Preventing or Reversing Immunosenescence

Can Exercise Be an Immunotherapy?

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

Disclosures

Immunotherapy. 2013;5(8):879-893. 

In This Article

Positive Effects

Tests that evaluate proliferation and cytokine secretion in response to different stimuli are most commonly used to assess the competence of T-lymphocyte functions and the adaptive immune system. A transversal study that evaluated elderly individuals who practiced regular aerobic activity (60.5–67.1 years old) and those who were sedentary (62.3–69.3 years old) showed that regular aerobic activity was associated with a smaller increase in T-cell function, as demonstrated by a greater proliferative response and cytokine production (IL-2, IFN-γ and IL-4) to the mitogens phytohemagglutinin (PHA) and pokeweed.[99] Stimulation with phorbol myristate acetate and ionomycin also resulted in an increase in IFN-γ-producing CD4+ T cells and IL-2-producing CD8+ T cells in elderly individuals who walked regularly compared with sedentary elderly individuals.[100] An increase in the proportion of IL-2-producing T cells was also reported in a group of elderly women (62–86 years old) who underwent a 2-year intervention program of moderate physical activity when compared with a group of sedentary elderly women.[101]

Another study showed an increase in CD25 expression by peripheral blood mononuclear cells stimulated with anti-CD3 in an elderly group who practiced moderate physical activity for more than 15 years when compared with a sedentary elderly group.[102] In this study, it was notable that, among the active elderly, a higher expression level of CD25 was correlated with more activity.

In most instances, mitogens were used in the experiments showing that the T lymphocytes of active elderly individuals responded to stimuli with greater proliferation and activation. This fact raises the question of whether physical activity could also have an impact on T-lymphocyte capacity when other physiological conditions were assayed, such as when specific microbial stimuli were used to induce such T-cell effector functions such as cytokine secretion and cytotoxicity. In this regard, Okutsu et al. used delayed-type hypersensitivity with purified protein derivative from Mycobacterium tuberculosis to evaluate the effect of 25 weeks of physical training on the Th1/Th2 response balance in the elderly.[103] The trained elderly presented an increased reactivity to the purified protein derivative and decreased IgG4 serum levels, with the latter being used as a marker for Th2 immune response. No changes in these parameters were found in the control sedentary group. Similar results were obtained by Shimizu et al. when evaluating the effects of a 6-month moderate physical training regimen on the expression of CD28 and the balance between CD4+IFN-γ+ T cells (Th1) and CD4+IL-4+ T cells (Th2) in elderly people.[104] Compared to sedentary individuals, the CD4+ T cells from the trained elderly presented increased CD28 and IFN-γ expression, although the percentage of CD4+IL-4+ T cells remained stable. These data support the hypothesis that regular physical activity favors in vivo Th1 immune responses in elderly people.

In addition to potentially inducing better adaptive immune responses, moderate physical activity appears to have a positive effect on the innate immune system. Yan et al. studied individuals who practiced aerobic physical activities twice weekly, for 1 h or more, for 3 years and verified that the number of NK cells increased significantly in active elderly individuals.[105] The phagocytic activity of neutrophils, which declines with aging, was also higher in an active elderly group than a sedentary elderly group.

Despite the key role of DCs in innate immunity and the subsequent adaptive immune responses, few studies have addressed the acute impact of different exercise intensities on DCs from young adults and athletes, and no studies have addressed the impact of regular physical activity on the elderly DC status. Suchánek et al. showed that, after intense physical activity, young adults presented an increase in the number of peripheral blood DCs, both of myeloid and plasmacytoid origin.[106] Nickel et al. verified that the number of myeloid DCs increased after a marathon, whereas the plasmacytoid DCs decreased.[107] Chiang et al. demonstrated in mice that aerobic training was capable of modulating the development of DCs, which expressed higher levels of MHC class II molecules and IL-12 upon activation, suggesting that exercise training shifted DCs toward a more mature state.[108] Another experimental exercise protocol also showed that 5 weeks of running promoted an increase in murine DC numbers.[109]

As discussed above, immunosenescence is accompanied by an increase in the inflammatory background known as inflammaging. Moderate physical activity (reaching 70–80% of the cardiac reserve) is associated with a lower percentage of peripheral blood monocytes and lower lipopolysaccharide-induced TNF-α production by these cells, including the CD14+CD16+ 'inflammatory' subpopulation.[110,111] In addition, the increase in aerobic physical activity performed by the elderly during their leisure time was associated with a decrease in serum levels of CRP, IL-6 and TNF-α and in the number of peripheral blood leucocytes.[112–114] Both the intensity and also the number of years over the lifetime that the activity had been performed appear to have a positive effect on the concentration of inflammatory markers, as individuals over 65 years with a history of many decades of physical activity presented a lower number of leukocytes and neutrophils and reduced concentrations of IL-6, IL-1, IL-1R antagonist and soluble TNF-RI in comparison with sedentary individuals.[115] An 18-month period of progressive resistance training decreased serum IL-6 concentration in healthy 50–79-year-old men.[116] Ortega et al. studied women with fibromyalgia and demonstrated that a program of pool-aquatic exercise (8 months, twice-weekly 60-min sessions) resulted in diminished proinflammatory responses.[117]

The effect of physical activity on the accumulation of memory T cells and the loss of the naive T-cell repertoire, which are typical of immunosenescence, was studied by Spielman et al..[118] The T cells of 102 healthy men (18–61 years old) were analyzed for senescent phenotype markers (KLRG1 and CD57) naive phenotype markers (CD28 and CD45RA), and a memory phenotype marker (CD45RO) expressed on the surface of CD4+ T cells and CD8+ T cells. Increase in age was found to be positively associated with an increase in the proportion of CD4+ and CD8+ senescent T cells (CD4+KLRG1+CD57+ and CD8+KLRG1+CD28) and negatively associated with naive cells (KLRG1/CD28+). One important measure of physical fitness is the maximal capacity of the body to transport and uptake oxygen during exercise of progressive intensity (maximal oxygen uptake [VO2 max]). VO2 max is assessed by an ergospyrometric test and is currently considered the gold standard of evaluating the maximal capacity of the cardiorespiratory system; indeed, it is the test most often used in athlete evaluation.[119] In Spielman's study, VO2 max was inversely associated with senescent CD4+ and CD8+ T cells.[118] However, age was no longer associated with senescent or naive T cells when adjusted for VO2 max, whereas the inverse associations between VO2 max and T-cell subsets persisted after the adjustment for age. Collectively, these data showed that aerobic fitness is associated with a lower accumulation of senescent T cells, highlighting the beneficial effects of an active lifestyle on the aging of the immune system.

Studies that evaluated the effect of physical activity on telomere length in peripheral blood mononuclear cells of the elderly indicate that the telomere length is preserved in elderly individuals with a history of physical activity, either moderate or vigorous, and that this effect correlated with an improvement in VO2 max.[120,121] The mechanism that would be implicated with regard to this benefit is the increased activity of telomerase in active elderly when compared with sedentary individuals.

Each year, the influenza virus infection is responsible for high morbidity and mortality rates in the elderly population.[122] Although vaccination is the best preventive action, as stated earlier, the capacity to respond to immunizations is compromised in the elderly because of changes related to the humoral arm of the adaptive immune system. Data from two different studies by Kohut et al. suggest that moderate-to-vigorous exercise training in older adults may be associated with a greater mean fold increase in antibody titer in response to influenza immunization.[123,124] More recently, Woods et al. demonstrated increased seroprotection against influenza virus in elderly persons on a 10-month moderate aerobic activity program in comparison with elderly individuals who only participated in flexibility exercises.[125]

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