Circadian clocks govern calorie restriction–mediated life span extension through BMAL1- and IGF-1-dependent mechanisms

Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock—transcriptional factor BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1)—results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR. The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on an ad libitum (AL) diet but failed to increase life span of Bmal1−/− mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CR vs. AL by 50 to 70% in WT mice at several daily time points tested, while in Bmal1−/− the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, while Bmal1−/− induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression of Bmal1 (...