"Clocks" in the NAD World: NAD as a metabolic oscillator for the regulation of metabolism and aging

Abstract

SIR2 (silent information regulator 2) proteins, now called "sirtuins," are an evolutionarily conserved family of NAD-dependent protein deacetylases/ADP-ribosyltransferases. Sirtuins have recently attracted major attention in the field of aging research, and it has been demonstrated that SIR2 and its orthologs regulate aging and longevity in yeast, worms, and flies. In mammals, the SIR2 ortholog SIRT1 coordinates important metabolic responses to nutritional availability in multiple tissues. Most recently, it has been demonstrated that SIRT1 regulates the amplitude and the duration of circadian gene expression through the interaction and the deacetylation of key circadian clock regulators, such as BMAL1 and PER2. More strikingly, we and others have discovered a novel circadian clock feedback loop in which both the rate-limiting enzyme in mammalian NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and NAD levels display circadian oscillations and modulate CLOCK:BMAL1-mediated circadian transcriptional regulation through SIRT1, demonstrating a new function of NAD as a "metabolic oscillator." These findings reveal a novel system dynamics of a recently proposed systemic regulatory network regulated by NAMPT-mediated NAD biosynthesis and SIRT1, namely, the NAD World. In the light of this concept, a new connection between physiological rhythmicity, metabolism, and aging will be discussed.

Fig. 1

A schematic diagram of the SIRT1-mediated regulation of the CLOCK:BMAL1-dependent circadian transcription. SIRT1 physically interacts with CLOCK, a key clock regulator that heterodimerizes with BMAL1, and deacetylates BMAL1 and histone H3 in a circadian manner at the promoters of circadian clock genes. SIRT1 also interacts with and deacetylates PER2, which heterodimerizes with CRY proteins and inhibits the CLOCK:BMAL1 function, and promotes its degradation. See text for details.

Fig. 2

NAD biosynthesis from nicotinamide in mammals. Nicotinamide (Nic) is the main precursor for mammalian NAD biosynthesis, and nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in this pathway, producing nicotinamide mononucleotide (NMN) from nicotinamide and 5′-phosphoribosyl-1-pyrophosphate (PRPP). Then, nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT) completes the conversion of NMN and ATP to NAD. Other pathways from nicotinic acid, tryptophan, and nicotinamide riboside are not shown. SIRT1 and other sirtuins use NAD for their functions and produce nicotinamide and O-acetyl-ADP-ribose. Other NAD-consuming enzymes are not shown in this figure.

Fig. 3

A novel NAMPT/NAD-driven feedback loop through SIRT1 and CLOCK:BMAL1. Whereas CLOCK:BMAL1-mediated circadian transcription comprises a positive limb of the transcription-translation circadian feedback loop, the complex of PER and CRY proteins inhibits the function of CLOCK:BMAL1, forming the negative limb of this feedback loop. NAMPT/NAD/SIRT1 comprises a novel circadian feedback cycle that mediates rhythmic regulation of many physiological events. In this NAMPT/NAD-driven feedback loop, NAD functions as a “metabolic oscillator.” See text for details.

Fig. 4

A schematic model of the interplay between tissues that provide “the aging clock” function and tissues that are frailty points in the NAD World. This interplay plays a critical role in the maintenance of systemic robustness through the entire body. The NAD World functions to orchestrate physiological responses to nutritional and environmental inputs and connects physiological rhythmicity, metabolism, and aging.