Voluntary running and caloric restriction reverse cerebrovascular endothelial dysfunction in old mice by restoring nitric oxide bioavailability

Abstract

We tested the hypothesis that age-associated cerebrovascular endothelial dysfunction can be reversed by exercise- and dietary-related lifestyle interventions. Maximal ex vivo endothelium-dependent dilation (EDD) to acetylcholine (ACh) in isolated middle cerebral arteries (MCA) was impaired in old (O, 29–31 mo, n=12) vs. young (Y, 6–8 mo, n=12) cage-control (C) B6D2F1 mice (30±7 vs. 73±7%, P<0.01). Inhibition of nitric oxide (NO) using L-NAME resulted in 73% (YC) and 12% (OC) reductions in EDD (P<0.05), abolishing age group differences. Voluntary wheel running (VR, 9–11 weeks: YVR, n=9, 10.1±0.8 km/day; OVR, n=5, 2.4±0.8) had no effect on EDD in Y mice (66±8%), but restored EDD in O mice to levels (63±9%) not different from YC. The improvement in EDD in OVR was mediated by enhanced NO bioavailability. In a separate group of O mice (n=7), lifelong caloric restriction (40% < ad libitum) improved (P<0.05) MCA EDD (to 52±8%) and increased sensitivity to ACh (IC50) and NO bioavailability. MCA endothelium-independent dilation to sodium nitroprusside was not influenced by age or interventions. VR and caloric restriction improve MCA EDD in O mice by increasing NO bioavailability. This preclinical evidence supports the efficacy of voluntary aerobic exercise and reductions in energy intake for treatment of cerebrovascular dysfunction and its clinical sequelae with aging in humans. NIH AG013038, AG029337, AG033196