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 impairedCR-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 (by 150%) and its downstream target genes Periods (by 470% for Per1 and by 130% for Per2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.