Aging Decreases Oxidative Metabolism and the Release and Synthesis of Acetylcholine

Abstract

Acetylcholine (ACh) synthesis in vivo is known to decrease during the aging process (senescence). To elucidate the molecular mechanism(s) of this age‐related decline, we studied brain slices from 3‐, 10‐, and 30‐month‐old mice of two strains (C57B1 and Balb/c). In low K+ media, oxidative metabolism as measured by 14 CO 2 production decreased with aging from 100% (3 months) to 85% (10 months) or 71% (30 months) whether [U−14 C]glucose, [3,4‐14 C]glucose, or [l‐14 C]pyruvate was the substrate. In the aged brain (3 months) the increase in 14 CO 2 production with K+ stimulation was about twofold higher than in the young brain (3 months). Thus, in high K+ media, only slight decreases (<10%) in oxidative metabolism occurred with aging. Changes in ACh synthesis paralleled the decreases in 14 CO 2 production. Synthesis of [14 C]ACh from [U‐14 C]glucose in low K+ media declined from 100% (3 months) to 85% (10 months) or 66% (30 months), while in high K+ media only slight decreases (<10.5%) occurred with aging. The Ca 2+‐dependent, K+‐stimulated release of [14 C]ACh declined from 100% (3 months) to 58% (10 months) or 25% (30 months). Only the decrease in the release of ACh declined to the same extent as the reduced in vivo synthesis of ACh with aging. The results suggest that decreases in oxidative metabolism, ACh synthesis, and in the release of ACh contribute to a reduction in cholinergic function in the senescent brain.