The study of the aging immune system is currently in its early phases, and the term immunosenescence has been used to identify this phenomenon.
For individuals older than age 65, infections are a major source of morbidity and mortality.
The innate immune system consists of neutrophils and macrophages, epithelial barriers, natural killer cells, dendritic cells, complement proteins, and the nonspecific defenses such as the production of mucus and antimicrobial peptides and mucociliary function. With aging, changes in the innate immune system result in chronic inflammation.
Elderly patients frequently demonstrate diminished protection following receipt of routine vaccinations compared with younger populations.
With an aging global population, the geriatric patient is increasingly likely to be encountered not only in the ambulatory setting but also in the critical care units. The study of the aging immune system is currently in its early phases, but there is some consensus on its impact on infection, malignancy, and autoimmunity. The term immunosenescence has been used to identify this phenomenon. Of note, it is difficult to separate a true change in immune function from other fundamental host defenses associated with aging. These defenses include alterations in barriers such as the skin, decreased acidity of the stomach, impairment in mucociliary clearance in the airways, impaired cough reflexes, malnutrition, changes in the urinary stream causing obstruction, and the impact of other comorbidities such diabetes. Of these, malnutrition has the potential to have a significant impact on immunosenescence and is not uncommon in the geriatric population.
To better understand the aging immune system, it can be subdivided into the traditional categories of an innate (neutrophils, macrophages, etc.) and adaptive system (B and T lymphocytes, immunoglobulins, etc.). While both are affected by aging, the impact seems to be larger on the adaptive system. However, there is some impact of aging on both neutrophil and macrophage oxidative burst and phagocytic activity.
The innate immune system, in addition to neutrophils and macrophages, consists of our epithelial barriers, natural killer cells, dendritic cells, complement proteins, and the nonspecific defenses such as the production of mucus and antimicrobial peptides and mucociliary function. With aging, changes in the innate immune system result in chronic inflammation. The adaptive immune system may be simplistically thought of as consisting of B and T lymphocytes, which, respectively, affect humoral and cellular immune responses. Both show age-related decreases in number and diversity.
The aging process is accompanied by a decline in numerous physiologic activities, and the immune system is no exception. The gradual deterioration in physiologic functions is referred to as senescence, which is derived from the Latin term senescere, meaning “to grow old.” The term immunosenescence refers to the alterations in immune system function that occur because of the normal biologic aging process, independent of any underlying diseases. This process affects all facets of the immune system, including both the innate and adaptive responses, with significant clinical implications in the development of infection, responsiveness to vaccination, and malignancy .
For individuals older than age 65, infections are a major source of morbidity and mortality. Interestingly, not all components of the immune system are adversely affected. Specifically, the ability to mount an effective response against previously encountered infectious organisms appears to remain intact, whereas activation of the immune system when faced with a novel pathogen diminishes over time. Clinically, these changes may manifest as deviations from the typical presentation of severe infection, including lack of fever in up to 30 percent of patients  as well as few localizing signs, and instead present with nonspecific symptoms including altered mental status, generalized weakness, and falls . These findings likely represent a diminished capacity to mount an inflammatory response in response to an infection.
The decreased responsiveness of the aging immune system to novel infectious agents also carries implications for vaccination in this population. Elderly patients frequently demonstrate diminished protection following receipt of routine vaccinations compared with younger populations. As a result, several different strategies have been developed to maximize vaccine effectiveness. These include administering higher doses , use of routine boosters , optimization of vaccine adjuvants , and altering the route of administration . These strategies will be discussed in detail later in this chapter.
In addition to increased susceptibility to infection, immunosenescence has also been associated with an increase in the incidence of cancer that is also observed with aging, particularly between the ages 65 and 85 years. This observed increase is multifactorial in nature and includes environmental factors (increased exposure to carcinogens over time) as well as biologic factors, which favor a selective advantage to tumorigenic cells. In addition, the immune system plays a key role in protection against the development of malignancy through the process of immunosurveillance, by which the immune system identifies cancerous or precancerous cells and eliminates them before they cause disease. However, alterations in the immune response that occur with aging, particularly the adaptive immune system, can result in tumor cells avoiding detection and the resulting immune activation .
Hematopoietic stem cells (HSCs) serve as the key progenitor cell from which all cellular constituents of the immune system are derived. While they make up only 0.01 percent of the cellular bone marrow population, they are the key to maintaining all mature components of the immune system, including both the innate and adaptive arms. It is their ability for long-term self-renewal as well as differentiation into multiple cell lineages that makes them essential for maintaining an immune system comprised of relatively short-lived mature effector cells. Studies have demonstrated that the process of aging affect both the number and the function of HSCs. Flow cytometry studies performed in different mice strains reveal that the HSC population may be either increased or decreased during the aging process, with unknown genetic factors likely playing a key role. However, with regard to function, multiple animal studies have demonstrated a marked decrease in the capacity of HSCs from aged animals to repopulate a fully functional immune system compared with younger animals following HSC or bone marrow transplantation. Additionally, the aging process also affect whether a given HSC will develop along a myeloid or a lymphoid differentiation pathway. Specifically, the myeloid pathway is favored over the lymphoid pathway, resulting in an overall decrease in the number of B and T lymphocytes relative to the myeloid cells. One potential explanation for these findings is a decrease in the expression of the interleukin 7 receptor (IL-7R) in older HSCs because IL-7 is key in initiating and maintaining lymphoid differentiation .
Changes in Specific Components of the Immune System
The innate immune system, which is also referred to as the ancestral part, consists of multiple cellular and noncellular defense mechanisms. These include neutrophils, monocytes/macrophages, natural killer (NK) cells, complement components, and mucosal barriers and cytokines. Thus the impact of aging on the innate immune system is characterized by complex changes of multiple individual components. Interestingly, while some innate functions do diminish with age, others exhibit enhanced activity. These asymmetric changes ultimately result in an overall increase in the inflammatory state and have led many to describe the age-related changes as immune dysregulation rather than pure senescence . Neutrophils are the predominant immune cells present in the circulation, and they provide a defense against bacterial and fungal infections. In general, they have a very short lifespan compared with hematopoietic cells, with a half-life of only 8 to 12 hours. Their lifespan may be extended by inflammatory cytokines such as granulocyte-macrophage colony-stimulating factor and interferon, as well as by bacterial products such as lipopolysaccharide (LPS), which maximizes their killing potential. They are summoned to infection sites by chemokines, where they use a host of mechanisms to destroy invading pathogens. These include ingestion of microorganisms through phagocytosis and subsequent killing via generation of reactive oxygen species (ROS) as well as proteolytic enzymes .
The aging process significantly affect multiple facets of neutrophil function. First, the chemotactic response becomes aberrant, likely impairing the ability of neutrophils to hone to a specific site of infection . However, in vivo this manifests as a decreased ability to resolve inflammation. One possible explanation for these findings is that there is diminished chemotactic response once the neutrophil reaches the infected tissue, which results in increased inflammation in surrounding tissues due to the lack of directional movement . In addition, neutrophils exhibit diminished phagocytic capacity with aging [10,13], as well as impaired respiratory burst, which may manifest as increased or decreased superoxide production depending on the stimulus . Finally, the ability of proinflammatory stimuli (LPS, granulocyte colony-stimulating factors, IL-6) to extend the lifespan of neutrophils also deteriorates with the aging process, which further impairs the ability of neutrophils to clear invading microbial pathogens .
Monocytes/macrophages constitute another key component of the innate immune system. Monocytes arise from myeloid progenitor cells and are present throughout the circulation. They subsequently differentiate into tissue-associated macrophages, which are present in multiple organ systems throughout the body, including brain, liver, lungs, skin, and bones. Their functional role varies depending on the specific organ where they reside. However, in general, they phagocytose and kill microorganisms and eliminate cellular debris. In addition, they also secrete myriad of cytokines, which may serve to direct and enhance the innate immune response and interact with the adaptive immune system by serving as key antigen-presenting cells .
The effect of aging on the number and function of monocytes and macrophages is varied. While there appears to be no impact on the number of circulating blood monocytes with advanced age, there does appear to be a decrease in the number of macrophages in the bone marrow isolated from older individuals [15,16]. With regard to the phagocytic function of macrophages, current data are conflicting, with some studies demonstrating a decreased phagocytic capacity with aging and others showing opposite results. These discrepancies may be secondary to differences in the activation state of the cells, their tissue source, or other experimental conditions .
Another key macrophage function that is disrupted by the aging process is antigen presentation. Activation of the adaptive arm of the immune system relies on a complex system of antigen recognition by either T or B lymphocytes. T-cell receptors rely on an interaction with the major histocompatibility complex class II (MHC class II) to recognize degraded products presented by macrophages and other antigen-presenting cells. Once T cells are activated, they further regulate cellular and humoral immune responses, including those which form the basis for immunologic memory. In addition, MHC class II complexes are also the key in generating the T-cell repertoire in the thymus. With advanced age, there is a significant decrease in MHC class II expression in macrophages, which is most likely secondary to decreased gene transcription following activation . Given the vital role MHC class II molecules play in activation of T lymphocytes, their decreased expression contributes to the dysfunction of the adaptive immune system with aging.
Natural killer (NK) cells are a population of cytotoxic lymphocytes that are responsible for MHC- independent killing of virally infected cells as well as tumor cells. They are divided into two separate populations based on their surface marker CD56. CD56bright cells comprise approximately 10 percent of the circulating NK cells and function primarily in the secretion of inflammatory cytokines, particularly interferon-gamma (IFN-γ). CD56dim cells, in contrast, constitute up to 90 percent of circulating lymphocytes and exhibit a predominantly cytotoxic function with minimal cytokine production. Interestingly, the total number of NK cells increases with aging, which is unlike what is seen with other lymphocyte populations. However, both subpopulations do not increase at the same rate; rather, there is a larger increase in the CD56dim population resulting in a change in the overall ratio between CD56dim and CD56bright cells. This increase in the number of NK cells appears to be a compensatory mechanism for declining function because decreased killing capacity has been observed when examined on a per-cell basis . In addition, cytokine production, including IFN-γ, is also diminished by the aging process. This impaired cytokine production is likely not overcome by increasing cell numbers and potentially contributes to higher infection risk and mortality in elderly individuals [11,19,20].
The adaptive immune system consists of B and T lymphocytes. These cells are responsible for antigen neutralization via antibody production as well as cell-mediated immunity directed against intracellular pathogens such as viruses and neoplastic cells, respectively. In addition, they also interact closely with the innate immune system to further hone the inflammatory response to pathogenic invasion. Both cell types become fully mature and activated via antigen recognition of cell surface receptors. In the case of B cells, these receptors consist of membrane-bound immunoglobulins, which are subsequently secreted once the cells fully mature into plasma cells. T cells, in contrast, recognize complementary antigen-MHC complexes that exist on the surfaces of antigen-presenting cells and further require costimulation with CD3 and other costimulatory molecules in order to become fully activated effector cells. The aging process has a significant impact on the total number and cellular subtypes, as well as receptor diversity, for both T and B lymphocytes. The overall impact of these changes is a decreased ability to recognize and mount an effective immune response. Interestingly, memory lymphocytes appear to be more resilient to the aging process, and long-term immunity is mostly preserved .
Aging of T Lymphocytes.
Naive T cells originate in the bone marrow and subsequently migrate to the thymus, where they undergo further selection prior to maturation in secondary lymphoid tissues. The thymus is most active early in life and subsequently undergoes a functional decline in a process termed involution . The size of the thymus peaks in the first year of life and then steadily decreases. As part of this process, the active portion of the thymus is slowly replaced by fatty tissue, which is nearly complete by 40 to 50 years of age . By age 70, only 10 percent of the thymus is involved in active replication .
Because of thymic involution, there is a marked decrease in the number of naive T lymphocytes and by extension T-cell receptor (TCR) diversity. One study estimated that between the ages of 25 and 60 years, there are 20 million different TCR β-chains compared with only 200,000 after age 70 . In addition, markedly low levels of recent thymic emigrants were identified in centenarians when compared with young (ages 20–45 years) or middle-aged volunteers, suggesting a marked depletion in the naive T-cell population with advanced age . This diminished naive T-cell population and TCR diversity significantly limits the ability of elderly patients to respond to new infections, placing them at higher risk for morbidity and mortality. In addition, it also contributes to diminished vaccine responsiveness in this population.
In addition to a decrease in the naive T-cell population and, by extension, TCR diversity, the aging process also induces changes in the number and composition of the circulating T-lymphocyte population. Studies have consistently demonstrated that there is an overall decline in the total T-cell population in elderly individuals, as measured by a decline in CD3+ cells. Furthermore, longitudinal studies have shown that an inversion of the CD4:CD8 ratio may occur over time, which is associated with increased mortality within 1 to 2 years .
Also, there is an emergence of a discrete subpopulation of T cells, which are CD28− cells, that predominantly affects CD8+ cells. CD28 is a very potent costimulatory molecule localized on the surface membrane of T lymphocytes. Activation of this receptor in the setting of TCR recognition of a MHC-antigen complex triggers the release of IL-2, which is key for T-cell proliferation. Furthermore, it also facilitates maturation into effector T cells, which no longer require costimulation. The cause of the emergence of this CD28− population remains unknown. However, it is hypothesized that this population derives from CD28+ lymphocytes, which undergo repetitive antigenic stimulation, resulting in loss of the CD28 receptor and entry into a quiescent state of replication [27,28]. Interestingly, this phenomenon has been observed in other settings as well, including HIV infection, autoimmune disorders, and following treatment with radiochemotherapies .
Another key phenomenon observed in aging T-cell populations is decreased production of IL-2. As mentioned earlier, IL-2 is a key cytokine that drives the expansion of T-lymphocyte populations as well as their differentiation. It is particularly key to mediating the CD4 response because it is the only cytokine capable of driving cell cycle progression. Furthermore, IL-1 is also responsible for maintaining survival in fully differentiated effector cells because they rapidly undergo apoptosis in its absence. With aging, the ability of CD4+ T lymphocytes to produce IL-2 following stimulation of the TCR is significantly reduced. This ultimately results in a diminished T-helper population in terms of both numbers and functional capacity. Furthermore, because T-helper cells are the key to a robust antibody response via stimulation of B lymphocytes, there is also a defect in the humoral response [29,30].