Aging Decreases Oxidative Metabolism and the Release and Synthesis of Acetylcholine

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 ¹⁴CO₂ production decreased with aging from 100% (3 months) to 85% (10 months) or 71% (30 months) whether U^?14C]glucose, 3,4-¹⁴C]glucose, or l-¹⁴C]pyruvate was the substrate. In the aged brain (3 months) the increase in ¹⁴CO₂ 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 ¹⁴CO₂ production. Synthesis of ¹⁴C]ACh from U-¹⁴C]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 Ca²⁺-dependent, K⁺-stimulated release of ¹⁴C]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.