Age-related loss of muscle protein may involve a decreased response to anabolic factors of muscle protein synthesis through dysregulation of translation factors. To verify this hypothesis, we simultaneously investigated muscle protein synthesis and expression of some factors implicated in insulin signal transduction during hyperinsulinemia and hyperaminoacidemia in 6 young (25+/-1 year; mean+/-sem) and 8 elderly subjects (72+/-2 year). Incorporation of L-[1-13C] leucine in muscle proteins (fractional synthesis rate, FSR) was measured in vastus lateralis, before and during a euglycemic hyperinsulinemic hyperaminoacidemic clamp, together with Western blot analysis of protein kinase B (PKB), mTOR, 4E-BP1, and S6K1 phosphorylation. In basal state, muscle protein FSR was reduced in elderly in comparison with young subjects (0.061+/-0.004% per hour) vs 0.082+/-0.010% per hour, elderly vs. young, P<0.05). During clamp, muscle protein FSR was stimulated in young (0.119+/-0.006% per hour; P<0.05), but this response was significantly lower in elderly subjects (0.084+/-0.005% per hour, P<0.05 vs young subjects). Phosphorylation of PKB, mTOR, and 4E-BP1 were similarly increased by insulin and amino acid in both groups, except for S6K1 phosphorylation, which was not stimulated in elderly subjects. In conclusion, 1) response of muscle protein synthesis to insulin and amino acid is impaired in elderly humans; 2) a defect in S6K1 pathway activation may be responsible for this alteration. This modification is a mechanistic basis of sarcopenia development during aging.