Zinc homeostasis and immunosenescence

For more than 50 years, zinc is known to be an essential trace element, having a regulatory role in the immune system. Deficiency in zinc thus compromises proper immune function, like it is observed in the elderly population. Here mild zinc deficiency is a common condition, documented by a decline of serum or plasma zinc levels with age. This leads to a dysregulation mainly in the adaptive immunity that can result in an increased production of pro-inflammatory cytokines, known as a status called inflamm-aging. T cell activation as well as polarization of T helper (Th) cells into their different subpopulations (Th1, Th2, Th17, regulatory T cells (Treg)) is highly influenced by zinc homeostasis. In the elderly a shift of the Th cell balance towards Th2 response is observed, a non-specific pre-activation of T cells is displayed, as well as a decreased response to vaccination is seen. Moreover, an impaired function of innate immune cells indicate a predominance of zinc deficiency in the elderly that may contribute to immunosenescence. This review summarizes current findings about zinc deficiency and supplementation in elderly individuals.     

Cell-mediated immunosenescence in birds

The phytohaemagglutinin (PHA) skin test response, used to assess cell-mediated immunity, is known to vary with many social and energetic factors, but the effects of age have received little attention. We found that the PHA response of immature birds was lower than those of the youngest breeding adults and were decreased in adults. Whenever possible, age should be included as a covariate when the PHA skin test is used to assess immunocompetence in ecological immunology. The rate of decline in PHA response differed between species and was inversely correlated with survival. The decrease in the PHA response averaged 57% over an average 80% of the maximum life span, but the absolute rate varied with species lifespan such that the short-lived species showed a greater loss per year than the long-lived species. This link between declining immune function and survival may reflect differences in resource partitioning between species, and suggests that selection may act on investment in immune function to influence maximum life span.     

Robustness and fragility in immunosenescence

We construct a model to study tradeoffs associated with aging in the adaptive immune system, focusing on cumulative effects of replacing naive cells with memory cells. Binding affinities are characterized by a stochastic shape space model. System loss arising from an individual infection is associated with disease severity, as measured by the total antigen population over the course of an infection. We monitor evolution of cell populations on the shape space over a string of infections, and find that the distribution of losses becomes increasingly heavy-tailed with time. Initially this lowers the average loss: the memory cell population becomes tuned to the history of past exposures, reducing the loss of the system when subjected to a second, similar infection. This is accompanied by a corresponding increase in vulnerability to novel infections, which ultimately causes the expected loss to increase due to overspecialization, leading to increasing fragility with age (i.e., immunosenescence). In our model, immunosenescence is not the result of a performance degradation of some specific lymphocyte, but rather a natural consequence of the built-in mechanisms for system adaptation. This “robust, yet fragile” behavior is a key signature of Highly Optimized Tolerance.     

Oxidative stress, inflamm-aging and immunosenescence

Immunosenescence is characterized by a decreased ability of the immune system to respond to foreign antigens, as well as a decreased ability to maintain tolerance to self-antigens. This results in an increased susceptibility to infection and cancer and reduced responses to vaccination [1-5]. The mechanisms underlying immunosenescence comprise a series of cellular and molecular events involving alteration of several biochemical pathways and different cellular populations, and for the most part our understanding of these molecular mechanisms is still fragmentary. In this review we will focus on the process of senescence associated with oxidative stress, in particular how protein oxidation alters the functionality of immune cells and how oxidative stress contributes to a chronic inflammatory process often referred as inflamm-aging.     

Nutritional regulation of immunosenescence for heart health

Immunosenescence via increased inflammatory cytokines may play key regulatory roles in facilitating cardiac infections and heart failure. Based upon recent evidence, we hypothesize that cytokine polarization due to aging directly dysregulates fibroblasts, leading to altered cardiac structure and dysfunction. Some dietary fatty acids should ameliorate heightened inflammatory cytokines thereby retarding cardiac pathology, loss of structural collagen and premature death from heart failure. For example, T-helper (Th) 2 cells' cytokine levels are very high in seniors who have increased heart disease due to suppressed resistance to cardiotrophic pathogens. In addition, such inflammatory cytokines deregulate fibroblasts, thus reducing collagen synthesis, weakening muscle structure and heart pump function for heart failure and hypertension. Therefore, supplementation with n-3 polyunsaturated fatty (PUFA) or conjugated linoleic acids, by reducing Th2 and increasing Th1 cytokines, may provide a sensible and widely available means to treat and even prevent excessive inflammatory cytokines and their cardiotoxic effects. On the other hand, dietary n-6 PUFA may promote cytokine polarization in seniors, exacerbating age-related heart dysfunction.     

NK and NKT cell functions in immunosenescence

Immunosenescence is defined as the state of dysregulated immune function that contributes to the increased susceptibility to infection, cancer and autoimmune diseases observed in old organisms, including humans. However, dysregulations in the immune functions are normally counterbalanced by continuous adaptation of the body to the deteriorations that occur over time. These adaptive changes are likely to occur in healthy human centenarians. Both innate (natural) and adaptive (acquired) immune responses decline with advancing age. Natural killer (NK) and natural killer T (NKT) cells represent the best model to describe innate and adaptive immune response in aging. NK and NKT cell cytotoxicity decreases in aging as well as interferon-gamma (IFN-gamma) production by both activated cell types. Their innate and acquired immune responses are preserved in very old age. However, NKT cells bearing T-cell receptor (TCR) gammadelta also display an increased cytotoxicity and IFN-gamma production in very old age. This fact suggests that NKT cells bearing TCRgammadelta are more involved in maintaining innate and adaptive immune response in aging leading to successful aging. The role played by the neuroendocrine-immune network and by nutritional factors, such as zinc, in maintaining NK and NKT cell functions in aging is discussed.     

A mathematical model for the immunosenescence.

We propose a model for the dynamics of the immune system by considering the subpopulations of virgin and memory T lymphocytes on a time scale corresponding to the human life span. In the deterministic balance equation we introduce a fluctuating term in order to take into account the chronic antigenic stress. Starting from the hypothesis that the depletion of virgin cells with cytotoxic properties (CD8+) is a mortality marker, the model provides survival curves quite similar to the demographic curves.     

Report from the second cytomegalovirus and immunosenescence workshop

The Second International Workshop on CMV & Immunosenescence was held in Cambridge, UK, 2-4th December, 2010. The presentations covered four separate sessions: cytomegalovirus and T cell phenotypes; T cell memory frequency, inflation and immunosenescence; cytomegalovirus in aging, mortality and disease states; and the immunobiology of cytomegalovirus-specific T cells and effects of the virus on vaccination. This commentary summarizes the major findings of these presentations and references subsequently published work from the presenter laboratory where appropriate and draws together major themes that were subsequently discussed along with new areas of interest that were highlighted by this discussion.     

Hallmarks of aging and immunosenescence: Connecting the dots

Aging is a natural physiological process that features various and variable challenges, associated with loss of homeostasis within the organism, often leading to negative consequences for health. Cellular senescence occurs when cells exhaust the capacity to renew themselves and their tissue environment as the cell cycle comes to a halt. This process is influenced by genetics, metabolism and extrinsic factors. Immunosenescence, the aging of the immune system, is a result of the aging process, but can also in turn act as a secondary inducer of senescence within other tissues. This review aims to summarize the current state of knowledge regarding hallmarks of aging in relation to immunosenescence, with a focus on aging-related imbalances in the medullary environment, as well as the components of the innate and adaptive immune responses. Aging within the immune system alters its functionality, and has consequences for the person's ability to fight infections, as well as for susceptibility to chronic diseases such as cancer and cardiovascular disease. The senescence-associated secretory phenotype is described, as well as the involvement of this phenomenon in the paracrine induction of senescence in otherwise healthy cells. Inflammaging is discussed in detail, along with the comorbidities associated with this process. A knowledge of these processes is required in order to consider possible targets for the application of senotherapeutic agents - interventions with the potential to modulate the senescence process, thus prolonging the healthy lifespan of the immune system and minimizing the secondary effects of immunosenescence.     

Cellular immunosenescence in adult male crickets, Gryllus assimilis

Ecological immunity studies in invertebrates, particularly insects, have generated new insights into trade-offs between immune functions and other physiological parameters. These studies document physiologically directed reallocations of immune costs to other high-cost areas of physiology. Immunosenescence, recognized as the age-related deterioration of immune functions, is another mechanism of radically altering immune systems. We investigated the hypothesis that aging brings on immunosenescence in adult males of the cricket, Gryllus assimilis. Our data show that the intensity of melanotic nodule formation decreased with adult age from after 3-week post-adult emergence. Circulating hemocyte populations similarly decreased from about 5,000 hemocytes/μl hemolymph to about 1,000 hemocytes/μl hemolymph. The numbers of damaged hemocytes in circulation increased from less than 10% at 1-week post-adult emergence to approximately 60% by 3-week post-adult emergence. The composition of hemocyte types changed with age, with increasing proportions of granulocytes and decreasing proportions of plasmatocytes. The declines in nodule formation were not linked to the adult age of sexual behaviors, which begin shortly after entering adulthood in this species. We infer that age-related senescence, rather than cost reallocations, may account for observed declines in various parameters of immune functions in insects, as seen in other animals.     

Preferential accumulation of mature NK cells during human immunosenescence.

The major histocompatibility complex-unrestricted, cell-mediated, constitutive anti-tumor cytotoxic function of natural killer cells is highly preserved in healthy elderly. A study of the dynamics of expression of natural killer cell-associated phenotypes during immunosenescence shows that selective, bidirectional, and disproportionate changes in certain natural killer cell subset number and ratio take place during aging. The mean natural killer cell subset ratio (%CD16+CD57+ over %CD56+CD57-) gradually increases from a young adult level of 0.7 to 4.6 with advancing age predominantly due to a tripling of %CD16+57+ cells as opposed to a moderate decrease (-54%) in %CD56+57- phenotype. The parallel increase in natural killer phenotype ratio and cytotoxic activity might represent a shift in the maturity status of these cells. Based on these findings, a model of natural killer cell immunosenescence is proposed. It is concluded that not all immunosenescent changes need be detrimental; some may even improve the potential for survival and represent an adaptational immunosenescent change.     

Factors that may impact on immunosenescence: an appraisal

The increasing ratio of ageing population poses new challenges to healthcare systems. The elderly frequently suffer from severe infections. Vaccination could protect them against several infectious diseases, but it can be effective only if cells that are capable of responding are still present in the repertoire. Recent vaccination strategies in the elderly might achieve low effectiveness due to age-related immune impairment. Immunosenescence affects both the innate and adaptive immunity. Beside individual variations of genetic predisposition, epigenetic changes over the full course of human life exert immunomodulating effects. Disturbances in macrophage-derived cytokine release and reduction of the natural killer cell mediated cytotoxicity lead to increased frequency of infections. Ageing dampens the ability of B cells to produce antibodies against novel antigens. Exhausted memory B lymphocyte subsets replace naïve cells. Decline of cell-mediated immunity is the consequence of multiple changes, including thymic atrophy, reduced output of new T lymphocytes, accumulation of anergic memory cells, and deficiencies in cytokines production. Persistent viral and parasitic infections contribute to the loss of immunosurveillance and premature exhaustion of T cells. Reduced telomerase activity and Toll-like receptor expression can be improved by chemotherapy. Reversion of thymic atrophy could be achieved by thymus transplantation, depletion of accumulated dysfunctional naive T cells and herpesvirus-specific exhausted memory cells. Administration of interleukin (IL)-2, IL-7, IL-10, keratinocyte growth factor, thymic stromal lymphopoietin, as well as leptin and growth hormone boost thymopoiesis. In animals, several strategies have been explored to produce superior vaccines. Among them, virosomal vaccines containing polypeptide antigens or DNA plasmids as well as new adjuvanted vaccine formulations elicit higher dendritic cell activity and more effective serologic than conventional vaccines responses in the elderly. Hopefully, at least some of these approaches can be translated to human medicine in a not too far future.     

T-cell immunosenescence and inflammatory response in atomic bomb survivors

In this paper we summarize the long-term effects of A-bomb radiation on the T-cell system and discuss the possible involvement of attenuated T-cell immunity in the disease development observed in A-bomb survivors. Our previous observations on such effects include impaired mitogen-dependent proliferation and IL-2 production, decreases in naive T-cell populations, and increased proportions of anergic and functionally weak memory CD4 T-cell subsets. In addition, we recently found a radiation dose-dependent increase in the percentages of CD25(+)/CD127(-) regulatory T cells in the CD4 T-cell population of the survivors. All these effects of radiation on T-cell immunity resemble effects of aging on the immune system, suggesting that ionizing radiation might direct the T-cell system toward a compromised phenotype and thereby might contribute to an enhanced immunosenescence. Furthermore, there are inverse, significant associations between plasma levels of inflammatory cytokines and the relative number of na?ve CD4 T cells, also suggesting that the elevated levels of inflammatory markers found in A-bomb survivors can be ascribed in part to T-cell immunosenescence. We suggest that radiation-induced T-cell immunosenescence may result in activation of inflammatory responses and may be partly involved in the development of aging-associated and inflammation-related diseases frequently observed in A-bomb survivors.     

The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence

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Highlights? Nlrp3 inflammasome senses age-related increase in thymic ceramides and free cholesterol ? Age-related intrathymic caspase-1 activation is mediated partly by Nlrp3 inflammasome ? Reduced Nlrp3 inflammasome activation slows thymic aging and T cell senescence ? Nlrp3 loss enhances T cell reconstitution after radiation and bone marrow transplantation     

Hallmarks of human “immunosenescence”: adaptation or dysregulation?

Is immunosenescence an intrinsic ageing process leading to dysregulation of immunity or an adaptive response of the individual to pathogen exposure? Age-associated differences in bone marrow immune cell output and thymic involution suggest the former. Accepted hallmarks of immunosenescence (decreased numbers and percentages of peripheral na?ve T cells, especially CD8?+?cells, and accumulations of memory T cells, especially late-stage differentiated CD8+ cells) suggest the latter, viewed as the result of depletion of the reservoir of na?ve cells over time by contact with pathogens and their conversion to memory cells, the basis of adaptive immunity. Thymic involution beginning early in life limits the generation of naive cells such that the adult is believed to rely to a great extent on the na?ve cell pool produced mostly before puberty. Thus, these hallmarks of immunosenescence would be markedly affected by the history of the individual??s exposure to pathogens. It would be predicted that in modern industrialized populations, the cumulative effects of antigenic ??stressors?? would be lower than in less hygienic societies, whereas intrinsic processes might be more similar in different populations. Identifying such stressors and taking steps to nullify their impact could therefore result in delayed immunosenescence and contribute significantly to improving public health. Here, I discuss some of the available data bearing on this prediction.     

Age-related immunosenescence in Fischer 344 rats: influence of exercise training.

The present investigation examined the extent to which 15 wk of endurance training could influence immune function in young, middle-aged, and older animals. Forty-eight male Fischer 344 rats were divided into trained and untrained groups. Training consisted of treadmill running at 75% maximal running capacity for 1 h/day, 5 days/wk, for 15 wk. Animals were killed at 8, 17, and 27 mo, at which time splenocytes were isolated. The capacity for lymphocyte proliferation in response to mitogen (concanavalin A, ConA), interleukin-2 (IL-2) production, and cytolytic activity against YAC-1 target cells was determined. ConA-induced proliferation declined significantly with age. Training suppressed the proliferative response in the young (-41%) and middle-aged animals (-27%) compared with the age-matched controls; however, training improved this response (+58%) in the older group. IL-2 production followed a pattern similar to that for mitogen-induced proliferation, such that production declined with age and was reduced with training in young and middle-aged animals but was significantly more improved in the older animals than in age-matched controls. The ability to lyse target cells, measured as percent cytotoxicity, declined steadily with advancing age at all effector-to-target cell ratios tested: 52, 14, and -16% for 8-, 17-, and 27-mo-old rats, respectively. It was concluded that the capacity for ConA-induced splenocyte proliferation, IL-2 production, and cytolytic activity declines significantly with advancing age. Furthermore, 15 wk of endurance training suppressed proliferation and IL-2 production in young animals but improved these responses in older animals. Training had no effect on cytolytic activity.     

Seasonal trade-offs in cell-mediated immunosenescence in ruffs (Philomachus pugnax)

The immune system is an energetically expensive self-maintenance complex that, given the risks of parasitism, cannot be carelessly compromised. Life-history theory posits that trade-offs between fitness components, such as self-maintenance and reproduction, vary between genders and age classes depending on their expected residual lifetime reproductive success, and seasonally as energetic requirements change. Using ruff (Philomachus pugnax), a bird with two genetically distinct male morphs, we demonstrate here a decrease in male immunocompetence during the breeding season, greater variance in immune response among males than females, immunosenescence in both sexes and male morphs, and a seasonal shift in the age range required to detect senescence. Using a phytohaemagglutinin delayed hypersensitivity assay, we assessed cell-mediated immunity (CMI) of males of typical breeding age during the breeding and nonbreeding seasons, and of a larger sample that included females and birds of a greater age range during the non-breeding period. CMI was higher for breeding-aged males in May than in November, but the increase was not related to age or male morph. In November, mean CMI did not differ between the sexes, but the variance was higher for males than for females, and there were no differences in mean or variance between the two male morphs. For both sexes and male morphs, CMI was lower for young birds than for birds of typical breeding ages, and it declined again for older birds. In males, senescence was detected in the non-breeding season only when very old birds were included. These results, generally consistent with expectations from life-history theory, indicate that the immune system can be involved in multifarious trade-offs within a yearly cycle and along an individual's lifetime, and that specific predictions about means and variances in immune response should be considered in future immunoecological research.     

Current status and future prospects in the search for protein biomarkers of immunosenescence

Complex adaptations including changes in cellular redox status, the production of high levels of pro-inflammatory cytokines and alterations in immunity occur as the result of aging of the immune system (immunosenescence). These events are thought to underlie the progression of chronic degenerative diseases of aging, such as atherosclerosis, Type 2 diabetes and Alzheimer's disease. It is envisaged that identifying early biomarkers of immune aging would aid in identifying individuals at risk of age-related disease and would allow the discovery of novel intervention strategies. Proteomics has emerged as a rapidly expanding and innovative field, investigating protein expression, interaction and function at a global level. Several proteomic strategies, including use of mass spectrometry and non-mass spectrometry-based detection systems (including secondary antibody labeling with fluorescent tags) may be particularly advantageous in identifying biomarkers of immune health. Application of these approaches may identify factors that both contribute to (and define) age-dependent deregulation of the immune system.