et al 1992; Utsuyama et al 1992; Miller 1996; Solana and Pawelec 1998; Franceschi et al 2000a; Linton and Thoman 2001). This is largely due to the accumulation of antigen-com- mitted memory T cells and a decrease in naïve T cells capable of responding to new antigens (Hong et al 2004; Naylor et al 2005). Other factors leading to T-cell dysregulation include age-associated changes in surface molecule expression (Schwab et al 1992; Xu et al 1992), alterations in intracellular signaling (Miller et al 1987; Ohkusu et al 1997), increased rates of apoptosis (Gupta 2000; McLeod 2000), and decreased proliferative capacity (Froelich et al 1988; Castle et al 1999). One cell surface molecule of particular interest is CD28, pres- ent on all CD4 T cells and some CD8 cells. CD28 expression may change with aging. CD28 has numerous functions, but is particularly important for the activation of CD8 T cells, as it binds to the co-stimulatory molecules CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells. The proportion of memory cells versus naïve cells in- creases with aging. As an organism ages and encounters pathogens over time, more memory cells are generated; the body has only a limited capacity of cells it can sustain, and immunity favors memory over naïve cells. These al- terations have been linked to immunosenescence (Kudlacek et al 2000; Hong et al 2004). However, one particular pool of memory cells, CD8+ CD25+ T cells, are found in older adults that demonstrate a more potent response to vaccines, and may represent a pool of memory cells with greater diversity (Herndler-Brandstetter et al 2005). The effects of aging on the Th1/Th2 balance in older adults have also received attention. A classic method for exploring changes in the Th1/Th2 balance has been to ob- serve changes in cytokine proﬁles: cytokines representative of a Th1 response include interleukin (IL)-2 and interferon (IFN)-γ, whereas cytokines such as IL-4, IL-6, and IL-10 are more indicative of a Th2 response. Based on recent reports, some researchers suggest that IL-10 is not a Th2 cytokine but should be considered a marker for T-regulatory cell or “suppressor T cell” activity. Rodent studies generally suggest that there is an age-associated shift in cytokine production. Findings from humans are less consistent. Most studies document an age-associated shift towards Th2 cytokine production in humans, for example, upon lipopolysaccharide (LPS), phytohemagluttinin (PHA), or Staphylococcus aureus (bacterium), or virus stimulation (Castle et al 1997; Rink et al 1998). Other investigators report a trend towards in- creased Th1 with aging upon LPS, PHA, PHA + phorbol myristate acetate (PMA), or 1,25-dihydroxyvitamin D3 Immunological outcomes of exercise in older adults stimulation (Fagiolo et al 1993; Riancho et al 1994). These discrepancies may be dependent on experimental factors such as stimulus chosen (Gardner and Murasko 2002). Immunosenescence also impacts B cells. Upon antigen encounter, these cells mature into plasma cells that secrete antigen-speciﬁc antibody. Immunosenescence is associated with decreased B cell numbers and function (eg, declines in both antibody titer and antibody efﬁciency) (Whisler and Newhouse 1985; Zheng et al 1997; Frasca et al 2005). As with T cells, a number of age-associated biological mecha- nisms have been proposed to explain these changes, includ- ing diminished differentiation capacity and alterations in intracellular signaling (Ennist et al 1986; Whisler and Grants 1993). However, current data suggest some of the age-associ- ated changes in B cell function are due not to changes in B cells themselves, but changes in their environment such as incomplete stimulation from other cells or alterations in the cytokine milieu (Spencer and Daynes 1997). With aging, B cell proliferation may be maintained, as when cultured in vitro with Staph protein A (SpA) (Ennist et al 1986), or may decline, as when cultured in vitro with monocytes pulsed with SpA (Whisler and Newhouse 1985). T cells and B cells constitute the two major classes of cells ascribed to adaptive immunity, but several other smaller subpopulations exist that are also impacted by immunosenes- cence. One such class is the natural killer T cells (NKT), a special group of T cells characterized by cell surface expres- sion of the NK receptor. Unlike typical T cells, numbers of NKT cells increase with age (Plackett et al 2004). The expan- sion of the CD28–, NK receptor-expressing T cell subset later in life may be a compensatory mechanism for the depleted and already differentiated T-cell pool (Abedin et al 2005). Another subgroup are the γδ T cells; however, the effects of immunosenescence on this population are less clear, as aging appears to inﬂuence these cells heterogeneously (Colonna- Romano et al 2000; Argentati et al 2002; Colonna-Romano et al 2004). Importantly, γδ T cells also stimulate T cells, and age-associated declines in the number of stimulatory γδ T cells may in turn contribute to loss of T cell function (Re et al 2005). NKT cells bearing the γδ receptor may be impor- tant facilitators of both innate and adaptive immunity in older adults (Mocchegiani and Malavolta 2004). Immunosenescence and innate immunity Innate immunity consists of cells such as dendritic cells (DCs), macrophages, natural killer cells (NKs), and neutrophils, as Clinical Interventions in Aging 2007:2(1) 5