Inflammation, hormones, and body composition at a crossroad.

Aprogressive decline in muscles and a parallel increase in adipose tissue are generally considered unavoidable consequences of the aging process. Changes in body composition that occur with aging form the basis for the stereotypical image of “skin on bones,” as depicted by Leonardo da Vinci in his self-portrait. Perhaps more importantly, the consequent decline in muscle function challenges our ability to function in the environment, enjoy social interaction, and maintain independence. Accordingly, a number of studies have demonstrated that poor muscle strength in older persons increases the risk of falls and disability (1,2). In the first 30 to 40 years of life, the blueprint inscribed in our genes is the principal determinant of muscle appearance and function. Over subsequent years, both muscle mass and muscle strength tend to decline (3). Studies have shown that the rate of decline varies widely between persons and is influenced by factors that modulate the balance between catabolic and anabolic processes. In extreme situations, such as diseases that cause prolonged hypercatabolic states, severe muscle “wasting” may develop over a short period, contributing to both morbidity and mortality (4). However, a certain degree of progressive muscle “shrinking” also occurs with age, independent of disease, and is possibly attributable to reduced capacity of skeletal muscles to synthesize new proteins (5). This imbalance ultimately leads to reduced muscle mass, protein content, and strength. Epidemiological studies have shown that, independent of other indicators of health status, poor muscle strength is a strong predictor of mortality, although the specific causal pathway that links strength to mortality is still a matter for discussion (6,7). Several lines of evidence suggest that insulin-like growth factor 1 (IGF-1), a hormone that stimulates protein synthesis and promotes the differentiation of satellite cells in muscle tissue, plays an important role in the maintenance of muscle mass and function with aging (8). Interestingly, the circulating and intramuscular concentration of IGF-1 and the responsiveness of muscle to IGF-1 stimulation are reduced in most medical conditions that are characterized by high circulating levels of proinflammatory cytokines and muscle wasting (4,9). Studies conducted in humans provide evidence that proinflammatory cytokines in concentrations that are often found in older persons are detrimental to muscle, and have suggested that part of the detrimental effect is mediated by a direct interference of cytokines with the IGF-1 gene and protein expression and receptor sensitivity in muscles (10,11). Even transient elevations in tumor necrosis factor (TNF) level can inhibit the degree of protein synthesis, both directly and by interfering with the IGF-1 signaling pathway over relatively long periods of time (9). For example, intense exercise causes a contemporaneous elevation in interleukin 6, TNF, and interleukin 1 levels, and a parallel decline in IGF-1 levels (12). In accordance with these findings, high circulating interleukin 6 and low circulating IGF-1 levels have recently been demonstrated to be synergistic risk factors for poor muscle strength (10), poor lower extremity performance, and disability in activities of daily living (13). Additionally, in this issue of the Journal, Roubenoff et al demonstrate that proinflammatory cytokines, IGF-1, and decline in muscle mass are independent risk factors for mortality (14). Using data from the Framingham Heart Study, Roubenoff et al report that, independent of behavioral risk factors and important clinical conditions, elevated cellular production of TNF, high serum interleukin 6 levels, and low IGF-1 levels were independent risk factors for all-cause mortality. Moreover, independent of cytokines and IGF-1, a decline in fat free mass was associated with higher mortality (14). The authors suggest that sarcopenia and high circulating levels of proinflammatory cytokines affect mortality through different pathways. We can certainly agree with their conclusions, since both proinflammatory cytokines and IGF-1 have specific receptors in tissues other than muscle, and both have been implicated in the pathophysiology of diseases, such as atherosclerosis and dementia, which are frequent causes of death in older persons (15). In addition, the findings of Roubenoff et al suggest the need for further studies to examine how the interaction of cytokines and hormones affects the pathogenesis of frailty in older persons (16,17). Data suggest that cytokines affect the production and Am J Med. 2003;115:501–502. From the Longitudinal Studies Section (LF), Clinical Research Branch, and Laboratory of Epidemiology, Demography and Biometry (JMG), National Institute on Aging, Baltimore, Maryland. Requests for reprints should be addressed to Luigi Ferrucci, MD, PhD, Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, National Institutes of Health, Harbor Hospital, 3001 Hanover Street, 5th Floor, Baltimore, Maryland 21225, or ferruccilu@ grc.nia.nih.gov.