Age-associated Decline In Immune Function Research Articles

Role of cytokines and reactive oxygen species in brain aging

Aging is a complex process that produces profound effects on the brain. Although a number of external factors can promote the initiation and progression of brain aging, peripheral and central changes in the immune cells with time, also play an important role. Immunosenescence, which is an age-associated decline in immune function and Inflammaging, a low-grade inflammatory state in the aging brain contribute to an elevation in cytokine and reactive oxygen species production. In this review, we focus on the pro-inflammatory state that is established in the brain as a consequence of these two phenomena and the resulting detrimental changes in brain structure, function and repair that lead to a decline in central and neuroendocrine function.

Does Regular Exercise Counter T Cell Immunosenescence Reducing the Risk of Developing Cancer and Promoting Successful Treatment of Malignancies?

Moderate intensity aerobic exercise training or regular physical activity is beneficial for immune function. For example, some evidence shows that individuals with an active lifestyle exhibit stronger immune responses to vaccination compared to those who are inactive. Encouragingly, poor vaccine responses, which are characteristic of an ageing immune system, can be improved by single or repeated bouts of exercise. In addition, exercise-induced lymphocytosis, and the subsequent lymphocytopenia, is thought to facilitate immune surveillance, whereby lymphocytes search tissues for antigens derived from viruses, bacteria, or malignant transformation. Aerobic exercise training is anti-inflammatory and is linked to lower morbidity and mortality from diseases with infectious, immunological, and inflammatory aetiologies, including cancer. These observations have led to the view that aerobic exercise training might counter the age-associated decline in immune function, referred to as immunosenescence. This article summarises the aspects of immune function that are sensitive to exercise-induced change, highlighting the observations which have stimulated the idea that aerobic exercise training could prevent, limit, or delay immunosenescence, perhaps even restoring aged immune profiles. These potential exercise-induced anti-immunosenescence effects might contribute to the mechanisms by which active lifestyles reduce the risk of developing cancer and perhaps benefit patients undergoing cancer therapy.

Immune senescence: significance of the stromal microenvironment.

The immune system undergoes age-associated changes known as immunosenescence, resulting in increased susceptibility to infections, cancers and autoimmunity in the aged. The basis of our understanding of immunosenescence has been derived primarily from studies examining intrinsic defects within many of the cells of the immune system. While these studies have provided insight into the mechanisms of immunosenescence, a picture is now emerging that the stromal microenvironment within lymphoid organs also contributes significantly to the age-associated decline of immune function. These extrinsic defects appear to impact the functional activity of immune cells and may offer a potential target to recover immune activity. Indeed, rejuvenation studies which have targeted the stromal niche have restored immune function in aged successfully, highlighting the impact of the microenvironment towards the aetiology of immunosenescence.

Is immunosenescence influenced by our lifetime "dose" of exercise?

The age-associated decline in immune function, referred to as immunosenescence, is well characterised within the adaptive immune system, and in particular, among T cells. Hallmarks of immunosenescence measured in the T cell pool, include low numbers and proportions of naïve cells, high numbers and proportions of late-stage differentiated effector memory cells, poor proliferative responses to mitogens, and a CD4:CD8 ratio <1.0. These changes are largely driven by infection with Cytomegalovirus, which has been directly linked with increased inflammatory activity, poor responses to vaccination, frailty, accelerated cognitive decline, and early mortality. It has been suggested however, that exercise might exert an anti-immunosenescence effect, perhaps delaying the onset of immunological ageing or even rejuvenating aged immune profiles. This theory has been developed on the basis of evidence that exercise is a powerful stimulus of immune function. For example, in vivo antibody responses to novel antigens can be improved with just minutes of exercise undertaken at the time of vaccination. Further, lymphocyte immune-surveillance, whereby cells search tissues for antigens derived from viruses, bacteria, or malignant transformation, is thought to be facilitated by the transient lymphocytosis and subsequent lymphocytopenia induced by exercise bouts. Moreover, some forms of exercise are anti-inflammatory, and if repeated regularly over the lifespan, there is a lower morbidity and mortality from diseases with an immunological and inflammatory aetiology. The aim of this article is to discuss recent theories for how exercise might influence T cell immunosenescence, exploring themes in the context of hotly debated issues in immunology.

Telomere Length as an Indicator of the Robustness of B- and T-Cell Response to Influenza in Older Adults.

Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age-associated decline of immune function is unknown. We selected 22 HLA-A2-positive healthy older adults who have relatively short or long telomere lengths to compare their antibody response against the influenza vaccine, and their CD8(+) T-cell response against an influenza antigen. B cells from individuals with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Monocyte-derived antigen-presenting cells of both short and long telomere groups induced similar expansions of influenza M1-specific CD8(+) T cells. Vaccination did not increase M1-specific CD8(+) T cells in blood, but M1-specific CD8(+) T cells from the long telomere group exhibited significantly greater expansion in vitro than those from the short telomere group. Finally, M1-specific CD8(+) T cells that underwent more expansions had significantly longer telomeres than cells with fewer divisions. Telomere length is positively associated with a robust lymphocyte response, and telomere attrition may contribute to the age-associated decline of adaptive immunity.

Analysis of human TCRβ repertoire by a RARE-sequencing method reveals distinct features of TCRβ diversity and distribution and their alterations with age (IRM10P.758)

Abstract The T cell receptor (TCR) repertoire (diversity and distribution) is a vital parameter of the overall function of T cells. Reduction of TCR diversity and alteration of TCR distribution is believed to occur with age and acts as a major contributor for age-associated decline of immune function. However, neither the actual size of the TCR repertoire nor its precise age-related change have been directly determined. Applying a RACE-next generation sequencing (RAP-Seq) method, we assessed the TCRβ repertoire of blood CD4+ and CD8+ T cells of 13 adults (21-94 years old) including 6 adults with longitudinal samples. We found that TCRβ diversity of CD4+ T cells is 3-4 times greater than CD8+ T cells. TCRβ CDR3 was distinct between CD4+ and CD8+ T cells with preferential amino acid usage. Reduced TCRβ diversity and expanded highly abundant TCRβ clones occurred from middle to old subjects (45-75 years old) but not in very old subjects (80-94 years old). Together, these findings reveal the distinct features and actual age-associated changes of TCRβ repertoire, which could serve as a measure of the immune competency and a guide for the clinical intervention in older humans.

Homeostasis of lymphocytes and monocytes in frequent blood donors

Age-associated decline of immune function is believed to be mainly due to alterations of immune cells. However, longitudinal changes of human immune cells with age have not yet been adequately addressed. To test the hypothesis that regeneration of lymphocytes and monocytes is robust throughout most of adult life until advanced age, we examined six leukapheresis donors (3 young and 3 middle-aged/old) who donated approximately 10% of their peripheral blood mononuclear cells (PBMC) every other month over 3–5 years. We found the number of both lymphocytes and monocytes were quite stable in the blood of all six donors. As expected, young donors had more T cell receptor excision circles (TRECs), CD31{}+ cells (CD4 only) and longer telomeres in T cells than did the middle-aged donors. Interestingly, more variation in TREC number, Vβ usages, and telomere lengths were observed in young donors during the 3–5 years course of donation whereas the middle-aged/old donors showed a rather striking stability in these measurements. This may reflect a more prominent role of thymic output in T cell regeneration in young than in middle-aged/old donors. Together, these findings provide an in vivo glimpse into the homeostasis of lymphocytes and monocytes in the blood at different ages, and support the notion that regeneration of lymphocytes and monocytes is robust throughout adult life up to the early 70s.

The Effect of Age on the Phenotype and Function of Developing Thymocytes

The immune system declines with age leading to a progressive deterioration in the ability to respond to infection and vaccination. Age-associated thymic involution is one of the most recognized changes in the ageing immune system and is believed to be a major contributor towards immunosenescence; however, the precise mechanisms involved in age-associated thymic involution remain unclear. In order to gain further insight into the effect of ageing on T-cell development, steady-state thymopoiesis was studied in mice ranging from 1 to 18 months of age. There was a decrease in thymic cellularity with age, but the most dramatic loss occurred early in life. Although there were no alterations in the proportion of the major thymocyte subsets, there was a significant decline in the expression of other key molecules including CD3 and CD24. There was a decline in the ability of thymocytes from older mice to respond to mitogens, which was demonstrated by a failure to up-regulate expression of the activation marker CD69 and to enter the G(2)--M phase of the cell cycle. This was concurrent with an increased resistance to apoptosis in thymocytes from aged animals. Together, these results suggest that T cells may be flawed even before exiting to the periphery and that this could contribute to the age-associated decline in immune function.

Why does the thymus involute? A selection-based hypothesis

Thymic involution remains a fundamental mystery in immunology. Here we present an argument that this seemingly counterproductive behavior may have evolved to allow for peripheral selection of a T-cell repertoire during young-adult life, optimized for fighting infections and avoiding reaction to self. Age-associated decline in immune function may be viewed as an unfortunate side effect of this selective process. Thus, the key to understanding thymic involution might lie in a more quantitative understanding of T-cell homeostasis in the periphery.

CD8 T Cells in Old Mice Contribute to the Innate Immune Response toMycobacterium tuberculosisvia Interleukin-12p70-Dependent and Antigen-Independent Production of Gamma Interferon

Elderly individuals have increased morbidity and mortality associated with infectious diseases due in part to the progressive age-associated decline in immune function. Despite this, the old mouse model of Mycobacterium tuberculosis infection has revealed a CD8- and gamma interferon (IFN-gamma)-dependent early resistance to infection. In this study, we investigated the mechanism by which CD8 T cells from old mice contributed to the early immune response to M. tuberculosis. Following a low-dose aerosol infection with M. tuberculosis, CD8 T cells were identified as being a dominant source of IFN-gamma expression in the lungs of old mice early after infection, before the typical onset of antigen-specific immunity. In addition, M. tuberculosis-induced IFN-gamma production by CD8 T cells isolated from naïve old mice was major histocompatibility complex class I independent but was dependent on interleukin-12p70, confirming an innate role of CD8 T cells during M. tuberculosis infection. Moreover, the ability of CD8 T cells from old mice to produce increased innate IFN-gamma levels in response to M. tuberculosis infection was defined as a unique function of CD8 T cells from old mice and not the aged lung environment. Finally, we have identified increased expression of SET as being one possible mechanism by which CD8 T cells from old mice produce enhanced levels of IFN-gamma. Additional characterizations of the signaling events that lead to enhanced innate IFN-gamma production by CD8 T cells in old mice may lead to novel strategies to further enhance or perpetuate beneficial immune responses in the elderly.

Effect of exercise, aging and functional capacity on acute secretory immunoglobulin A response in elderly people over 75 years of age

Age-associated decline in immune function and regulation, referred to as immunosenescence, brings about an increased incidence of infectious diseases in the aged; however, there are few data on the effect of aging and exercise on mucosal immune function in elderly people. Moreover, there is no evidence on whether the change in functional capacity affects mucosal immunity in elderly people. Therefore, the aim of the present study was to examine the effects of exercise, aging and functional capacity on mucosal immune function in elderly people over 75 years of age. The subjects were 92 community-dwelling elderly women aged over 75 years who lived in a rural community in Miyagi Prefecture. The subjects periodically performed approximately 20 min of low intensity exercise. Saliva samples were collected before and after exercise, and saliva flow (SF), secretory immunoglobulin A (SIgA) concentration (SIgA-C) and SIgA secretion rate (SIgA-SR) were determined. The Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) was used to measure functional capacity. In comparison with before exercise, SF, SIgA-C and SIgA-SR were significantly increased after exercise in elderly subjects. In addition, when low and high value groups of resting SIgA levels were compared, acute SIgA responses were observed only in the low value group; however, there was no significant effect of aging and decline in functional capacity on exercise-induced SIgA response. These results suggest that resting SIgA levels influence the mucosal immune function response to exercise in elderly people over 75 years of age.

Is thymocyte development functional in the aged?

T cells are an integral part of a functional immune system with the majority being produced in the thymus. Of all the changes related to immunosenescence, regression of the thymus is considered one of the most universally recognised alterations. Despite the reduction of thymic size, there is evidence to suggest that T cell output is still present into old age, albeit much diminished; leading to the assumption that thymocyte development is normal. However, current data suggests that recent thymic emigrant from the aged thymus are functionally less responsive, giving rise to the possibility that the generation of naïve T cell may be intrinsically impaired in the elderly. In light of these findings we discuss the evidence that suggest aged T cells may be flawed even before exiting to the periphery and could contribute to the age-associated decline in immune function.

Exercise and Psychosocial Factors Modulate Immunity to Influenza Vaccine in Elderly Individuals

Decreases in immune responsiveness with age contribute to the increased incidence and severity of infectious disease among elderly adults. The immune response to immunization also decreases with advancing age. Lifestyle factors (exercise, diet) have been established to play an important role in immunosenescence, and the practice of "healthy" behavior may minimize the age-associated decline of immune function. The objective of this study was to determine whether exercise, diet, and psychosocial factors were associated with altered immune response to influenza vaccine. Adults aged 62 years and older were categorized into one of three groups: active (> or =20 min vigorous exercise three or more times per week), moderately active (regular exercise but with less intensity, frequency, and/or duration), or sedentary (no exercise). Two weeks postimmunization, serum was frozen for antibody analysis, and peripheral blood mononuclear cells (PBMC) were cultured in vitro with influenza vaccine to elicit antigen-specific responses (proliferation and cytokine [IL-2, IFN-gamma, IL-10] production). Cytokines and antibody were measured by enzyme-linked immunosorbent assay. The results demonstrated that anti-influenza IgG and IgM were greater in active as compared with moderately active or sedentary participants. PBMC proliferation was lowest in sedentary subjects. Perceived stress was a significant predictor of IL-2. Greater optimism and social activity were associated with greater IL-10. Daily multivitamin intake was significantly correlated with IL-2. These results suggest that lifestyle factors including exercise may influence immune response to influenza immunization. The practice of regular, vigorous exercise was associated with enhanced immune response following influenza vaccination in older adults.

Vitamin E and infectious diseases in the aged.

The incidence of infectious diseases, particularly respiratory diseases, increases with age. Age-associated decline in immune function contributes to the increased susceptibility of the aged to infections. Vitamin E supplementation has been shown to improve some aspects of immune function in aged animals and human subjects. The protective effect of vitamin E against viral or bacterial infections in experimentally-challenged young animals has been reported. We investigated the effects of supplementation with vitamin E and other antioxidants on resistance to influenza infection in young and old animals. While vitamin E-supplemented young mice showed only a modest reduction in lung viral titre, vitamin E-supplemented old mice exhibited a highly significant (P < 0.05) reduction in viral lung titre. In subsequent studies, we focused on the mechanism of vitamin E-induced reduction of influenza viral titre. The results of these studies as well as those reported by other investigators on the relationship between vitamin E and infectious diseases will be reviewed.

Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12

Reflective of age-associated decline in immune function among elderly individuals is a decrease in in vitro T cell proliferative ability. Impaired T cell proliferation in the elderly may result from disruption of the well-balanced network of regulatory cytokines produced during an immune response. The purpose of this study was to identify age-related changes in the production of interleukin (IL)-10 and IL-12, and to determine whether in vitro T cell proliferation can be enhanced in the elderly by modulation of these two key cytokines. The superantigen Staphyloccocus entertoxin B (SEB) was used to stimulate proliferation and IL-10 and IL-12 production in peripheral blood mononuclear cells (PBMC) in vitro. Proliferation was determined by standard tritiated thymidine uptake. Cytokine levels in culture supernatants were measured by ELISA. We observed impaired SEB-induced proliferation of PBMC in the elderly that is comparable to that seen with the polyclonal mitogen Con A. This age-related decline in proliferation was associated with increased production of both IL-10 and IL-12. Modulation of PBMC proliferative response with either recombinant IL-12 or IL-10-neutralizing antibodies can boost proliferation of elderly PBMC to the levels seen in unmodulated young controls.

The effect of long-term dietary supplementation with antioxidants.

The impact of diet and specific food groups on aging and age-associated degenerative diseases has been widely recognized in recent years. The modern concept of the free radical theory of aging takes as its basis a shift in the antioxidant/prooxidant balance that leads to increased oxidative stress, dysregulation of cellular function, and aging. In the context of this theory, antioxidants can influence the primary "intrinsic" aging process as well as several secondary age-associated pathological processes. For the latter, several epidemiological and clinical studies have revealed potential roles for dietary antioxidants in the age-associated decline of immune function and the reduction of risk of morbidity and mortality from cancer and heart disease. We reported that long-term supplementation with vitamin E enhances immune function in aged animals and elderly subjects. We have also found that the beneficial effect of vitamin E in the reduction of risk of atherosclerosis is, in part, associated with molecular modulation of the interaction of immune and endothelial cells. Even though the effects of dietary antioxidants on aging have been mostly observed in relation to age-associated diseases, the effects cannot be totally separated from those related to the intrinsic aging process. For modulation of the aging process by antioxidants, earlier reports have indicated that antioxidant feeding increased the median life span of mice to some extent. To further delineate the effect of dietary antioxidants on aging and longevity, middle-aged (18 mo) C57BL/6NIA male mice were fed ad libitum semisynthetic AIN-76 diets supplemented with different antioxidants (vitamin E, glutathione, melatonin, and strawberry extract). We found that dietary antioxidants had no effect on the pathological outcome or on mean and maximum life span of the mice, which was observed despite the reduced level of lipid peroxidation products, 4-hydroxynonenol, in the liver of animals supplemented with vitamin E and strawberry extract (1.34 +/- 0.4 and 1.6 +/- 0.5 nmol/g, respectively) compared to animals fed the control diet (2.35 +/- 1.4 nmol/g). However, vitamin E-supplemented mice had significantly lower lung viral levels following influenza infection, a viral challenge associated with oxidative stress. These and other observations indicate that, at present, the effects of dietary antioxidants are mainly demonstrated in connection with age-associated diseases in which oxidative stress appears to be intimately involved. Further studies are needed to determine the effect of antioxidant supplementation on longevity in the context of moderate caloric restriction.

The age-associated decline in immune function of healthy individuals is not related to changes in plasma concentrations of β-carotene, retinol, α-tocopherol or zinc

The decline in the lymphoproliferative response to mitogenic stimuli shows marked heterogeneity in elderly individuals. Adequate nutriture is required for optimal immune function, yet nutritional status may be compromised in the elderly. To address whether this variation in the proliferative response of elderly individuals is related to their nutritional status, we studied 61 elderly (80.5±5.7 year-old) and 27 young (27.3±3.8 year-old) individuals participating in an ongoing assessment of their immune response to influenza vaccine. Ambulatory elderly individuals were recruited from five different retirement communities and were in good health upon enrollment in the study. Thirty-three percent of young and 54% of elderly subjects reported consuming micronutrient supplements daily during the study. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from fasting individuals twice, 4–6 weeks apart. At both times, proliferative responses to the mitogens phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) were significantly lower ( P<0.004) in the elderly compared to the young. However, at both times, elderly participants had plasma concentrations of β-carotene, retinol, α-tocopherol and zinc that were either significantly greater than, or equal to, those of young subjects. No significant correlations between plasma concentrations of β-carotene, retinol, α-tocopherol and zinc and level of proliferative responses to each stimuli were observed in elderly individuals at either time. Thus, the heterogeneity in the proliferative response to mitogenic stimuli exhibited by a healthy elderly population cannot be attributed to differences in these nutritional parameters.

The Influence of an Aging Immune System on Cancer Incidence and Progression

The majority of cancers occur in patients over the age of 65 years, and yet the important interactions of normal aging upon the neoplastic process remain to be thoroughly explored. For example, there is no unifying and conclusive explanation for the increased risk of cancer with advancing age. The age-associated decline in immune function has previously been implicated in this regard. However, it is likely that other factors, such as the time it takes to proceed through the multistep neoplastic process, and the combined influence of age-associated increased susceptibility to carcinogen and decreased DNA repair are more important. Nevertheless, immune senescence does influence various aspects of tumor growth and spread. In this article these aspects are reviewed.

Tumors and aging: the influence of age-associated immune changes upon tumor growth and spread.

There has been a clinical impression that tumors are less malignant in older people. Such has been claimed for breast, colon, prostate and lung carcinomas (Schottenfield and Robbins, 1971; Berkson et al., 1957, Calabrese et al., 1973; Ershler et al., 1983; Pickren et al., 1982; Suen et al., 1974). The great heterogeneity in clinical populations, confounded by antecedent illness, medicines, exposures, and social circumstances have precluded a statistical confirmation of such age-associated changes. Nonetheless, in experimental animals, ’we and others have found significant differences in tumor growth and spread when the common variable is host age. Weakly immunogenic tumors such as B16 melanoma or Lewis lung carcinoma (3LL) growrnore slowly in old mice, but more immunogenic tumors such as methylcholanthrene-induced fibrosarcomas grow more rapidly. We have explored a variety of proposed mechanisms for the observed differences and have concluded that the age-associated decline in immune function (immune senescence) is central to the reduced aggressiveness of weakly antigenic tumors in older hosts.

Immune responses of systemic and mucosal lymphoid organs to Pnu-Imune vaccine as a function of age and the efficacy of monophosphoryl lipid A as an adjuvant.

A murine model system was established to study immune responses to the Pnu-Imune vaccine, which is made up of 23 different pneumococcal capsular polysaccharides. In this animal model, antibody-forming cell responses to 21 of 23 individual polysaccharides in the vaccine were detected. The Pnu-Imune vaccine elicited good antibody responses from the spleens and mesenteric lymph nodes (MLN) of young mice, whereas a variety of other peripheral lymph nodes were unresponsive. The immunoglobulin M plaque-forming cell (PFC) response in the spleen to the Pnu-Imune vaccine (given intraperitoneally or subcutaneously) decreased dramatically with increasing age. However, the spleen and MLN differed in their susceptibility to an age-associated decline in immune function. While the PFC responses in the spleen declined with age, the PFC response in the mucosa-associated MLN did not decline with age but instead remained constant over the entire age span of 4 to 28 months studied. These studies showed that the spleen, peripheral lymph nodes, and MLN did not demonstrate parallel age-associated defects in antibody responses to pneumococcal polysaccharides when the antigen was administered systematically. Also, the deficient splenic antibody response to Pnu-Imune vaccine in aged mice could be enhanced by injecting a combination of Pnu-Imune vaccine and the nontoxic adjuvant monophosphoryl lipid A. Moreover, an immunoglobulin G response was induced when the immunogen was a mixture of vaccine and adjuvant.