Stress and Exercise: Getting the Balance Right for Aging Immunity

Anna C. Phillips; Victoria E. Burns; Janet M. Lord


Exerc Sport Sci Rev. 2007;35(1):35-39. 

In This Article

Immunity and Stress Hormones in Aging

The immune system can be considered as two distinct, but interconnected, elements-the innate and the adaptive immune systems. The innate response is often referred to as the "first line of defense" against infection because it comprises mechanisms that are the first to react to an infection. The adaptive immune system is slower to respond but has the advantage in that it includes memory of each pathogen encountered and that its response is specific for each pathogen, thus conferring a tailored and long-lasting protection against further infection by the same pathogen. Aging is known to have deleterious effects on both the innate and adaptive immune responses, although the latter is much better characterized.

The innate immune system consists of soluble components, namely, the complement system and cellular elements, including neutrophils that deal with rapidly dividing bacteria, eosinophils that respond to parasitic infections, and macrophages that secrete soluble factors (tumor necrosis factor (TNF) α, interleukin (IL) 1, IL-6) to coordinate and amplify the immune response and also provide immunity to intracellular bacteria.

With aging, innate immune responses decline, although not universally. For example, complement activation seems to be unaffected, but neutrophil bactericidal and phagocytic function is dramatically reduced. The latter is explained, in part, by a reduction in the number of cell surface receptors (CD16) that bind to the antibody coating bacterial pathogens.[4] Macrophage function is also modified, although the literature is rather contradictory, including reports of reduced phagocytosis and superoxide function as seen in neutrophils, but enhanced secretion of IL-6 and IL-8 in response to mitogens and lipopolysaccharide. Natural killer (NK) cells are also affected by aging; although their numbers do not change with age, their cytotoxic capacity is reduced. That these changes affect immunity can be established by longitudinal studies. For example, in a recent study by Ogata and colleagues,[19] NK cell cytotoxic capacity was measured in 188 people older than 65 yr and mortality recorded over a 5-yr period. Low NK cell function was associated with reduced survival in people older than 75 yr, suggesting that age-related changes to NK cell function do affect mortality.

Adaptive immunity is provided by T and B lymphocytes, which develop and mature in the thymus and bone marrow, respectively. T cells can be further classified into CD4-expressing helper cells (which in turn can be split into Th1 and Th2 types), CD8-expressing cytotoxic cells, and CD25-expressing T regulatory cells, which have immune suppressive function. When a naive T cell encounters antigen (presented by specialized cells such as dendritic cells), it will proliferate and differentiate into an effector cell or a memory cell, so that if the pathogen is encountered a second time, a more rapid response can be achieved.

With aging, the thymus atrophies and fewer naive T cells are produced. As the size of the T-cell pool is maintained at a constant level, the proportion of T cells that are memory cells increases. Consequently, as we age, we are less able to deal with new pathogens, as our immune systems have been fashioned to deal with the threats that we encounter on a regular basis throughout life. In addition to changes in the ratio of naive to memory T cells, there is a decrease in the number and proliferative capacity of Th1 cells and an increase in memory Th2 cells; the latter have enhanced production of IL-10, which further suppresses the function of the Th1 cells. The end result is reduced cell-mediated Th1-type immunity. Finally, B cells produce antibody to provide extended protection against infections. With aging, antibody production in response to antigen declines; for example, older people produce a lower antibody titre in response to vaccination than younger individuals, and the antibodies produced are of lower affinity. This is thought to be largely the result of a decline in T cell help for B cells, and a reduced vaccination response has been shown to correlate with a low clonal expansion of CD4 T helper cells in older adults.

Stress, whether physical or psychological, is broadly sensed by two systems within the hypothalamus: the HPA axis and the sympathetic-adrenal-medullary system. Stress induces the release of catecholamines from the adrenal medulla and both cortisol and DHEA from the adrenal cortex. Catecholamines and cortisol can both be immunosuppressive if chronically elevated. In contrast, DHEA is a precursor to sex hormones and is immune enhancing. Our own in vitro studies have shown that cortisol suppresses neutrophil function, and this can be overcome by coincubation with DHEA sulfate.[5]

As adrenocortical hormones are generated in response to stress and modulate immune function in an apposite manner ( Table 2 ), any differential change in their production could therefore affect immunity. In humans, the production of DHEA and its sulfated form, DHEAS, declines with age, a process termed the adrenopause (Figure 1). The synthesis of DHEA is maximal in humans at ages 20-30 yr and declines gradually thereafter, so that by the seventh decade, levels of DHEA can be as low as 10% of that seen in young adulthood.[20] Adrenopause occurs at similar rates in both men and women and is a physiological phenomenon unique to the higher primates. However, although DHEAS levels fall with age, the production of glucocorticoids such as cortisol is remarkably unaltered,[20] resulting in a relative excess of cortisol over DHEAS and an imbalance of immune suppression over immune enhancement.

Changes in DHEAS levels with age.

Dehydroepiandrosterone is a C19 steroid synthesized from cholesterol in the zona reticularis of the adrenal cortex, a process that requires two enzymes-P450scc and P450c17. A significant proportion of DHEA is converted to DHEAS by the hydroxysteroid sulfotransferase SULT2A1, and DHEAS is the major form of this steroid in serum (Figure 2). As levels of both DHEA and DHEAS fall with age, but cortisol levels do not, a loss of P450c17 function with age has been proposed, although levels of SULT2A1 activity may also decline. The reason for this loss is not well established, although numbers of zona reticularis cells containing P450c17 are reduced with age.

Synthesis of DHEA and downstream metabolites.


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