TY - JOUR
T1 - "Clocks" in the NAD World
T2 - NAD as a metabolic oscillator for the regulation of metabolism and aging
AU - Imai, Shin ichiro
N1 - Funding Information:
I apologize to those whose work is not cited due to the focus of this review and space limitations. I thank all members of the Imai lab for their helpful discussions and comments. This work was supported by grants from the National Institute on Aging ( AG024150 ), Ellison Medical Foundation, and Longer Life Foundation to S. I.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
KW - Aging
KW - Aging clock
KW - BMAL1
KW - CLOCK
KW - Circadian rhythm
KW - Metabolic oscillator
KW - Metabolism
KW - NAD
KW - NAD World
KW - NAD biosynthesis
KW - NAMPT
KW - SIRT1
UR - http://www.scopus.com/inward/record.url?scp=77953290430&partnerID=8YFLogxK
U2 - 10.1016/j.bbapap.2009.10.024
DO - 10.1016/j.bbapap.2009.10.024
M3 - Review article
C2 - 19897060
AN - SCOPUS:77953290430
SN - 1570-9639
VL - 1804
SP - 1584
EP - 1590
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
IS - 8
ER -