Cytokine-related aging process.

CYTOKINES are soluble peptide messengers that are synthesized by lymphocytes (thus, they were originally called lymphokines), neutrophils, macrophages, and neuronal cells. The first experimental evidence that circulating factors could modulate the immune system was published in 1932 (1). It was not, however, until more than 30 years later that peptide mediators of lymphocyte activity were identified (2). Two years later, Gery and colleagues (3) isolated soluble peptide messengers from macrophages, and the concept of cytokines as ‘‘the great communicators’’ between immune and somatic cells in response to inflammation was born. Today, it is recognized that cytokines can be both proinflammatory and antiinflammatory and have a wide range of effects on organ systems throughout the body (Figure 1). Originally, each cytokine was named after the function it was recognized to perform. However, it soon was realized that cytokines produced multiple functions, and, thus, in 1979, a consensus committee decided to rename the cytokines ‘‘interleukins’’ followed by a number (4). Nonetheless, some cytokines have retained other names, for example, tumor necrosis factors (TNFs) (originally cachectins), interferons, and, most recently, the adipocyteproduced cytokines, or adipocytokines, such as adiponectin and leptin. Recently, there has been an increasing awareness that the cytokine response to nonspecific inflammation may be a component of the pathophysiology of frailty, functional decline, and death in older persons (5,6). Some cytokines, such as interleukin-10 (IL-10), are antiinflammatory and oppose the actions of the proinflammatory cytokines. Westendorp has suggested that the balance between proinflammatory and antiinflammatory cytokines favors either a long life or reproductive success (7). Thus, persons with high levels of tumor necrosis factor alpha (TNFa) and low levels of IL-10 will have few children but live a long time. This is the modern version of Thomas Kirkwood’s ‘‘disposable soma’’ theory, which stated that investment in maintenance and repair comes at the expense of investment in reproduction. Tissue destruction or infection leads to a nonspecific acute-phase response. Markers of this nonspecific response are C-reactive protein (CRP) and serum amyloid protein, which increase rapidly (within 6 hours and peak within 48 hours) following an acute-phase stimulus. CRP derived its name from its ability to precipitate the C-polysaccharide of streptococcus pneumoniae (8). Both CRP and serum amyloid protein are members of the pentraxin family (Gk. penta5 five; ragos5 berries). When CRP binds to damaged cell membranes or lipids, it activates the classical complement pathway through C1q. CRP is increased after acute and chronic infection, in arthritic and other inflammatory disorders, tissue necrosis, neoplasia, cardiovascular disease, insulin resistance syndromes, obesity, smoking, stress, atrial fibrillation, oral estrogen intake, smoking, and coffee consumption (9). Liver disease, weight loss, exercise, moderate alcohol intake, and hepatic hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase inhibitors are associated with lower CRP levels. Autoimmune diseases, such as systemic lupus erythematosus, fail to produce a CRP response. Thus, while CRP is a sensitive marker of disease processes, it is notoriously nonspecific. In older persons, CRP has been shown to be a marker of functional decline and mortality (10–13). Because of the nonspecificity of CRP, there has been a search for more specific markers that could explain the pathophysiology of functional deterioration with aging, sarcopenia, and the anorexia of aging (6,14–21). Interleukin-6 (IL-6) was one of the first cytokines to be linked to the aging process, and has been termed the ‘‘geriatric cytokine’’ (22). IL-6 is released from macrophages and T lymphocytes. Both TNFa and interleukin-1 beta (IL-1b) are potent releasers of IL-6. IL-6, on the other hand, once released, feeds back to down-regulate the release of TNFa and IL-1b giving it an antiinflammatory, as well as a proinflammatory role. Increased IL-6 leads to loss of muscle and bone mass, fever, activation of the hypothalamic-pituitary-adrenal axis, activation of the hepatic acute phase response, and hemodilution, resulting in a decline in hemoglobin levels (23–26). In bone, IL-6 is produced by osteoblasts and promotes osteoclast activity and subsequent bone resorption (27). Testosterone, which declines with aging in men (28,29), suppresses IL-6 production from bone (30). Parathyroid hormone levels, which increase with the age-associated decline in vitamin D (31), increase the production of IL-6 from osteoblasts (32). Parathyroid hormone also results in hepatic production of IL-6 and its soluble receptor (33). In older persons, elevated IL-6 levels have been shown cross-sectionally to be inversely associated with muscle mass and strength, physical performance, balance, and walking speed, and positively associated with death (13,35–37). Ferrucci and colleagues (38) reported in a cross-sectional study that elevated IL-6 levels predicted