Senchina and Kohut found to a greater extent in frail subjects (Leng et al 2004). Although preliminary data from our laboratory suggests that exercise training in healthy older adults may favorably alter the percentages of T cells expressing CD28 (Senchina et al 2006), the one study involving frail subjects failed to improve CD28 expression (Kapasi et al 2003). This limited data suggests that an intervention may be necessary before frailty has occurred. Inﬂammatory mediators, particularly elevated serum levels of IL-6 have been associated with frailty and mortal- ity in numerous studies. A growing body of literature has demonstrated that elevated proinﬂammatory cytokines are not only associated with numerous chronic diseases, but are also found to some extent with advancing age. Different proinﬂammatory mediators have been evaluated, but most of the published studies in older adults have focused on IL-6. Elevated levels of IL-6 have been shown to increase the risk of mortality, with the relative risk ranging from just over 1.0 to >4 fold depending on the study (Volpato et al 2001; Bruunsgaard et al 2003; Cohen et al 2003). In men, elevated TNF-α, another proinﬂammatory cytokine, was also associated with increased risk of mortality (Bruunsgaard et al 2003). Elevated levels of IL-6 as well as other inﬂammatory mediators also predicted functional disability (Cohen et al 1997; Reuben et al 2002). Multiple inﬂammatory markers (IL-6, TNF-α, C-reactive protein [CRP]) predicted mobil- ity limitations, speciﬁcally the inability to climb 20 steps or walk one-quarter mile (Penninx et al 2004), and women with elevated IL-6 demonstrated declines in walking speed over time and disability in activities of daily living (Ferrucci et al 2002). The declines in functional ability are associated with frailty, and frailty itself is associated with greater risk of insti- tutionalization and mortality (Rockwood et al 2004). Clearly, if exercise shows some beneﬁt with respect to reducing the levels of inﬂammatory mediators, a reduction in mortality risk as well as functional decline would be expected. Evidence from several epidemiological studies in older adults have shown that greater levels of physical activity or ﬁtness in terms of walking speed were associated with lower serum levels of several inﬂammatory markers includ- ing IL-6, TNF-α, and CRP (Taaffe et al 2000; Geffken et al 2001; Colbert et al 2004). In addition, greater knee exten- sor and grip strength as well as larger muscle mass were associated with lower proinﬂammatory cytokines (Visser et al 2002). It was also recently shown that active older adults demonstrated reduced serum CRP as well as a decrease in LPS-stimulated IL-6, IL-1β, TNF-α, and Toll-like receptor 4 (TLR-4), as compared with inactive older adults (McFarlin et al 2006). These studies suggest that exercise may reduce serum inﬂammatory markers and this possibility is supported by several exercise intervention trials. For example, studies in middle-aged adults reported that exercise and diet interven- tions resulting in weight loss reduced serum CRP, IL-6 and IL-18, whereas exercise training alone reduced serum CRP, IL-6, and blood mononuclear cell production of TNF-α and IL-1α in patients at risk for heart disease (Smith et al 1999; Esposito et al 2003; Goldhammer et al 2005). The ﬁndings from one exercise intervention study with older adult subjects showed no signiﬁcant reduction in serum CRP (Hammett et al 2004). Recently, our laboratory has conducted a longer- term intervention (10 months) in older adults, and compared aerobic exercise with ﬂexibility/balance/resistance exercise training. We observed that aerobic exercise training reduced serum IL-6, CRP, IL-18, and both types of training were associated with reduced TNF-α (Kohut et al 2006). These ﬁndings suggest that the type and intensity of exercise may be important in reducing inﬂammatory markers. Finally, it is important to recognize that although el- evated inﬂammatory markers have been associated with poorer health outcomes, inﬂammation remains an essential component of immune defense. In fact, it has been sug- gested that frailty in old age is the net result of the risk of dying from chronic inﬂammatory disease versus infectious disease (van den Biggelaar et al 2004). A reduction in the ability of LPS-stimulated mononuclear cells to produce inﬂammatory mediators (IL-6, TNF-α, IL-1β) as well as anti-inﬂammatory mediators (IL-1Ra, IL-10) was associ- ated with a greater than 2-fold mortality risk. The authors concluded that a malfunctioning innate immune response including lower production of inﬂammatory cytokines predicts frailty in old age. Other beneﬁts of exercise This review has focused on the immunological outcomes of exercise in older adults; however, the beneﬁts of exercise extend well beyond immunity. These additional beneﬁts encompass both physical and psychosocial realms; for a more thorough treatment, readers should consult (Bean et al 2004). At the physical level, exercise may improve mobility and motor control in older adults (Whitehurst et al 2005), reducing rates of falls or other ambulation-associated injuries (Schoenfelder and Rubenstein 2004). Exercise improves functional outcomes for disease states such as osteoarthritis (Foy et al 2005) and may positively impact on cancer treatment 12 Clinical Interventions in Aging 2007:2(1)