Senchina and Kohut among older adults, yet further information is needed with respect to speciﬁc populations (frail elderly, nursing home residents, “overtrained” older adults). Exercise and immune alterations Although there are numerous studies that have evaluated the effects of an acute bout of exercise on immune responses, this section will focus on the effects of exercise training and long-term physical activity in older adults. The response of a given immune parameter to an acute bout of exercise may not be predictive of how the same immune parameter responds to long-term training. Numerous studies have used question- naires to assess the extent of physical activity, or measures of physical ﬁtness in an effort to correlate physical ﬁtness with immune responses. Other studies have employed an exercise intervention, with the assessment of immune func- tion before or after the intervention. The results from both types of studies are discussed. The age-related decline in lymphocyte proliferative response is a well-documented phenomenon. Four studies have compared lymphocyte proliferation in active elderly compared with sedentary elderly, and in three of these stud- ies mitogen (PHA or pokeweed mitogen [PWM]) induced proliferation was greater in active older adults (Nieman et al 1993; Shinkai et al 1995, 1998). The active adults in these studies participated in vigorous activity (running). When inﬂuenza virus was used as the stimulus, the lymphocytes from active older adults proliferated to a greater extent than those from sedentary individuals (Kohut et al 2002). In the study with inﬂuenza virus, both vigorous activity as well as moderate activity (walking) appeared to be beneﬁcial. Natural killer cell activity has been assessed in several studies as well, although not all studies report an age-related decline in NK function. The concentration of CD16+CD56+ NK cells was greater in elderly exercisers as compared with sedentary subjects (Yan et al 2001). Elderly runners tended to have a greater NK cytotoxic function compared with sed- entary subjects in two studies (Nieman et al 1993; Shinkai et al 1998), but no difference was found in a separate study (Shinkai et al 1995). Lymphocyte expression of CD25 (IL-2 receptor) may indicate how well lymphocytes respond to activating sig- nals. CD25 expression has been reported to decline with advancing age, although others have observed an increase speciﬁcally in the CD4+ population (Froelich et al 1988; Dennett et al 2002; Gregg et al 2005). In a comparison of active and inactive women aged 60–98, CD25 expression in response to mitogen activation was greater in the active women (Gueldner et al 1997). Another aging-related change that has been observed in some studies is a shift in the bal- ance of Type 1 and Type 2 cytokines, although the extent to which this occurs in humans is less clear. A comparison of Type 1/Type 2 cytokines in active elderly, sedentary, and young showed that the number of CD8+ cells producing IL-2 was greater in the active elderly than in the sedentary elderly (Ogawa et al 2003). In the same study, IL-2 production by CD4+ cells tended to be higher in the trained elderly, but the difference was not statistically signiﬁcant, likely due to larger variability in response. Antibody titer and response to inﬂuenza vaccine has also been evaluated in several studies. Antibody (immunoglobulin M [IgM] and immunoglobulin G [IgG]) response to inﬂuenza vaccine measured 2 weeks post-immunization was greater in older adults who regularly participated in vigorous activity (intense enough to work up a sweat) than in moderately active or inactive adults (Kohut et al 2002). Similarly, a correlation between physical activity and greater antibody response to the H3N2 component of the inﬂuenza vaccine was found one-week post-immunization (Schuler et al 2003). Another study that included patients with congestive heart failure measured granzyme B levels after immunization and found that higher granzyme B was correlated with performance on the 6 minute walk test (McElhaney et al 2004). Granzyme B levels post-immunization correlate with resistance to inﬂu- enza infection (McElhaney et al 2001). Although the response to influenza vaccination has important clinical implications, inﬂuenza would generally not be considered a novel antigen as older adults are likely to have produced antibody to previous immunization or infections that may demonstrate cross-reactivity with an- tigens contained in the vaccine. It has been suggested that the immune response to novel antigens is compromised with advancing age. A recent study compared the response with a novel antigen (keyhole limpet hemocyanin [KLH]) in physically active and sedentary young and old subjects. As expected, IgM and IgG antibody titers were reduced in older adults compared with young. However at day 21 post- immunization, anti-KLH IgG and IgM was greater in older physically active than in older sedentary subjects. Anti-KLH IgG1 was also greater in the active older subjects, but there was no difference with respect to IgG2 (Smith et al 2004). In summary, cross-sectional comparisons generally show that greater activity in older adults is associated with greater immune responsiveness to immunization. 10 Clinical Interventions in Aging 2007:2(1)