SIRT在代谢调节中的作用.doc

Sirtuins as regulators of age-related disease and metabolism Introduction Since the discovery of the yeast sirtuin silence information regulator 2 (Sir2) being able to extends yeast lifespan, Sirtuins have received significant attention and was originally described as a regulator of transcriptional silengcing of mating-type loci, telomeres and ribosomal DNA[1,2]. In mammals, the sirtuin family which involves 7 proteins (SIRT1-SIRT7) can be divided into 4 classes, and vary in tissue specificity, subcellular localization, enzymatic activity and targets (TABLE 1). Studies have proved the key roles of sirtuins in caloric restriction, age-related disease and metabolic homeostasis. Some other researches also discovered that the activation of sirtuins can relief disease relating to metabolism or neurodenegeration, such as type 2 diabetes and Parkinson’s disease. As a consequence, regulation of sirtuins can be a potential method for age-related disease or metabolic disorder. In this article, I present my current knowledge about the regulation of sirtuins, namely SIRT1, SIRT5 and SIRT7 in age-related disease and metabolic homeostasis. NAD+ as a rate-limiting substrate for sirtuin deacylases The deacetylase activity of the sirtuin proteins requires NAD+ as a substrate, the density of which is determined by the nutritional state of the cell[3]. Therefor, NAD+ has a powerful metabolic impact by modulating the activity of sirtuins and their downstream effectors. It is well known that nicotinamide mononucleotide (NM) and nicotinamide riboside (NR) are NAD+ precursors, and DNA repair proteins, poly(ADP-ribose) polymerase proteins (PARP) - with PARP1 and PARP2 representing the main PARP activities in mammals are NAD+-consuming proteins[4]. Both activation of NM/NR and inactivation of PARP increased tissue NAD+ levels and activated mitochondrial metabolism[5-7]. In the research of Laurent Mouchiroud, et al.[8], they show that NAD+ is causally reduced in aging, and PARP inhibitors or