Aging is associated with decreased skeletal muscle mass and function. These changes are thought to derive, in part, from alterations in the biochemical processes that regulate skeletal muscle protein balance; specifically, a reduction in skeletal muscle protein synthesis. Although some studies have shown reduced postabsorptive muscle protein synthesis with age in humans, recent studies have failed to find an age effect. In addition, few studies have attempted to characterize the hormonal factors which may contribute to age-related changes in muscle protein synthesis. Thus, we examined the effect of age on skeletal muscle protein metabolism, with a specific emphasis on myosin heavy chain (MHC) protein, and the relationship of muscle protein synthesis rates to plasma hormone levels. We measured body composition, muscle performance, muscle protein metabolism using ¹³C-leucine, MHC and actin protein content, MHC isoform distribution and plasma concentrations of cytokines and insulin-like growth factor-1 (IGF-1) in 7 young (mean ± SE; 29 ± 2) and 15 old (72 ± 1 yr; P<0.01) volunteers. Old volunteers were characterized by reduced skeletal muscle mass, strength and aerobic capacity. Mixed muscle (-19%; P=0.11), MHC (-22%; P=0.08), and non-myofibrillar (-17%; P=0.10) protein synthesis all tended to be lower in old compared to young volunteers. Old volunteers were characterized by increased circulating concentration of tumor necrosis factor- receptor II (P<0.05) and reduced IGF-1 (P<0.01). In addition, plasma C-reactive protein, interleukin-6 and tumor necrosis factor- receptor II concentrations were negatively related to mixed muscle and MHC protein synthesis rates (range of r-values: -0.422 to -0.606; P<0.05 to <0.01). No differences in MHC or actin protein content were found. Old volunteers showed reduced (P<0.05) MHC IIx content compared to young volunteers, but no differences in MHC I or IIa content. Our data show strong trends toward reduced postabsorptive skeletal muscle protein synthesis with age. Moreover, reduced muscle protein synthesis rates were related to increased circulating concentrations of several markers of immune activation.