Circadian Clock Control by Polyamine Levels through a Mechanism that Declines with Age

Abstract

Polyamines are essential polycations present in all living cells. Polyamine levels are maintained from the diet and de novo synthesis, and their decline with age is associated with various pathologies. Here we show that polyamine levels oscillate in a daily manner. Both clock- and feeding-dependent mechanisms regulate the daily accumulation of key enzymes in polyamine biosynthesis through rhythmic binding of BMAL1:CLOCK to conserved DNA elements. In turn, polyamines control the circadian period in cultured cells and animals by regulating the interaction between the core clock repressors PER2 and CRY1. Importantly, we found that the decline in polyamine levels with age in mice is associated with a longer circadian period that can be reversed upon polyamine supplementation in the diet. Our findings suggest a crosstalk between circadian clocks and polyamine biosynthesis and open new possibilities for nutritional interventions against the decay in clock's function with age.

Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism

“…In mammals, disruption of circadian rhythms leads to many pathophysiological conditions such as cognitive dysfunction, psychiatric disorders, cancer, obesity, insulin resistance, metabolic syndrome, and inflammation (Albrecht, 2013; Altman et al, 2015; Antunes et al, 2010; Bechtold et al, 2010; Kawachi et al, 1995; Parkes, 2002; Reppert and Weaver, 2002; Sharifian A, 2005). Recent work shows the circadian clock is intimately connected to metabolism and sheds light on metabolic pathways that are potentially under circadian control (Asher and Schibler, 2011; Bass, 2012; Eckel-Mahan and Sassone-Corsi, 2013; Green et al, 2008; Papagiannakopoulos, 2016; Zhang et al, 2014; Zwighaft et al, 2015)…”

Daily Eating Patterns and Their Impact on Health and Disease

“…Polyamines also regulate the activity of core clock proteins by modulating the interaction of PER2 and CRY1 [81]. Nevertheless, their biological levels decrease with age, leading to longer circadian periods [81].…”

“…Polyamines also regulate the activity of core clock proteins by modulating the interaction of PER2 and CRY1 [81]. Nevertheless, their biological levels decrease with age, leading to longer circadian periods [81]. Supplementation with dietary polyamine results in reversal of age-related changes to the circadian period [81].…”

“…Nevertheless, their biological levels decrease with age, leading to longer circadian periods [81]. Supplementation with dietary polyamine results in reversal of age-related changes to the circadian period [81]. These new studies not only suggest that circadian gene expression and, with it, host metabolism can be affected with ingestible supplements, but that other, undiscovered compounds in the diet can potentially have a tremendous influence in the rhythmicity of the circadian clock program.…”

Time is ripe: maturation of metabolomics in chronobiology

“…Recently, metabolomics has yielded more causal links of the circadian clock to targeted metabolite outputs in mice[23,24], and also uncovered unique signaling roles of a specific lipid (PC 18:0/18:1) in regulating diurnal variability in metabolism across tissues[25]. Thus the field currently consists of a collection of untargeted analyses, where larger swaths of metabolites are detected without bias, and targeted analyses, which contain fewer but more confidently identified metabolites.…”