One primary manner in which GCs modify immune function is via inducing apoptosis of lymphoid cells, primarily CD[4.sup. ]CD[8.sup. ] thymocytes (Ashwell et al. 2000). There are two major apoptotic pathways: activation-induced apoptosis (AIA) and damage-induced apoptosis (DIA). AIA occurs via ligands binding to death-promoting receptors on the cell surface, whereas DIA occurs via damage to the nucleus or mitochondria. AIA results in a down-regulation of the immune response following infection that is necessary to prevent saturation of the system, whereas DIA responds to damaging events such as oxidative stress. DIA is therefore necessary for the removal of damaged immune cells (Kokoszka et al. 2001). Immunosenescence displays a shift to an AIA-dominant pattern of apoptosis, resulting in an aged immune cell phenotype (see Fig. 1) (De Martinis et al. 2007). GCs play a part in the cell aging process by inhibition of the transcription factor nuclear factor kappa B (NF-[kappa]B). NF-[kappa]B acts to inhibit the AIA response that is induced by inflammatory cytokines such as tumor necrosis factor alpha (TNF-[alpha]). GCs, however, inhibit NF-[kappa]B activation via an inhibitor of kappa B kinase, and therefore promote the apoptotic shift.
A second means by which GCs promote immunosenescence is by inducing a shift from a CD[4.sup. ]- to a CD[8.sup. ]-dominant pattern of immunity (Webster et al. 2002; Lancaster et al. 2004). GCs inhibit the production of proinflammatory cytokines interleukin-12 (IL-12), interferon-7 (IFN-[alpha]), and TNF-[alpha] by T-helper type 1 cells (Thl), while promoting production of anti-inflammatory cytokines IL-4 and IL-10 by Th2 cells (Hawkley and Cacioppo 2004; Elenkov 2004; Elenkov and Chrousos 2002). Aging is accompanied by a similar pattern of increased Th2 cytokines versus Thl cytokines, thereby suppressing the cellular immune response. Diminished CD[4.sup. ] support for B cells may therefore be responsible for the age-related decline in antibody production. While humoral immunity (i.e., production of immunoglobulins) may be more important in preventing infections (Gleeson 2000), cell-mediated immunity can be more valuable in clearing infections (Mosmann et al. 1986). Therefore, a depression of cell-mediated immunity may be a major cause for concern for elderly persons who are also being affected by the other previously mentioned immunosenescence-contributing factors.
Immuno-enhancement via DHEA(S)
DHEA and its sulfated form (DHEAS) are the most abundant circulating adrenal steroids in humans (Dillon 2005). These hormones are secreted by the adrenal cortex in response to ACTH. The non-sulfated form is further metabolized into androstenedione, testosterone, and estrogens (Schmidt et al. 2006). DHEA is thought to induce an increase in mitogen-stimulated IL2 production from CD[4.sup. ] cells to counteract the CD[8.sup. ] shift induced by glucocorticoids (Dillon 2005). However, Padgett and Loria (1998) reported that androstenetriol, but not DHEA, showed antiglucocorticoid affects in vitro, so it is possible that it is a metabolite of DHEA, rather than DHEA itself, that is exerting this effect.
A means for buffering chronic stress is necessary for prevention of immune decrements. In terms of psychological stress, social support has long been known to be associated with more efficient immune functioning (Cohen and Wills 1985). Acute stress can also be immuno-enhancing by providing an adaptive response to prepare an individual for immunological challenge by subsequent stress hormone release (Dhabhar and McEwen 1997). A recent review has also thoroughly discussed that acute exercise can improve the efficacy of vaccines (Edwards et al. 2007). It has been demonstrated that DHEAS levels increase following exercise (Filaire and Lac 2000; Riechman et al. 2004), and one recent study reported increased DHEA and cortisol in postmenopausal women following exercise (Kemmler et al. 2003). These data, in conjunction with evidence that increased DHEAS levels improve physical performance while also improving wound-healing and reducing infection rates in the elderly (Emery et al. 2005; Leveille et al. 2000; O'Donnell et al. 2006) indicate that physical exercise can act as an immuno-stimulator. Moderate-intensity exercise also appears to improve resilence to stress-induced cortisol production (Traustadottir et al. 2005) and immunosenescence with age (Kohut and Senchina 2004). Improvements in the DHEA:cortisol ratio may be partially responsible for these improvements. Exercise is therefore highly recommended for the elderly in conjunction with the many other health benefits that may stem from physiological adaptations to exercise.
Since aerobic exercise can significantly impact the functioning of the immune system in persons of advanced age (Traustadottir et al. 2005), it is recommended as a preventative or therapeutic measure. It is currently unclear if significant differences exist between aerobic exercise and resistance training in terms of immuno-modulating capabilities. Given that DHEA has been reported to increase in response to resistance exercise (Riechuran et al. 2004), moderate-intensity resistance exercise may be beneficial to the elderly immune system as well. Although further research is certainly warranted in this area, the known benefits on bone and skeletal muscle also make resistance training an important component of exercise programs for elderly persons.
Conclusions:Although not the sole origin, an increased cortisol:DHEA ratio appears to be a contributing factor to the age-related decline in immune function termed immunosenescence. Although not definitive, it appears likely that a reduction in the CD[4.sup. ]-CD[8.sup. ] ratio of T helper cells that occurs with GC dominance in aging may lead to increased inability to clear infections in the elderly. In addition, GCs inhibit NF-[kappa]B, which contributes to reduced DIA and results in an aged T cell phenotype. Supplementation with DHEA in the elderly may be beneficial to immune function, although in vivo human studies are needed to confirm this. Stress management and acute exercise appear to be the most effective way of improving the cortisol:DHEA ratio and thereby slowing immunosenescence.