Circadian Clocks and Metabolism: Implications for Microbiome and Aging

Abstract

The circadian clock directs many aspects of metabolism, to separate in time opposing metabolic pathways and optimize metabolic efficiency. The master circadian clock of the suprachiasmatic nucleus synchronizes to light, while environmental cues such as temperature and feeding, out of phase with the light schedule, may synchronize peripheral clocks. This misalignment of central and peripheral clocks may be involved in the development of disease and the acceleration of aging, possibly in a gender-specific manner. Here we discuss the interplay between the circadian clock and metabolism, the importance of the microbiome, and how they relate to aging.

Keywords: aging; circadian clock; gender specificity; metabolism; microbiome.

Figure 1

The mammalian circadian clock. Photosensitive melanopsin ganglion cells within the retina relay light information to the neurons of the suprachiasmatic nucleus (SCN). The neurons of the SCN fire with a rhythm of approximately 24 hours that is driven by autoregulatory transcriptional and translational feedback loops known as circadian clock. Circadian clocks exist in most cells and consist of transcriptional activators Brain Muscle Arnt-Like Protein 1 (BMAL1) and Clock Locomotor Output Kaput (CLOCK) that drive the expression of genes during the daytime. Among those genes are Period (Per) and Cryptochrome (Cry) that encode repressors of BMAL1 and CLOCK and Rors, Rev-erbs. PER and CRY form complexes with casein kinase 1 ε/δ (CK1ε/δ) that translocate to the nucleus during early night and repress the transcriptional activity of BMAL1 and CLOCK. Degradation of PER and CRY ends the repression on BMAL1 and CLOCK and allows the initiation of a new transcriptional cycle. Postranslational modifications of PER and CRY delay the transcriptional translational loop to a period of approximately 24 hours. The nuclear receptors RAR-related orphan receptor (ROR) (α, β, γ) and REV-ERB (α, β) translocate to the nucleus to activate and repress the expression of Bmal1. The circadian clocks of the SCN synchronize the clocks of the rest of the body to the same phase to generate 24 hour rhythms of physiology and behavior. Environmental cues such as feeding synchronize peripheral clocks but not the SCN clocks to the time of feeding.

Figure 2

Interplay between the circadian clock and cellular energy state. The circadian clock imposes rhythms of nicotinamide phosphoribosyltransferase (NAMPT) that catalyzes the synthesis of NAD⁺ from the conversion of nicotinamide (NAM) to nicotinamide mononucleotide (NMN). The rhythmic synthesis of NAD⁺ drives rhythms in the activity of the NAD⁺-dependent deacetylases sirtuins (SIRTs). SIRT3 generates rhythms of mitochondrial oxidative phosphorylation by rhythmic acetylation of mitochondrial proteins. Rhythmic ATP production imposes a rhythm in the phosphorylation of casein kinase 1 ε/δ (CK1ε/δ) and Cryptochrome (CRY) by adenosine monophosphate-activated protein kinase (AMPK). SIRT1 binds BMAL1:CLOCK in a rhythmic manner and promotes the deacetylation of clock proteins.

Figure 3

Circadian clock and the enteral microbiome. The circadian clock imposes a rhythm in the abundance of enteral microbiota mainly through feeding rhythms. In turn rhythms in the composition and localization of the enteral microbiota generate rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites. This rhythmic exposure modulates circadian gene expression in enteral epithelium and remote tissues such as the liver.