OBJECTIVE: Glutamine synthetase (GS), a key enzyme in the production of glutamine, is preserved in skeletal muscle during early aging (<24 mo). Because the effects of advanced age on GS are unknown, we investigated the effect of advanced age (>24 mo) on GS activity in skeletal muscle. We hypothesized that advanced age would enhance muscle GS activity. METHODS: Muscle GS activities were assessed in adult (8 mo), mature adult (15 mo), aged (20-22 mo), advanced age (25-27 mo), or very advanced age (29-32 mo) female Wistar rats. Male Wistar (6-27 mo) were used to investigate the effect of gender on this activity. RESULTS: Glutamine synthetase activity remained low and unaltered in rats from 8 to 22 mo of age, as previously demonstrated. In contrast, GS activity was high ( approximately 75% of individual values were higher than the low value mean) in 25-mo to 27-mo-old rats. In very-old-aged rats (29-32 mo), approximately 55% of GS activity data points exhibited low values. Changes in GS protein content paralleled those in GS activities. In male rats, GS activity was also high ( approximately 80% of individual values were higher than the mean value of 6-mo to 19-mo-old rats) at the upper limit of life expectancy (27 mo). CONCLUSION: There is enhanced GS activity in old female and male rats suggesting a greater need for glutamine. In some very old rats, low GS activity may be associated with longevity or reflect a limitation in glutamine production due to extremely advanced age per se.