Feeding behavior, metabolism and circadian clocks are interlinked. Calorie restriction (CR) is a feeding paradigm known to extend longevity. We found that CR significantly affected the rhythms in the expression of circadian clock genes in mice on the mRNA and protein levels, suggesting that CR reprograms the clocks both transcriptionally and post-transcriptionally. The effect of CR on gene expression was distinct from the effects of time-restricted feeding or fasting. Furthermore, CR affected the circadian output through up- or down-regulation of the expression of several clock-controlled transcriptional factors and the longevity candidate genes. CR-dependent effects on some clock gene expression were impaired in the liver of mice deficient for BMAL1, suggesting importance of this transcriptional factor for the transcriptional reprogramming of the clock, however, BMAL1- independent mechanisms also exist. We propose that CR recruits biological clocks as a natural mechanism of metabolic optimization under conditions of limited energy resources.

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 2/2 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 2/2 the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, while Bmal1 2/2 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.-Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N., Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1-and IGF-1-dependent mechanisms. FASEB J. 30, 1634-1642 (2016). www.fasebj.orgCalorie restriction (CR) is a robust intervention that increases longevity across different species, including mammals (1-4). The precise molecular mechanisms of CR are unknown, and multiple theories have been put forward to explain CR-mediated effects on life span and health. Several physiologic systems-such as the mammalian target of rapamycin (mTOR) signaling pathway, the insulin/IGF-1 signaling pathways, and the sirtuin-controlled pathway-are affected by CR in animals and are considered to be potential mediators of CR (5-7). Activation of the NADdependent protein deacetylase sirtuin (silent mating type information regulation 2 homolog) 1 (SIRT1) is necessary for the full benefits of CR (8-11). Indeed, several behavioral and physiologic changes induced by CR in wild-type (WT) mice are impaired in SIRT1-null mice: these animals do not demonstrate an increase in daily activity (12). CR has different effects on several metabolic parameters in WT and SIRT1-null mice (13,14). Finally, there is no increase in the life span of SIRT1-null mice on CR (14).SIRT1 regulates the activity of many transcription factors. The helix-loop-helix transcription factor BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1) is one of the direct targets of SIRT1 (15). BMAL1 is a component of the circadian clock mechanism (16). The circadian clock is an internal timekeeping system that generates daily rhythms in physiology, metabolism, and behavior (17)(18)(19)(20). BMAL1 also has other physiologic functions, such as control of metabolism, g...

Here we review, with an emphasis on transcriptional control, the circadian-clock-dependent control of oxidative stress response system as a potential mechanism in age-associated diseases. We will discuss the roles of the core clock components such as brain and muscle ARNT-like 1, Circadian Locomotor Output Cycles Kaput, the circadian-clock-controlled transcriptional factors such as nuclear factor erythroid-2-related factor, and peroxisome proliferator-activated receptor and circadian clock control chromatin modifying enzymes from sirtuin family in the regulation of cellular and organism antioxidant defense.

The circadian clock regulates IGF-1 production and signaling through proteins called cryptochromes, which regulate the activity of transcriptional factor STAT5B and control mouse body and organ size.

The mTOR signaling pathway modulates metabolic processes with respect to nutrient availability and other growth-related cues. According to the existing paradigm, mTOR complex 1 (mTORC1) activity in vivo is induced by food and gradually decreases during fasting. We found that mTORC1 activity is controlled by an internal clock mechanism different from the known light-entrainable circadian clock. We observed 24-hr rhythms in phosphorylation of mTORC1 downstream targets, which were entrained by food, persisted during fasting and could be uncoupled from oscillating expression of the canonical circadian clock genes. Furthermore, these rhythms were present in tissues of mice with disrupted light-entrainable circadian clock. We propose tissue-specific rhythms in the expression of tor and its negative regulator deptor as the molecular mechanism of the mTORC1 activity oscillation. Our data demonstrate the existence of at least two independent molecular circadian clocks: one providing metabolic adaptation to periodic light/darkness and the other - to feeding.