by cytokine treatment. The reduction in the production of Abeta by ibuprofen was presumably due to a decreased production of betaAPP, which in contrast to the control proteins M2 pyruvate kinase, beta-tubulin and the cytokine inducible ICAM-1 was detected at low concentration in ibuprofen treated cells. The data demonstrate a possible mechanism how ibuprofen may decrease the risk and delay the onset of AD.

Imrich Blasko , Gerhard Ransmayr , Robert Veerhuis , Piet Eikelenboom , Beatrix Grubeck-Loebenstein c,) a Department of Neurology, UniOersity Hospital of Innsbruck, Innsbruck, Austria b Departments of Psychiatry and Pathology, Research Institute of Neurosciences, Vrije UniOersiteit Amsterdam, Amsterdam, Netherlands c Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria

Chronic inflammation and astrocytosis are characteristic histopathological features of Alzheimer's Disease (AD). Astrocytes are one of the predominant cell types in the brain. In AD they are activated and produce inflammatory components such as complement components, acute phase proteins, and cytokines. In this study we analyzed the effect of cytokines on the production of amyloid beta (Abeta) in the astrocytoma cell line U373 and in primary human astrocytes isolated postmortem from healthy aged persons as well as from patients with AD. Astrocytes did not produce Abeta in the absence of stimuli or following stimulation with IL-1beta, TNFalpha, IL-6, and TGF-beta1. Neither did combinations of TNFalpha and IL-1beta, IL-6 or TGF-beta1, or the coadministration of IFNgamma and IL-6 or TGF-beta1 induce Abeta production. In contrast, pronounced production of Abeta1-40 and Abeta1-42 was observed when primary astrocytes or astrocytoma cells were stimulated with combinations of IFNgamma and TNFalpha or IFNgamma and IL-1beta. Induction of Abeta production was accompanied by decreased glycosylation of APP as well as by increased secretion of APPsbeta. Our results suggest that astrocytes may be an important source of Abeta in the presence of certain combinations of inflammatory cytokines. IFNgamma in combination with TNFalpha or IL-1beta seems to trigger Abeta production by supporting beta-secretase cleavage of the immature APP molecule.

Age-dependent immunological alterations are responsible for a large number of diseases in the elderly. It was the aim of a Symposium held in Kuhtai, Austria, from December 3–5, 1998, to bring together basic scientists, clinicians, and representatives of pharmaceutical companies to discuss immunosenescence and its consequences. Strategies were worked out for applying recent research results to the prevention and treatment of diseases in the aged and for organizing collaborations between teams throughout Europe within the 5th EU Framework Programme.

The appearance of inflammatory markers associated with amyloid plaques indicates a state of chronic inflammation in Alzheimer's disease (AD). Multiple epidemiological studies also suggest that pati...

The function of the immune system declines with age. It is the aim of the present review to demonstrate that it makes sense to distinguish between primary and secondary alterations of immune reactivity in the elderly. Primary changes occur as the result of an age-dependent intrinsic decline of immune responsiveness. They also occur in healthy persons, i.e. persons selected according to the criteria of the SENIEUR protocol of the European Community's Concerted Action Program on Aging (EURAGE). T lymphocytes are hereby more severely affected than B cells or antigen presenting cells, possibly due to the involution of the thymus, which is almost complete at the age of 60. Secondary immunological changes occur as the result of environmental factors including diet, drug intake, physical activity etc. or are alternatively due to underlying diseases. In this article, the effects of high lipid intake as well as the impact of diseases, such as for instance Alzheimer's disease and atherosclerosis, will be addressed. The results underline the complexity of immunological alterations to be expected in old age. Changes in the aging immune system represent an opportunity for increased frequency and severity of disease and endanger the protective effect of vaccination.

UnlabelledDemographic changes and a more active life-style in older age have contributed to an increasing public awareness of the need for lifelong vaccination. Currently many older persons have been vaccinated against selected pathogens during childhood but lack regular booster immunizations. The impact of regular vaccinations when started late in life was analyzed in an open, explorative trial by evaluating the immune response against tetanus and diphtheria in healthy older individuals. 252 persons aged above 60 years received a booster vaccination against tetanus, diphtheria, pertussis and polio and a subcohort (n=87) was recruited to receive a second booster vaccination against tetanus, diphtheria and pertussis 5 years later. The percentage of unprotected individuals at the time of enrollment differed substantially for tetanus (12%) and diphtheria (65%). Despite protective antibody concentrations 4 weeks after the first vaccination in almost all vaccinees, antibodies had again dropped below protective levels in 10% (tetanus) and 45% (diphtheria) of the cohort after 5 years. Protection was restored in almost all vaccinees after the second vaccination. No correlation between tetanus- and diphtheria-specific responses was observed, and antibody concentrations were not associated with age-related changes in the T cell repertoire, inflammatory parameters, or CMV-seropositivity suggesting that there was no general biological "non-responder type." Post-vaccination antibody concentrations depended on pre-existing plasma cells and B cell memory as indicated by a strong positive relationship between post-vaccination antibodies and pre-vaccination antibodies as well as antibody-secreting cells. In contrast, antigen-specific T cell responses were not or only weakly associated with antibody concentrations. In conclusion, our findings demonstrate that single shot vaccinations against tetanus and/or diphtheria do not lead to long-lasting immunity in many elderly persons despite administration at relatively short intervals. Sufficient antigen-specific B cell memory B generated by adequate priming and consecutive booster vaccinations and/or exposure is a prerequisite for long-term protection.Trial registrationEU Clinical Trials Register (EU-CTR); EudraCT number 2009-011742-26; www.clinicaltrialsregister.eu/ctr-search/trial/2009-011742-26/AT.

Alone among herpesviruses, persistent Cytomegalovirus (CMV) markedly alters the numbers and proportions of peripheral immune cells in infected-vs-uninfected people. Because the rate of CMV infection increases with age in most countries, it has been suggested that it drives or at least exacerbates “immunosenescence”. This contention remains controversial and was the primary subject of the Third International Workshop on CMV & Immunosenescence which was held in Cordoba, Spain, 15-16th March, 2012. Discussions focused on several main themes including the effects of CMV on adaptive immunity and immunosenescence, characterization of CMV-specific T cells, impact of CMV infection and ageing on innate immunity, and finally, most important, the clinical implications of immunosenescence and CMV infection. Here we summarize the major findings of this workshop. The Workshop was partially supported by the University of Cordoba and the Spanish Ministry of Science (SAF2011-16169-E)

In the last two decades hyperthermia has increasingly been used as adjuvant therapy for the treatment of malignant tumours. The effects of heat were therefore analysed on cultured thyroid epithelial cells from patients with thyroid cancer and from non-malignant control thyroids. Purified thyroid cells were subjected to heat treatment (42.5 degrees C; 90 min). After 24 h [3H]thymidine incorporation was assessed and the expression of heat shock protein 72 (hsp72), thyroglobulin, CD54 (ICAM-I) and MHC class-Il were analysed by immunofluorescence staining. Additionally mRNA analysis was performed by Northern blotting. Whereas hyperthermia inhibited the proliferation of thyroid cells, it significantly increased the expression of hsp72, thyroglobulin, CD54 and HLA-DR (P < 0.05). Our results suggest that hyperthermia may suppress growth while supporting differentiation and immune recognition in thyroid cancer. It may therefore be beneficial as a treatment for patients with thyroid carcinoma.

Age-related changes of the immune system increase incidence and severity of many infectious diseases in the elderly. This makes them a particular target population for vaccination, the most effective measure to prevent infectious disease. However, most vaccines are less immunogenic in the elderly population. Vaccinations against influenza, Streptococcus pneumoniae, and herpes zoster are specifically recommended for elderly persons. A large number of recent studies have demonstrated age-related impairments of immunogenicity and efficacy of vaccines. Strategies to improve vaccination for the elderly include the introduction of adjuvants and new forms of application, and several innovative approaches for novel vaccine candidates are currently under investigation. Regular booster vaccinations against tetanus, diphtheria, and pertussis are performed in many countries and are a prerequisite for adequate protection in old age. Due to the steadily rising travel activity of elderly persons travel vaccines are increasingly important for this age group. Vaccination against noninfectious disease is also an emerging field. Currently vaccine candidates against Alzheimer’s disease are under development. Summarizing, awareness needs to be created that not only children, but also adults, and in particular the elderly, greatly benefit from vaccination. Further research to gain deeper insight into basic mechanisms of immunosenescence, investigations on the effect of licensed vaccines in elderly persons, adaptation of vaccination strategies, development of new vaccines, and new modes of administration will help to achieve optimized protection against disease in old age.

T-T cell interactions are known to be of importance in the generation of immune responses and have been postulated to play a role in autoimmunity. Antiergotypic T lymphocytes are cells, which react with other activated T cells, which they may consecutively neutralize. Antiergotypic T cells have been described to play a role in animal models of autoimmunity and have been found in patients with rheumatoid arthritis. It was the aim of the present study to analyse, whether antiergotypic T cells were also present in the blood of patients with endocrine autoimmunity and to characterize them in vitro. We found that peripheral blood mononuclear cells from patients with Graves' disease, Hashimoto's thyroiditis and Diabetes mellitus show a pronounced proliferative response, when stimulated with autologous T cell lines. This response is dependent on the state of activation of the stimulator cell population, but is independent of its phenotype and is not MHC restricted. In contrast to normal control cells PBMC from patients with endocrine autoimmune disorders respond better to autologous T lymphocytes, than to allogeneic T cells and to autologous E- monocytic cells. T cells responsive to activated autologous T cell lines can also be expanded from PBMC. They may be CD4+ or CD8+ and recognize autologous T cells in the presence of autologous PBMC as feeder cells. These results suggest the presence of a T-T cell network in patients with endocrine autoimmune disease, which may have an important regulatory role in the disease process.

In Austria significant progress in the field of biogerontology has been achieved in the past years. Biogerontological research is performed in academic and extramural institutions. The Institute for Biomedical Aging Research of the Austrian Academy of Science at Innsbruck is the largest institution dealing with biogerontology in Austria. Moreover, gerontologic research is performed at the Universities of Salzburg and Graz, the Medical Universities of Vienna, Innsbruck and Graz, the University of Veterinary Medicine (Vienna) and the University of Natural Resources and Applied Life Sciences (Vienna). This article describes the work of selected research groups involved in biogerontology in a geographic arrangement.

From the *Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria; †‘‘Amt fur Gesundheit, Marktund Veterinarwesen’’ of the Township of Innsbruck, Austria; ‡Swiss Serum and Vaccine Institute, Berne, Switzerland Correspondence to: Beatrix Grubeck-Loebenstein, MD, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria; E-mail: Beatrix.Grubeck@oeaw.ac.at Received 19 January 2000; accepted for publication 7 February 200

The high burden of infectious diseases in adults aged 60 years and older is disproportionate, considering that many of these diseases are vaccine-preventable. Based on careful analysis of the reasons for vaccination barriers/failures in the European population, the two European geriatric and gerontological societies (the European Union Geriatric Medicine Society [EUGMS] and the International Association of Gerontology and Geriatrics - European Region [IAGG-ER]) propose careful adaptation of current vaccine guidelines to promote preventive aspects, concerning both life threatening-diseases (influenza, pneumococcal pneumonia and tetanus/diphtheria) and diseases which adversely impact patients' quality of life (pertussis and herpes zoster). This consensus statement is designed to support official recommendations and improve the willingness to vaccinate the most rapidly growing segment of the population. The following guidelines are based on the importance of the sustainability of vaccine programs from midlife till extreme old age: - Promote healthy aging by optimizing health determinants of daily functions, active participation in society and individual quality of life; - Provide useful information to contribute toward harmonizing vaccine strategies at European level; - Support the public health, social and economic values of vaccination. Both healthcare professionals and consumers associations have a critical role to play in the implementation of such consensus clinical guidelines.

Vaccines are an underused public health strategy for healthy aging. Considering the risks of vaccine-preventable diseases and the current low vaccine coverage rates in older European citizens, the two European geriatric and gerontological societies (European Union Geriatric Medicine Society [EUGMS] and International Association of Gerontology and Geriatrics-European Region [IAGG-ER]) convened a Joint Vaccine Working Group to develop a consensus document advocating routine vaccination of aging populations. The mandate of this Working Group was to improve the uptake of routine vaccinations in adults aged 60 years and over. The consensus statement underlines the need to establish, strengthen, and harmonize European policies that continue routine vaccinations to adulthood and that will include older populations. Improved vaccination rates will promote healthy aging by reducing the burden of vaccine-preventable infectious diseases in older populations, a population that is rapidly increasing in Europe.