Chonnam Med J.  2010 Aug;46(2):67-73. 10.4068/cmj.2010.46.2.67.

Sirt1 as a New Therapeutic Target in Metabolic and Age-Related Diseases

• Lee DH

• KMID: 1730001
• DOI: http://doi.org/10.4068/cmj.2010.46.2.67

Abstract

Sirt1 among the mammalian sirtuins has generated intense scientific interest in recent years, mainly because of its effects on longevity, metabolism, and other aging-related processes. Via nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylation, Sirt1 can regulate important metabolic regulators. Sirt1 is involved in insulin secretion in the pancreas, fatty acid oxidation in liver and skeletal muscle, hepatic gluconeogenesis during fasting, the suppression of fat storage in white adipose tissue, and the enhancement of insulin sensitivity in skeletal muscle. It also communicates with AMP-activated protein kinase (AMPK). Resveratrol, a prototype of Sirt1 activator, can induce similar changes reminiscent of caloric restriction in insulin-resistant obese rodent models, although clinical studies are still limited. Intensive research efforts are now targeting Sirt1 for pharmacologic interventions in aging and age-related metabolic and degenerative disorders.

Keyword

Sirt1; AMP-activated protein kinases; Caloric restriction; Longevity

MeSH Terms

Adipose Tissue, White
Aging
AMP-Activated Protein Kinases
Caloric Restriction
Fasting
Gluconeogenesis
Insulin
Insulin Resistance
Liver
Longevity
Muscle, Skeletal
NAD
Pancreas
Rodentia
Sirtuins
Stilbenes
AMP-Activated Protein Kinases
Insulin
NAD
Sirtuins
Stilbenes

Figure

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  Fig. 1 The enzymatic activities of Sirtuins. Sirtuins have two different NAD+-consuming activities. Sirt1, Sirt2, Sirt3, and Sirt5 act as deacetylase enzymes, using NAD+ to cleave acetyl groups from ε-acetyl lysine residues of target proteins in a reaction that generates NAM and 2'-O-acetyl-ADP-ribose. Sirt4 acts as a mono-ADP-ribosyl transferase, in a reaction where the ADP-ribosyl moiety of NAD+ is transferred to a substrate protein. Sirt6 has both enzymatic activities.

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  Fig. 2 NAD synthesis and salvage pathway. NAD is synthesized from tryptophan via a de novo pathway or in the NAD salvage pathway from its precursors NA, NAM, or NR. NAPT, NA phosphoribosyltransferase; NAMPT, NAM phosphoribosyltransferase; NMNAT, NMN adenylyltransferase; QPRT, quinolinate phosphoribosyltransferase.

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  Fig. 3 The convergent actions of AMPK and Sirt1 on PGC-1α. Pharmacological (AICAR, metformin) and physiological (fasting or exercise) activation of AMPK in muscle increases the NAD+/NADH ratio, leading to the activation of Sirt1. AMPK can phosphorylate PGC-1α directly, priming it for subse-quent deacetylation by Sirt1. The impact of AMPK and Sirt1 on the acetylation status of PGC-1α and other transcriptional regulators, such as the FOXO family of transcription factors, will then modulate mitochondrial function and lipid metabolism.

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  Fig. 4 The chemical structure of trans-resveratrol.

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