To evaluate the effect of advanced age on central nervous system noradrenergic activity, cerebrospinal fluid (CSF) and plasma norepinephrine (NE) concentrations were measured concurrently in 14 older [mean, 65 +/- 9 (+/- SD) yr] and 33 younger (25 +/- 2 yr) normal men. CSF NE was significantly higher in older men than in young men [214 +/- 75 (+/- SD) vs. 164 +/- 56 pg/mL (1.26 +/- 0.44 vs. 0.97 +/- 0.33 nmol/L); P less than 0.02] as was plasma NE [282 +/- 103 vs. 211 +/- 63 pg/mL (1.67 +/- 0.61 vs. 1.25 +/- 0.37 nmol/L); P less than 0.02]. Subgroups of young and older men underwent two lumbar punctures, one of which was performed 100 min after the administration of 5 micrograms/kg oral clonidine. The young (n = 7) and older (n = 7) men had similar plasma clonidine levels [1.0 +/- 0.1 vs. 0.8 +/- 0.1 ng/mL (4.35 +/- 0.43 vs. 3.48 +/- 0.78 nmol/L)] and CSF clonidine levels [0.18 +/- 0.02 vs. 0.22 +/- 0.03 ng/mL (0.78 +/- 0.09 vs. 0.96 +/- 0.13 nmol/L)]. The suppression of CSF NE by clonidine was significantly greater (P less than 0.015) in young men [189 +/- 44 to 104 +/- 26 pg/mL (1.12 +/- 0.26 to 0.62 +/- 0.15 nmol/L)] than in older men [190 +/- 49 to 164 +/- 58 pg/mL (1.12 +/- 0.29 to 0.97 +/- 0.34 nmol/L)]. In contrast, the suppression of plasma NE by clonidine did not significantly differ between young [242 +/- 72 to 93 +/- 24 pg/mL (1.43 +/- 0.43 to 0.55 +/- 0.14)] and older men [285 +/- 102 to 167 +/- 84 pg/mL (1.68 +/- 0.60 to 0.99 +/- 0.50 nmol/L)]. These data suggest that decreased sensitivity of alpha 2-adrenergic mechanisms regulating CNS noradrenergic activity may contribute to increased CNS noradrenergic activity with aging.