In order to evaluate the potential role of insulin insensitivity as a cause of the glucose (G) intolerance of aging, we performed 230 hyperglycemic clamps, 85 on young (Y, 24 to 39 years), 47 on middle age (M, 40 to 59 years), and 98 on old (O, 60 to 90 years) carefully screened subjects of the Baltimore Longitudinal Study of Aging. The 2-h plasma G levels on an oral glucose tolerance test (OGTT) were < 7.8 mmol/l in Y and M and < 10 mmol/l in old; the latter group was further dichotomized at 7.8 mmol/l into a "normal" group, ON, and an impaired group, OI. Four hyperglycemic plateaus were created: 3.0, 5.4, 7.9, and 12.8 mmol/l above basal. Three measures of glucose tolerance--1) G at 2 h after glucose ingestion, 2) glucose utilization, M, at each hyperglycemic plateau, and 3) glucose decay constant, K, obtained at the conclusion of each clamp--showed the best performance in the young group (Y > M = ON > OI). Despite these differences in glucose tolerance, plasma insulin responses (I) during the clamp were not significantly different except that ON < Y at the basal + 12.8 plateau (300 +/- 42 vs. 456 +/- 48 pmol/l, p < 0.01). Insulin-dependent glucose uptake, a measure of tissue sensitivity to insulin, was decreased in the old-impaired group at every plateau except the highest. We conclude that healthy, active older subjects showed moderate intolerance to oral and IV glucose and that the mechanism of this physiological aging process is most likely decreased insulin sensitivity.