The immunogenetics of immune senescence.

Immune senescence is characterized by a dysregulation of the immune system. With respect to humoral immunity, aging is associated with an increased level of many autoantibodies and a decreased antibody response to most foreign antigens. This observation reflects a decreased capacity to activate antibody production by CD5-negative B cells despite a normal or increased capacity to generate antibodies produced by the CD5-positive B cells. A similar dysregulation of cell-mediated immunity is manifested by an altered balance in cytokine production by T cells from old as compared to young subjects. Thus, the production of interleukin-2 (IL-2), IL-3 and granulocyte-macrophage colony-stimulating factor by T cells from old subjects is decreased although the production of IL-4, IL-5 and IL-6 is undiminished or actually increased.     

Effect of moderate exercise on immune senescence in men

The purpose of this study was to examine the relationship between active compared to inactive life-styles and immunocompetence in men. Subjects, all male volunteers, regularly exercising moderately were separated into three age groups: young (20–39 years), middle-aged (40–59 years) and elderly (more than60 years). Age-matched sedentary male subjects served as controls in each group. Immunological assessments were, total leucocyte count, lymphocyte subpopulation counts, natural killer cell activity and neutrophilic phagocytosis. Total leucocyte and T-cell (CD3⁺) counts were not significantly different among the groups. Among T-cell subsets, there was a slight increase in helper T-cell (CD3⁺CD4⁺) and a decrease in cytotoxic/suppressor T-cell (CD3⁺CD8⁺) concentrations in the older sedentary subjects, resulting in an age-associated significant increase in the CD4:CD8 ratio among those control groups. However, among the exerciser groups, no such increase and decrease in the T-cell subpopulations or an age-related increase of the CD4:CD8 ratio were observed. Considering the components of innate immunity, the concentration of NK-cells (CD16⁺CD56⁺) significantly increased in the elderly exercisers, compared to that of the age-matched control subjects, or of the young group. The phagocytotic activity of neutrophils showed an age-associated decline, but of lesser degree in the elderly exercisers than in the elderly controls. Taken together, these results suggest that habitual and moderate training in later life is associated with a lesser age-related decline in certain aspects of circulating T-cell function and innate immunity. Electronic Publication     

Biological and social predictors of immune senescence in the aged primate

The transition to geriatric status occurs at around 20 years of age in monkeys after which there is typically a decline in immune responses. However, the loss in immune vigor may be quite dissociated from chronological age in some of these long-lived animals. The degree to which natural killer (NK) cell activity is sustained in aged monkeys has proven to be a valuable prognostic of ultimate health and longevity. Another useful biomarker of cellular aging in the monkey is interleukin-6 (IL-6) release. For example, when endothelial cell cultures were generated from cerebral blood vessels, those derived from aged donors produced significantly more IL-6 in response to IL-1, LPS, and hypoxia. Despite this evidence of intrinsic aging, we have found that immune responses in old animals are quite responsive to contemporaneous conditions, including changes in housing or the first onset of illness. Indeed, these changes, especially the pathological processes associated with disease, may promote many age-related immune alterations at the end of the life span.     

Hard graft? Future challenges in transplantation.

A small group of transplantation surgeons, immunologists and molecular biologists gathered in Vienna in early February to discuss the prospects for organ transplantation. Participants at the meeting were challenged with setting goals for transplantation research and with speculating on how this research might influence the practice of transplantation in the next two decades. Some goals were set, but the most vigorous discussion focused on the existing barriers that stand in the way of achieving these goals.     

Red cell transfusion in medicine: Future challenges

Many side-effects of red blood cell transfusion have been described. They include iron-overload, as well as allo- and autoantibody formation against red cells. During storage, erythrocytes undergo complex structural and biochemical changes. It has been suggested that accelerated and/or aberrant forms of the physiological erythrocyte aging process underlie the red cell storage lesion. This storage lesion may contribute to side-effects of transfusion as endothelial damage by release of internal erythrocyte constituents, (pro)inflammatory consequences, hampered microcirculation and oxygen delivery. Understanding the process that determines the fate of red blood cells after transfusion may contribute to the prevention of side-effects after red blood cell transfusion. This should be the focus of research on red blood cell transfusion in clinical transfusion medicine.     

Intrinsic and environmental influences on immune senescence in the aged monkey.

Several factors associated with the age-related decline in immunity were examined in three studies on aged rhesus monkeys. Natural killer (NK) cell activity was found to be low in many monkeys after 20 years of age, but exceptionally long-lived animals, older than 25 years, often had vigorous cytolytic responses. When NK activity was decreased in an aged monkey, it was predictive of fewer years of survival and a younger age at death. This prediction of mortality was associated with one nonimmune biomarker of aging in the monkey: nail growth rate. Monkeys with very slow nail growth and low NK activity were likely to die sooner. Although these findings might suggest an immutable course for the aging process, the housing conditions of old monkeys also had a pronounced effect on their NK activity. The highest NK responses were found in old monkeys housed with just one other old animal when compared to living alone or with just a young, juvenile monkey. It remains to be determined whether this type of psychosocial influence could have a sustained effect on immunity and ultimately change the pace of aging and time to mortality.     

Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic infection or neuroinflammation and the onset of the disease. METHODS: The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging. RESULTS: We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, its mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Abeta peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD. CONCLUSION: Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Abeta plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.     

Telomeres, replicative senescence and human ageing

Ageing concerns the extracellular environment and cells that are either post-mitotic or capable of division during life. Primary human cells have a finite division capacity in culture before they enter a state of viable cell cycle arrest termed senescence. Cell division occurs during life in many tissues, either as part of normal tissue function or in response to tissue damage. The accumulation of cells at the end of their replicative lifespan in the elderly might contribute to aged tissue either because of a reduced ability to undergo proliferation or because of the known altered gene-expression patterns of senescent cells. This has been illustrated experimentally using a transgenic telomerase-negative mouse, which shows some premature ageing phenotypes. The mechanism whereby cells count divisions uses the gradual erosion of the ends of chromosomes (telomeres) with cell division caused by the repression of the telomere-maintenance enzyme telomerase in most human cells. Telomere erosion ultimately triggers replicative senescence in many cell types; this can be prevented experimentally by forcibly expressing telomerase. This extends the lifespan of normal human cells and those from progeroid syndromes such as Werner's. Telomere-driven senescence did not evolve to cause ageing, but is instead a by-product of a system devised to provide a tumour-suppression function, a concept that fits well with evolutionary arguments regarding trade-offs between somatic maintenance and reproduction. Work in the future will focus on the development of new animal models to critically address the quantitative significance of this ageing mechanism.     

Immunohistochemical detection of senescence markers in human sarcomas

IntroductionSenescent cells in tumors are not inert cells but exert bystander effects by developing secretory phenotypes affecting the extracellular matrix and interfering the biological behavior of adjacent tumor cells.Materials and MethodsWe assessed putative senescent cell content in a series of human sarcomas, using in parallel markers related to cell proliferation (Ki67), DNA damage (γH2Ax), lipofuscin detection (SenTraGor®) and two cyclin-dependent kinase CDK-inhibitors (p16/INK4a and p21/cip/waf21).ResultsNecrosis was directly linked with the size of tumors (p = 0.02, r = 0.25), number of mitosis (p = 0.05, r = 0.21) and inversely with the expression of γH2Ax (p = 0.01, r = 0.28). Smaller tumors (less than 3 cm) had a higher p16 expression (p = 0.07); Moreover, in group analysis, tumors with lack of expression of p16 had significantly higher necrosis score (p = 0.03). Linear regression analysis showed that p21 expression was strongly and directly related with MIB1 (p < 0.0001, r = 0.44) and with Lipofuscin expression (p = 0.02, r = 0.26).ConclusionSenescence markers are extensively expressed in human sarcomas and correlated with histopathological features. However, p16, p21 and Lipofuscin expression show different patterns, suggesting that these markers may detect different senescence phenotypes. In addition, our data suggest that the novel marker SenTraGor® may detect phenotypes of senescent cells involving p21 activation.     

A model for personalized in vivo analysis of human immune responsiveness

Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies. Immunodeficient mice receiving human fetal thymus grafts and fetal CD34(+) cells intravenously produce robust human immune systems, allowing analysis of human T cell development and function. However, to use humanized mice to study human immune-mediated disorders, immune systems must be generated from adult hematopoietic cells. Here, we demonstrated robust immune reconstitution in mice with hematopoietic stem cells (HSCs) aspirated from bone marrow of adults with type 1 diabetes (T1D) and healthy control volunteers. In these humanized mice, cryopreservation of human leukocyte antigen allele-matched fetal thymic tissue prevented allogeneic adult HSC rejection. Newly generated T cells, which included regulatory T cells (T(regs)), were functional and self-tolerant and had a diverse repertoire. The immune recognition of these mice mimicked that of the adult CD34(+) cell donor, but the T cell phenotypes were more predominantly "na?ve" than those of the adult donors. HSCs from T1D and control donors generated similar numbers of natural T(regs) intrathymically; however, peripheral T cells from T1D subjects showed increased proportions of activated or memory cells compared to controls, suggesting possible HSC-intrinsic differences in T cell homeostasis that might underlie immune pathology in T1D. This "personalized immune" mouse provides a new model for individualized analysis of human immune responses that may provide new insights into not only T1D but also other forms of immune function and dysfunction as well.     

Translational research in immune senescence: Assessing the relevance of current models

Advancing age is accompanied by profound changes in immune function; some are induced by the loss of critical niches that support development of naïve cells (e.g. thymic involution), others by the intrinsic physiology of long-lived cells attempting to maintain homeostasis, still others by extrinsic effects such as oxidative stress or long-term exposure to antigen due to persistent viral infections. Once compensatory mechanisms can no longer maintain a youthful phenotype the end result is the immune senescent milieu – one characterized by chronic, low grade, systemic inflammation and impaired responses to immune challenge, particularly when encountering new antigens. This state is associated with progression of chronic illnesses like atherosclerosis and dementia, and an increased risk of acute illness, disability and death in older adults. The complex interaction between immune senescence and chronic illness provides an ideal landscape for translational research with the potential to greatly affect human health. However, current animal models and even human investigative strategies for immune senescence have marked limitations, and the reductionist paradigm itself may be poorly suited to meet these challenges. A new paradigm, one that embraces complexity as a core feature of research in older adults is required to address the critical health issues facing the burgeoning senior population, the group that consumes the majority of healthcare resources. In this review, we outline the major advantages and limitations of current models and offer suggestions for how to move forward.     

Antigenic analysis of immune complexes formed in normal human pregnancy.

Immune complexes, isolated from pregnancy sera by absorption to immobilized protein A, were dissociated and the antigen components separated from the IgG antibodies, which possessed immune reactivity directed against the plasma membrane of the syncytiotrophoblast layer of the placenta. Gel filtration studies demonstrated that five separate antigens could be identified and were of placental origin, as observed by their reactivity in an ELISA with affinity purified anti-trophoblast antibodies isolated from maternal sera. The five antigens of apparent mol. wt 2 X 10(6), 400,000, 150,000, 13,000 and less than 10,000 daltons were designated maternally recognised trophoblast antigens (MRTA), numbers V-IX; the relative proportions of these antigens in the sera were 14%, 68%, 16%, 0.5% and 1%, respectively. Immune complexes were also identified in nulliparous non-pregnant female sera and consisted of the 150,000 and the less than 10,000 daltons antigen components. The relationship between the MRTA present in the immune complexes and the MRTA (numbers I-IV) previously identified as components of the trophoblast plasma membrane is discussed.     

Impaired apoptosis and immune senescence – cause or effect?

Summary: Aged animals and humans exhibit a decreased T‐cell activation response although they also exhibit increased susceptibility to responses to self‐antigens and a loss of self‐tolerance. The age‐related alteration in T‐cell reactivity, polyclonal expansion of T cells, and enhanced production of autoantibodies may reflect the numerous age‐associated alterations in the T‐cell arm of the immune system that have been revealed in numerous studies. These studies suggest that subpopulations of T cells are not deleted appropriately in older animals. They further suggest that an age‐related impairment of Fas/Fas ligand (FasL)‐mediated apoptosis – which plays a major role in activation‐induced cell death (AICD) of T cells – may contribute to compromised regulation of the immune system. The likely mechanisms that may lead to impaired induction of FasL in AICD senescent T cells include an age‐related shift from the apoptosis‐sensitive T‐helper 1 cell (Th1) response to the AICD‐resistant Th2 response, aberrant T‐cell receptor/CD3 downstream‐signaling pathways, and altered CD28/B7‐mediated T‐cell costimulatory signals. Pathologically, accumulation of AICD‐senescent T cells is associated with a defective cytotoxic T lymphocyte response and generation of autoreactive T cells. Based on the accumulating evidence, we propose that the emergence of the FasL^lo AICD‐senescent T cells is not only an effect of immune aging but also an important cause of T‐cell proliferative senescence in both humans and mice.     

Changes in human T lymphocytes after thymectomy and during senescence

Peripheral lymphocytes from individuals who had been thymectomized in adult life for myasthenia gravis (MG) or for other, nonimmunological reasons showed a moderate decrease in proliferative response capacity to several T-cell mitogens as compared to lymphocytes from normal individuals. The decrease of the response to mitogens and allogeneic lymphocytes was 20–30% within 5 years after thymectomy and about 50% more than 15 years after thymectomy. A comparable decrease in lymphocyte proliferative response capacity was found in healthy aged humans (68–97 years old). Analysis of T lymphocytes from both aged and thymectomized individuals with monoclonal (OKT) antibodies showed a similar pattern: the proportion of T lymphocytes binding OKT3 was reduced, and the OKT4/OKT8 ratio was increased. Hardly any T lymphocytes binding OKT6, OKT10, or OKT1 were found. A biochemical parameter for human T-cell differentiation, the lactate dehydrogenase (LDH) isoenzyme pattern, showed a significantly lower H/M ratio in the group of elderly people compared to young individuals. Furthermore, among patients thymectomized for MG, a significant correlation was observed between the LDH isoenzyme pattern of the T lymphocytes and the proliferative response to mitogens of these cells. In contrast, in healthy thymectomized individuals the LDH isoenzyme pattern appeared to be normal. These findings indicate that, after thymectomy or involution of the thymus, at least part of the peripheral blood T lymphocytes have properties different from those of the cells of young individuals. These cells might represent immature and/or not fully differentiated lymphocytes.     

Protein analysis in human cerebrospinal fluid: Physiological aspects, current progress and future challenges

The introduction of lumbar puncture into clinical medicine over 100 years ago marks the beginning of the study of central nervous system diseases using the human cerebrospinal fluid (CSF). Ever since, CSF has been analyzed extensively to elucidate the physiological and biochemical bases of neurological disease. The proximity of CSF to the brain makes it a good target for studying the pathophysiology of brain functions, but the barrier function of the CSF also impedes its diagnostic value. Today, measurements to determine alterations in the composition of CSF are central in the differential diagnosis of specific diseases of the central nervous system (CNS). In particular, the analysis of the CSF protein composition provides crucial information in the diagnosis of CNS diseases. This enables the assessment of the physiology of the blood-CSF barrier and of the immunology of intrathecial responses. Besides those routine measurements, protein compositional studies of CSF have been extended recently to many other proteins in the expectation that comprehensive analysis of lower abundance CSF proteins will lead to the discovery of new disease markers. Disease marker discovery by molecular profiling of the CSF tissue has the enormous potential of providing many new disease relevant molecules. New developments in protein profiling techniques hold promise for the discovery and validation of relevant disease markers. In this review, we summarize the current efforts and progress in CSF protein profiling measurements using conventional and current protein analysis tools. We also discuss necessary development in methodology in order to have the highest impact on the study of the molecular composition of CSF proteins.     

Ageing of the gut microbiome: Potential influences on immune senescence and inflammageing

Advancing age is accompanied by changes in the gut microbiota characterised by a loss of beneficial commensal microbes that is driven by intrinsic and extrinsic factors such as diet, medications, sedentary behaviour and chronic health conditions. Concurrently, ageing is accompanied by an impaired ability to mount a robust immune response, termed immunesenescence, and age-associated inflammation, termed inflammaging. The microbiome has been proposed to impact the immune system and is a potential determinant of healthy aging. In this review we summarise the knowledge on the impact of ageing on microbial dysbiosis, intestinal permeability, inflammaging, and the immune system and investigate whether dysbiosis of the gut microbiota could be a potential mechanism underlying the decline in immune function, overall health and longevity with advancing age. Furthermore, we examine the potential of altering the gut microbiome composition as a novel intervention strategy to reverse the immune ageing clock and possibly support overall good health during old age.