Immunosenescence: How the Immune System Ages
The immune system undergoes constant physiological changes over the human lifespan.[7] The infant has no immunity of its own at birth; immune function develops quickly over the first few years and then builds to a complete maturation by puberty.[8] In fertile women, immunity fluctuates cyclically in sync with the menstrual cycle; dramatic changes occur during pregnancy as well as the postpartum period.[8]
Throughout life, homeostasis is preserved in all systems through tightly regulated interactions between numerous interdependent body tissues (Figure 1).[7] Driven by inalterable genetic factors, environmental insults, such as UV light, and lifestyle factors like nutrition and nicotine use,[9] body tissues, with age, experience a progressive deterioration of cellular and tissue functions, largely due to genetic decay and the byproducts of metabolism.[9] The study of aging in the immune system has revealed that immunosenescence represents a substantial remodeling of major immune functions.[7]
Figure 1.
Interaction between genetic factors, estrogen and aging in the development of Th1/TH2 differentiation and subsequent autoimmune diseases in aging women.
DC: Dendritic cell; Th: T-helper cell.
Immunosenescence in both genders impacts cellular, humoral and innate immunity.[10] Significant consequences of aging include atrophy of the thymus, changes in both the total numbers and subsets of lymphocytes, changes in the function of both B and T cells, changes in the patterns of secretion of cytokines and growth factors, disruption of intracellular signaling, changes in the patterns of antibody production, loss of antibody repertoire, loss of response to antigens and mitogens and disruption of immunological tolerance (Table 1). Gender-specific increases in some aspects of immunosenescence have been observed and will be discussed below.
Although aging affects many immune cell types, the cumulative effects of aging on T-cell function are the most consistently observed and most extensive.[11] The human thymus decreases in both size and cellularity in a process called thymic involution; thymus tissue is replaced with fat.[12] By 60 years, thymus-derived hormones are absent from the circulation.
Involution of the thymus in humans occurs in concert with a depletion of naive T cells and a shift in the T-cell population toward memory CD4+ cells.[13] In young adulthood, the CD4+ subset is characterized by roughly equivalent numbers of memory and naive CD4+ cells but in older adults becomes predominantly memory CD4+,[14] a shift that reduces the potential antigenic repertoire.[15] The shift toward memory T cells with age is largely a consequence of the imbalance in T-cell maturation produced by thymus involution[16] paired with an age-related impairment of T-cell proliferation[17] in concert with clonal expansion of T cells activated by specific antigens.[15] The shift toward memory cells in the T-cell compartment affects cytokine production as well, with less IL-2 produced (primarily a product of naive T cells) but more IL-4 (primarily a product of memory T cells).[18]
The cumulative loss of T helper (Th) cells with age plays a profound role in immunosenescence, ultimately affecting both cellular and humoral immunity. Disruption of Th cells and alterations of cytokine levels that control B-cell functions compromise humoral immunity substantially, with decreased production of long-term immunoglobulin (Ig)-producing B cells as well as a reduction of Ig diversity.[5] Although B-cell numbers do not change significantly, there is a significant impairment of B-cell response to primary antigenic stimulation;[15] specific immunoglobulins produced become more random, and those produced have decreased affinity for their specific antigen.[15] With age, therefore, the B-cell repertoire poised to respond to new antigenic challenge is limited, and the predominance of memory T cells seen with thymic involution is mirrored in the B-cell compartment.[19] IL-15, particularly, stimulates proliferation of memory T cells; IL-15 levels are nearly double in healthy adults 95 years or older (3.05 pg/ml compared with both older adults [60–89 years] 1.94 pg/ml and midlife adults [30–59 years] 1.73 pg/ml).[20]
Immunosenescence is compounded by the presence in the aged of a chronic low-grade inflammation characterized by increased proinflammatory cytokines, such as IL-6 and TNF-a, compounds that create oxidative stress and decrease cellular antioxidant capacity.[10] These proinflammatory cytokines are positively associated with stress as well as salivary cortisol levels and may play a significant role in creating the degenerative changes associated with aging.[17] Other body processes, most notably innate immunity[21] and interactions of immunity with the neuroendocrine system,[22] also contribute to immune system aging.
Antigen-presenting cells such as dendritic cells (DCs) and macrophages serve as a bridge between the innate and the adaptive immune systems. Antigen-presenting cells interact with foreign molecules and release pathogen-specific cytokines that drive the activation of naive CD4 helper cells into either Th1 or Th2 effector cells.[23]
Production of IL-12 and IFN-g drive commitment of naive T cells to the Th1 lineage. Th1 cells produce cytokines that favor a cell-mediated response (IL-2, lymphotoxin, IFN-γ and TNF-β), warding off intracellular pathogens, mounting delayed-type hypersensitivity responses to viral and bacterial antigens and eliminating tumor cells.[15]
Production of IL-4 and IL-10 drive commitment to the Th2 subtypes.[23] Th2 cells release cytokines which produce an environment favoring humoral immunity (IL-4, -5, -6, -10, and -13) by stimulating Th2 cell proliferation, differentiation, and participation in humoral immunity.[15]
In the aged, however, naive cells are less likely to become effectors. In those that do, there is a documented shift towards a Th2 cytokine response.[15]
The molecular and cellular changes associated with aging have substantial clinical ramifications. The elderly have impaired ability to achieve immunization but much higher levels of circulating autoantibodies, (due to the lack of naive effectors) impaired response to viral infections, increased risk of bacterial infections, and increased risk of both neoplastic and autoimmune disease.[7]
Expert Rev of Obstet Gynecol. 2012;7(6):557-571. © 2012 Expert Reviews Ltd.
