Potential Mechanisms

To-date it remains unclear the mechanisms associated with exercise mediated immune enhancement, but it is likely to be multi-factorial. Exercise and energy balance have direct influences on a number of systems with immunomodulatory properties, including metabolism, inflammation, endocrine, oxidative stress and muscle function [66]. Many of these systems are exclusively associated with adipose tissue and adipose influenced inflammation. Even in the absence of weight changes with exercise training, fitness and metabolism are often improved and go hand in hand with multi-organ functional improvements. Unlike model in vitro experimental designs, it is difficult to untangle these interactions in human research.

Simpson and colleagues have suggested that repeated bouts of acute exercise are sufficient to mobilize cells from the marginal space into the peripheral blood whereby dysfunctional T-cells are selectively removed [65, 70i . Although others have suggested that apoptosis is increased following exercise it remains unclear which cell sub-types are being ‘selectively’ removed [101, 102 i . If exercise does selectively remove dysfunctional T-cells then reconstitution of T-cells with functional perhaps immature or naive T-cells would imply an improved thymic function. Thymic atrophy is a hallmark of ageing and is associated with reduced naive T-cell output [103]. Recently, administration of IL-7 therapy is associated with a temporary increase in thymic mass and production of naive T-cells [103]. Interestingly exercise induces production of IL-7 from the muscle and IL-7 has been observed to increase systemically following exercise, suggesting a possible feedback mechanism [104]. Measures of thymic function in response to exercise are limited with few studies assessing recent thymic emigrants (RTE), which can be assessed by enumerating T cells bearing T-cell receptor excision circles (TREC). Recently it was shown that compared to age- matched controls elite athletes had lower TREC levels [105]. This would imply a negative impact for older exercisers in response to naive T-cell output.

The impact of exercise and physical activity on adaptive immune function in older adults appears less pronounced than effects on the innate arm. Neutrophils and monocytes are relatively short-lived cells and at any given time the peripheral blood contains unknown proportions of cells at the end of their lifespan than at the beginning. It is plausible that exercise also selectively removes more innate cells at the end of their lifespan, improving the balance and function. Neutrophils at the end of their lifespan begin to express markers for homeostatic clearance including CXCR4 and lose markers such as CD62L, and are more susceptible to apoptotic signaling [106]. Acute exercise mobilizes neutrophils into the blood which are more susceptible to apoptosis [18 ] . Additionally, regular exercise training is associated with reduced apoptosis and increased expression of CD62L on neutrophils; suggesting that the balance of ‘old’ to ‘newer’ neutrophils has been changed [18, 21]. Further work needs to be conducted to determine if this is the case and understand the mechanisms. Neutrophils mature in the bone marrow; therefore it is likely that the effects of exercise may be influencing bone marrow biology.

Recently, gene and microRNA analysis has attempted to determine changes in immune cell functional mechanisms responding to acute exercise. Radom-Aizik and colleagues are leading the way with changes in response to exercise in multiple cell types [107-110]. These studies employ analysis of gene changes in response to acute exercise, and although interpretation is difficult due to the compositional changes in immune cells caused by acute exercise the results are fascinating. A short bout of acute exercise was sufficient to alter gene expression profiles of monocytes that were characterized by antiinflammatory and anti-atherogenic alterations. These included downregulation of TNFa, TLR4 and CD36 genes and upregulation of epiregulin (EREG) and CXCR4 genes [107]. These findings were recently strengthened by Abbasi and colleagues who determined gene profiles following high intensity acute exercise [111]. Similarly, 986 NK-cell gene alterations were characterized by increased tumor cytotoxicity such as tumor-cell communications, p53 signaling pathway, tumor cell adherens and focal adhesion genes [108]. Both neutrophils and PBMCs appear to have altered gene expression characterized by increased inflammatory and growth and repair processes [109, 110]. The next step for these studies is to assess the effect of an exercise intervention and determine whether gene expression results in protein translation. Together, these studies suggest that although we may be unable to see phenotype and functional changes of immune cells, the potential is there for them to adapt to exercise training.

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