We investigated age and sex effects and determined whether androgen replacement in elderly individuals (> or = 60 yr) could augment protein synthesis. Thirty young men and 32 young women (18-31 yr) were studied once, whereas 87 elderly men were studied before and after 1 yr of treatment with 5 mg/day testosterone (T), 75 mg/day dehydroepiandrosterone (DHEA), or placebo (P); and 57 elderly women were studied before and after 1 yr of treatment with 50 mg/day DHEA or P. [(15)N]Phenylalanine and [(2)H(4)]tyrosine tracers were infused, with measurements in plasma and vastus lateralis muscle. Whole-body protein synthesis per fat-free mass and muscle protein fractional synthesis rate (FSR) were lower in elderly than in young individuals (P<0.001), not significantly affected by hormone treatments, and higher in women than in men (P<0.0001), with no sex x age interaction. In regression analyses, peak O2 consumption (VO2peak), resting energy expenditure (REE), and sex were independently associated with muscle FSR, as were VO2peak, REE, and interactions of sex with insulin-like growth factor-II and insulin for whole-body protein synthesis. Women maintain higher protein synthesis than men across the lifespan as rates decline in both sexes, and neither full replacement of DHEA (in elderly men and women) nor partial replacement of bioavailable T (in elderly men) is able to amend the age-related declines.