Immune Aging and Challenges for Immune Protection of the Graying Population

The trajectory for increased numbers of older adults aged ≥65 years worldwide [1, 2] has become a subject of great interest in many circles, from policymakers, to scientists and physicians, and to entrepreneurs of so-called anti-aging products [3–7]. For developing countries, much of the interest on aging relates to social concerns about an associated projection for increased poverty [8]. Aging and longer survivorship in these countries are also considered significant contributing factors to anticipated greater incidences of non-communicable chronic diseases such as diabetes and cardiovascular conditions, and therefore add to their already heavy burden of communicable diseases [9]. For industrialized countries, much of the social interest on aging seems to be driven by the escalating cost of health care [10]. Indeed, socioeconomic studies on aging, dying, and survivorship for the United States alone has led to a prediction for a 50 to 69% increase in the per capita cost of personal care for elderly Americans between their 65^th and 85^th years of life [11]. This is considered a conservative prediction that further puts into question the future sustainability of the US health care system, a national issue that is currently muddled by political party ideology rather than by serious rational discourse.

This health-centric view of aging and survivorship permeates into the Sciences. Epidemiological and observational studies have been showing not only the overall age-related increases of chronic diseases such as diabetes, breast cancer, systemic lupus erythematosus, and rheumatoid arthritis, but also the insidious onset of some of these diseases in late life [12–14]. Genetic studies on humans, mice, and lower taxa of animals have been uncovering genes encoding for longevity [15–17], with some genes or their variants associated either with poorer health or with maintenance of good health into old age [18–21]. Clinical studies have been advancing novel concepts of functional independence or dependence based on new discoveries about the unique physiology of aging [22–25]. And translational studies have been developing new models of elder care [26, 27] with corresponding innovation on interventions to promote better health in old age [28–30].

Aging, Health, and Immunity: Three Special Issues of Aging and Disease

Clearly, there is tremendous interest on health and aging on a global scale. Given that health and fitness, at any age, depends on immunity, it is fitting to examine the impact of chronologic aging on the organization and function of the immune system, and how age-related changes of immune function might influence health outcomes in late life. Aging and Disease has therefore dedicated the next three issues on the topic of “Aging and Immunity” to highlight achievements of scientists and clinicians whose creativity will no doubt continue flourish even within a turbulent economic climate [31–33]. The special issues are titled as follows:

• Issue 1: Age-related alterations in the immune system, Lessons from murine and human studies

• Issue 2: Immunological and inflammatory processes underlying risk of age-related disease

• Issue 3: Clinical challenges of immune protection and promotion of successful aging

In this first issue, seven articles synthesize research findings on fundamental aspects of the immunophysiology of aging.

Of mice and men: Alterations of classical immune functions with age

Immune defenses of mice and humans, and for the rest of the vertebrate taxa, have been classified as either innate or adaptive. This is a classification based on original concepts of immediate non-specific responses, and of antigen-specific memory recalling responses, respectively. Both of these arms of the immune system become altered with age.

Innate immunity in rodent models

The article by Brubaker and colleagues [34] presents a rather comprehensive summary of age-related changes in innate immune function. Phenotypes and functions of neutrophils, macrophages, dendritic cells, natural killer (NK) cells, and NK-T cells of mice and rats are discussed within the context of infection, trauma, tumor immunity, autoimmunity, and protective immunity. While there appears a common theme for the varying degrees of functional insufficiency for each of these cell types, there are the notable findings for the increased generation of neutrophils, and the skewing of macrophage population towards the Mac1⁺CD11b⁺ subset. These latter observations raise the question as to whether they might represent compensatory, if not novel, innate immune mechanisms instead of age-related defects. The authors do acknowledge that there is yet much to learn above development and differentiation of innate immune cells in aged animals.

Adaptive immunity in rodent models

Frasca and Blomberg [35] summarize research on B cell function. They conclude that aging is associated with impairment of function at various levels, from B cell development in the bone marrow, to immunoglobulin isotype switching, to germinal center reaction, to antigen-specific antibody responses, and to mucosal immunity. A provocative idea that the authors stir is a notion that functional deficits of B cells might be related to a prevailing systemic inflammation during aging. Low level upregulation of cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 that have classic inflammatory activity, has been considered a feature of human aging, and that higher quartiles of TNF-α and IL-6 have been associated with disability in old humans [36]. Similar elevated level of TNF-α in aged mice have been reported [37]. Frasca and Blomberg now indicate that they have seminal evidence, albeit still awaiting publication, for the suppression of immunoglobulin isotype switching when B cells are incubated with TNF-α in vitro. These are indeed interesting findings that could suggest a link between inflammation and B cell dysfunction. However, it might be noted that it is not yet known if the low level upregulation of TNF-α and/or IL-6 during normal aging in humans or in mice truly represent inflammation that cause pathology in old individuals. It is perhaps worth pointing out that young patients of inflammatory diseases such as rheumatoid arthritis have chronically higher levels of systemic TNF-α [38], yet young patients do not exhibit syndromes such as frailty and sarcopenia that have been associated with low levels of TNF-α in old people [39, 40].

For mouse T cells, Haynes and Lefebvre [41] conclude similar age-related dysfunction. Their main conclusion is that age appears to have more deleterious effects on naïve T cells relative to memory T cells. Contrary to the apparent gloom about immune aging, this conclusion by the authors has two positive messages. First, it lends support to the importance of vaccination, or to antigenic exposure in general, at an early age. Indeed, recent studies do show that exposure of young mice and young primates to herpesviruses, whose latent property is thought to cause chronic stimulation of T cells that lead to the accumulation of dysfunctional cells in old individuals, actually results in the elicitation of long lasting and protective memory response into old age [42, 43]. The second positive message is a notation that aged animals can be induced to generate new naïve T cells that are in fact functionally competent [44]. This latter observation lends support to an emerging interest on a potential immune intervention of aging through the regeneration of the thymus [45, 46], the seat of T cell production that normally involutes with advancing age.

T cell function in aged humans

Two papers focus on the function of T cells in humans, both of which are set on a backdrop that CD28 is irreversibly lost with age [47]. The latter is a feature of human aging that is not observed in mice, and therefore underscore the indispensability of human-oriented research on the biology of aging. It also cautions transposition of results of animal studies to human biology.

The paper by Dock and Effros [48] summarizes replicative senescence of CD8 T cells. A notable finding is that the loss of CD28 is linked to loss of telomerase activity. Indeed, their own work indicates reconstitution of telomerase in CD28^null T cells restores not only CD28 expression, but also mitotic activity. The paper also extends discussion of the role CD8 T cell replicative in the pathogenesis and disease management of HIV-AIDS as well as in persistent cytomegalovirus (CMV) infection. It is perhaps important to recognize that senescent CD8 T cells were first identified during the early years of the AIDS epidemic [49], although at the time CD28^null CD8 T cells were thought to be immature cells. Findings about the induction of senescent CD8 T cells with chronic infection illustrates how T cell aging can be elicited independent of age and that preponderance of senescent T cells in the young may contribute to immunopathology [50].

The paper by Cavanagh et al [51] summarizes findings about the expression of various receptors on CD28^null T cells. It appears that many of these receptors are those normally expressed by NK cells, indicating a transformation of the conventional T cell to NK-like T cells with aging consistent with immune repertoire remodeling [50]. Cavanagh and colleagues cites evidences in favor of the idea of programming for the acquisition of NK receptors with aging. They conclude that expression of these NK receptors on T cells may not be indicative of functional exhaustion, but rather an endowment of new function. Since the said receptors have either stimulatory or inhibitory functions on their own, a current research challenge is to decipher conditions in which to favor activation, or conversely to attenuate T cell function. Akin to Dock and Effros, Cavanagh et al extends discussion on the expression of these novel receptors on T cells in the setting of immune-mediated disease even at a young age. A key question then is whether there are disease- or age- specific regulatory machineries controlling expression of these receptors, and the immunopathways they trigger.

Linking immune aging other organ systems

Chronologic aging affects all organ systems. Aging phenotypes are most likely a result of feedback loops between different tissues and organs. The paper by Shimada and Hasegawa-Ishii [52] illustrates parallel patterns of aging in the immune system and in the brain of senescence-accelerated mice (SAM). Remarkably, the phenotype of SAM encapsulates much of what has been observed among unmanipulated animals with aging, including the acceleration of thymic involution, and T/B/NK cell functional insufficiency. The prematurely aged immune phenotype is paralleled by brain atrophy, loss of neuronal cells, and varying impairments of learning and memory of otherwise chronologically young mice. While it is not clear as to whether brain aging and immune aging of SAM are independent or interdependent processes, it is remarkable that inflammatory cytokines are elevated in both the blood and in the brain of these animals. If indeed the notion that aging leads to the elaboration of an inflammatory environment, as invoked by the articles of Brubaker et al [34] and of Frasca and Blomberg [53], and the literature cited therein, then SAM is a valuable model to elucidate how immune aging influences brain aging. Feedback between these two organ systems in determining aging phenotypes might not be totally surprising considering that certain brain cells like microglia are in fact specialized immune cells [54], and that there are already well-documented neural-immune communications in young mice and humans that operate in the context of normal health or in the setting of diseases of the brain [55–58].

Immune aging and evolution

Among the most controversial, but certainly more interesting, questions of Biogerontology is the evolutionary significance of aging. Is aging is a random or programmed process? Does aging confer any advantage to the perpetuation of the species? Are old individuals important for the species? Does the evolution of immune defense itself presents costly trade off with lifespan?

While these issues are beyond the scope of this special issue, the article by Aw and Palmer [59] elicits provocative questions pertinent as to how and why the immune system may need to age. The article focuses on mechanisms underlying the involution of the thymus with age, synthesizing studies from mice and humans, and from evolutionary studies. Their main argument is that thymic involution is a necessary event in the life history of mice and human, and probably for all vertebrates. Support for this argument comes from observations that thymic involution in fact occurs very early in life, way before pubescence or sexual maturation. This suggests that keeping the thymus through life does not add further survival advantage. However, studies on children and adults who underwent total or partial thymectomy as infants show conflicting results as to whether or not their mature peripheral T cells provide immune protection [60–63]. Thus, debate as to the relevance or irrelevance of the thymus in normal adult health, or why thymic aging occurs will likely continue.

Research opportunities

The common, and perhaps intuitive, theme of aging in the immune system is a chilly doom for the decline in classical innate and adaptive immune functions. An example used by many investigators to illustrate this gloomy picture is the continuing dismal outcome of vaccination against seasonal influenza, namely, the elderly population is subject to disproportionately higher influenza-related morbidity and mortality annually despite increased vaccination coverage [64–68]. The fundamental challenge then is how to transform this seemingly chilly doom of immune aging into a rosier outlook for the increasing numbers of older adults. If longer survivorship is a socially and/or biologically inevitable event, then the obvious goal is to ensure good quality of life of elders.

The articles in this special issue provide guiding principles for translational research for the immediate future. These principles are replacement/rejuvenation, enhancement/potentiation, early life intervention, and development of alternatives.

Approaches for immune replacement or rejuvenation are already being tested in research programs in Regenerative Medicine. As already noted, the best immunological example is the notion for the rejuvenation or regeneration of the aged thymus. Advantage of this approach is however cautioned by the conserved involution of the thymus with age in various species. Another example of regenerative approach, and perhaps the most provocative idea, is hematopoietic stem cell transplantation to replace most of the cellular compartments of the aging immune system [69].

Aging in the immune system is not so much about suppression or extinction of classical immune responses, but about less vigorous or reduced magnitudes of responses. Hence, there is rationale for the development of strategies to enhance or potentiate immunity. As suggested by Haynes and Lefebvre [70], a key area of investigation is the development of adjuvants to boost adaptive immunity. A notation by Brubaker et al [34] about intact expression of certain toll-like receptors in aged animals suggest an area of investigation to boost innate immunity via these receptors.

Early life immune intervention is exemplified by vaccination programs and by natural pathogen exposures in childhood. Indeed, it has been shown that varicella zoster vaccine for older adults is much more efficacious among those who either had prior exposure to the zoster virus (shingles/chicken pox) or who have been vaccinated against chicken pox as children or as young adults [71, 72]. Another example is the apparent protection of elderly people from the recent 2009 H1N1 influenza pandemic [73, 74]. These observations emphasize the importance of immune memory. As it is however unlikely that one can develop vaccines for all pathogens, and for endogenous antigens such as tumors, a research challenge is to determine there are ways on how to maintain a robust pool memory lymphocytes and protect them from cell autonomous deleterious effects of age. A provocative idea is whether one’s history of pathogenic exposure could be harnessed to promote better immunity and reduce risk of serious diseases such as cancer in old age [75]. In principle, the latter is an achievable goal considering that immune memory is no longer just a characteristic of the adaptive arm of the immune system, but includes the innate immune system [76]. Furthermore, antigen-specificity of adaptive immunity is not a one-antigen one-T/B receptor rule but a spectrum of specificity, and so cross-protection is a likely mechanism of host defense [77, 78].

Development of alternative approaches for immune intervention will depend on new discoveries unique to old age physiology. New discoveries could include specific genetic elements that may favor better immune health, although such immune-assurance genes have not yet been identified unlike genes linked to longevity [15–17]. Nevertheless, potential areas for new immune intervention is the reconstitution of telomerase in lymphocytes as implicated by Dock and Effros [48], and as already being tested for cancer therapy [79]. Another area is to harness the function of new receptors expressed by aging T cells as described by Cavanagh et al [51]. In both instances, the challenge is to target specific cell populations to elicit particular cellular outcomes that are protective.

In summary, there are yet many research challenges on the immunology of aging. It is the view of this Special Issue editor that immune aging, and aging in general, is not all a picture of gloom and doom. One important fact that investigators perhaps need to ponder upon is that old people have very heterogeneous health phenotypes, ranging from the chronically ill to those who are functionally independent. The challenge then is to not simply focus on what one loses with age, but what one retains or maintains in old age. The next two special issues of Aging and Disease are anticipated to provide further insight into frameworks for disease risk (Aging and Immunity, Special Issue 2), on one hand, and for preserved or better health (Aging and Immunity, Special Issue 3), on the other hand. Readers and subscribers of the journal are therefore enjoined to look forward to the next two issues.