Figure 5.

The circadian clock machinery regulates the biosynthesis of NAD⁺ through control of the NAD⁺ salvage pathway. BMAL-1:CLOCK heterodimer binds to the promoter region of NAMPT to regulate the rhythmic transcription of this gene and thus the levels of NAD⁺. Expression of SIRT1 silences the expression of NAMPT (the rate-limiting enzyme in NAD⁺ biosynthesis), which leads to a decrease in the concentration of NAD⁺, diminishing the activity of SIRT1. When the activity of SIRT1 decreases significantly, then the activity of CLOCK:BMAL-1 begins to increase, which restores the expression levels of NAMPT and thus completes the cycle. NAMPT: nicotinamide phosphoribosyltransferase; CLOCK: basic helix-loop-helix-PAS transcription factor; BMAL1: Brain and muscle ARNT-like 1 protein; NMN: nicotinamide mononucleotide; NAM: nicotinamide.