The Increasing Importance of Immune Regulatory Effects by Physical Activity

The aging process in the second half of life is accompanied by a concurrent increased systemic-inflammatory activity, which is why the term inflammaging is frequently used in the scientific literature. Inflammaging implies that with increasing age, the basal activity of the innate and adaptive immune systems is upregulated (8). The accumulation of senescent cells plays an important role, which solidified in a phase of the cell cycle form large quantities of inflammatory cytokines. One speaks here of a cellular switch to a Senescent-Associated Secretory Phenotype (SASP), which is currently in the focus of age-related dysfunctions of organs and thus as the cause of age-attendant diseases (12). Lifestyle-related risk factors or diseases, like adiposity, accelerate and potentiate inflammaging, since metabolism-induced stress signals in adipocytes of the visceral fat tissue also induce inflammatory processes. A metabolism-induced, sterile inflammatory process which has its origin primarily in metabolic cells is called metaflammation (7, 12).

Systemic inflammatory processes are not only closely associated but are in fact part of the aging of the immune system, the immunosenescence. A number of studies in Sweden showed that the development of systemic inflammations is important in the so-called Immune-Risk-Profile (IRP) (15). This describes immunological changes in age, which are related to increased mortality and morbidity. Along with the moderate increase in pro-inflammatory cytokines in the blood, a reduced ratio of CD4+/CD8+ T-cells, an accumulation of T-cells of a senescent phenotype and a reduction of naive T-cells also belong to the IRP (15). The increased accumulation of senescent T-cells has two prominent characteristics. First, they may be cytomegalovirus (CMV)-specific T-cells, if the subject was CMV-positive. This gives a CMV infection a not unimportant role in immunosenescence (13). Second, there is accumulation of so-called TEMRA cells (T effector memory cells re-expressing CD-45RA), which have a high autoreactivity and produce pro-inflammatory cytokines, but at the same time, have a low capacity for proliferation in antigen contact. Thus the accumulation of senescent, highly-differentiated cells, also called exhausted T- cells, appears to favor both the weakening of immune defense in age and inflammaging. Conversely, it is known that a basal elevated TNF-α concentration also induces differentiation and thus the senescence of T-cells, which characterizes the bidirectionality of these processes (8, 12).

A Circulus vitiosus of inflammation and immunosenescence arises which turns out to be of great clinical relevance. In addition to promoting several internal, orthopedic, neurological and emotional diseases, immunosenescence and inflammation affect, for example, the effectiveness of vaccination. It has been known for a long while that the immunization of elderly people after an influenza-vaccination is often considerably lower than that in younger people. The combination of age and underlying inflammatory activity also appears to be important. Data of a relatively recent publication show that prophylactic influenza vaccination in adipose adults has a clearly reduced protective effect compared to the vaccination of normal-weight, age-matched subjects (9). Despite a robust serological response, the adipose study participants were more than double as likely to get influenza. Vaccination attempts in overweight mice confirm these data, since they also showed considerably lower protection against the diseases involved. There is thus a lot indicating a close relationship between systemic inflammation and cellular senescence with the consequence of a reduced immune function (12).

These close bidirectional relationships between subclinical inflammation and cellular immunofunction provide numerous starting points for preventive or therapeutic exercise measures. On the one hand, physical activity has anti-inflammatory, resp. inflammation-regulating effects, which have been shown in the context of many diseases (6). Regular physical activity reduces the systemic concentration of IL-6, TNF-α and numerous other cytokines and chemokines. Mechanistically, the increased expression of various myokines, which are secreted in the contracting muscle, is of primary interest. Especially IL-6 and IL-15 appear to be important here, since they inhibit TNF-α production, promote the release of anti-inflammatory cytokines like IL-1ra and IL-10 and at the same time stimulate lipolysis (3, 11). On the other hand, regular physical activity has diverse influence with respect to T-cells. Regular endurance training in advanced age increases the CD4/CD8- T-Zell ratio and reduces the proportion of senescent T-cells. Moreover, regular training increases the relative proportion of regulatory T-cells (14). The increased mobilization of hematopoietic precurser cells from bone marrow after athletic load may promote an increase in the proportion of naive T-cells (2, 5). On the functional side, regular activity has a positive influence on the proliferation of T-cells after antigen contact. Clinically-relevant interactions between the adaptive immune system and sports activity have been shown with respect to a reduced frequency of infection, as well as an increased efficacy of vaccinations after moderate endurance training (4, 10). Kohut et al. (4) showed that older subjects had a significantly greater increase in the antibody titer after influenza vaccination following a training intervention over 10 months compared to an inactive control group.

Due to a lack of longitudinal intervention studies, what the optimal practical implementation of training adapted to immunoregulatory effect should be cannot yet be clearly defined. The study situation shows at first glance that important immunological effects are associated with a longer training duration, usually more than 6 months. The precise sports modality appears less important here than the selected intensity. It appears recommendable that patients with a low-grade inflammation should select a more moderate intensity and scope than healthy, younger persons. High-grade intensive training sessions combined with a long duration, as well as sudden increases in load appear to miss the target from an immunological point of view, since even healthy athletes train in a temporary immunosuppression under these conditions (14). The concrete choice of the type of sports should take into account the wishes, tendencies and interests of the target person, since this increases the probability of longer-lasting participation (figure 1).

So, physical activity induces immunoregulatory effects at various levels, in which many mechanistic relationships and causal interactions are still unclear. Basic scientific work is needed here to examine the molecular and cellular relationships between sports activities and the various compartments in the immune system. Moreover, there are only a few longitudinal intervention studies which couple immunological changes with clinical effects in order to gain knowledge for prevention and therapy by sports and exercise. It would be helpful to expand the panel of inflammatory biomarkers, like TNF-α or IL-6, with further biomarkers from the large number of pro- and anti-inflammatory plasma markers which may reflect the sports-therapeutic effects more sensitively.