Preventing or Reversing Immunosenescence

Can Exercise Be an Immunotherapy?

Adriana L de Araújo; Léia CR Silva; Juliana Ruiz Fernandes; Gil Benard


Immunotherapy. 2013;5(8):879-893. 

In This Article

Inflammaging, Fragility & Other Consequences

Inflammaging is defined as low-grade chronic systemic inflammation established during physiological aging. Altered levels of proinflammatory cytokines (e.g., IL-6 and TNF-α), acute-phase reactants (C-reactive protein [CRP]), and decreases in IL-10 impair the maintenance of immunological homeostasis.[76] Inflammaging is considered a predictor of fragility and this condition is currently accepted as a pathogenic factor in the development of several, age-related diseases, such as cardiovascular disease,[77] cancer,[78] osteoporosis[79] and Alzheimer's disease.[80] It was found that individuals over 60 years of age being treated with anti-TNF are less vulnerable to hospitalization with infectious complications compared with a group that had discontinued the therapy.[81] The progressive accumulation of TNF-α is also related to obesity, smoking, psychological stress and CMV infection in addition to aging.[76,66]

However, the current notion that accumulation of senescent cells (concomitant to the reduction in the naive cell pool) carries severe deleterious effects has been challenged. In studies of the very old population, it was verified that besides the reduction of naive cells, the accumulation of late-differentiated effector memory cells was correlated with a prolonged survival of this population. This population was highly exposed to CMV; it was then reported that CMV-specific memory cells were relevant to the prolonged survival. Moreover, they showed that individuals who developed pure proinflammatory responses towards the CMV-specific peptides had prolonged survival compared with those who predominantly developed anti-inflammatory responses to these peptides. Thus, the immunosurveillance against CMV appears to be crucial to the longevity of these very old individuals.[82]

Despite these findings, there is not a consensus on the definition of biomarkers of immunosenescence and death risk. In addition, it is not clear whether there is a correlation between the frail elderly and more frequent CMV reactivation or between higher titers of anti-CMV antibodies and shortened survival.[83] In a study of 2-year survival of an aged (>65 years) population, multiple logistic regression analysis revealed that only increased CRP levels and thymic function reduction (measured by the recently described sj/b-TREC ratio quantification method, which directly measures thymic-emigrant cells) were independently associated with increased mortality of healthy elderly.[84]

Although several transversal studies suggest that persistent CMV infection is the main inducer of inflammaging,[66] a longitudinal study found a lack of a role for CMV. In this study, 249 individuals with a mean age of 67.5 years old were followed for 10 years,[76] reporting an increase in proinflammatory status over time (elevation of CRP, TNF-α, IL-6, IL-10 and IFN-γ) that was comparable between individuals seropositive and seronegative for CMV. Within this context, a longitudinal study conducted in a Swedish population of octo- and nonagenarians identified a set of immunological parameters associated with immune dysfunction during aging that forecasted early mortality.[85] These parameters were referred to as the immunological risk profile and comprised the accumulation of CD28 T lymphocytes, a decreased CD4/CD8 ratio, seropositivity to CMV, the decreased proliferative capacity of T cells and a decreased number and functionality of B lymphocytes. Interestingly, another study described the increased proportion of a subset of cells expressing CD25 within the CD8+ memory cell compartment in the elderly. These CD8+CD25+ cells would represent CD8+ T cells in an initial phase of differentiation, presenting long telomeres and a polyclonal TCR repertoire, and are associated with a better function of the immune system in these individuals.[2]

During aging, impairment of the gut-associated lymphoid tissue (GALT) capacity to efficiently synthesize strain-specific secretory IgA, together with the reduced efficiency of innate immune defenses, such as L-defensins, antimicrobial peptides and mucus secretion, may result in failure to control the resident microbiota, allowing an uncontrolled microbial growth on the enterocyte surface. In this context, enterocytes could engage the activation of inflammatory cytokines and chemokines, forcing DCs of the underlying GALT to drive the differentiation of effector Th1, Th2 and Th17 cells that induce a strong proinflammatory response (Figure 2). Indeed, the proinflammatory state of the GALT may be a driving force behind the systemic inflammation (inflammaging) of the elderly.[86]

Figure 2.

The main factors contributing to inflammaging.
Chronic viral infections, such as CMV, lead to an expansion and increased cytotoxicity of memory T cells and promote the release of proinflammatory cytokines. Accumulation of intra-abdominal fat on WAT leads to activation of adipocytes and macrophages to secrete proinflammatory cytokines. Oxidative stress also plays a major role in determining and maintaining the low-grade inflammation observed in aging. In this context, free radicals, such as ROS promote inflammatory response through activation of TLR-8 and the adaptor molecule MyD88. Impairment of the GALT capacity to efficiently synthesize strain-specific secretory IgA, together with the reduced efficiency of innate immune defenses, may result in failure to control microbiota. Enterocytes then engage the activation of inflammatory cytokines and chemokines through activation of effector cells.
CRP: C-reactive protein; DC: Dendritic cell; GALT: Gut-associated lymphoid tissue; ROS: Reactive oxygen species; TLR: Toll-like receptor; WAT: White adipose tissue.