The role of mammalian sirtuins in the regulation of metabolism, aging, and longevity

Abstract

Ever since the discovery of sirtuins a decade ago, interest in this family of NAD-dependent deacetylases has exploded, generating multiple lines of evidence implicating sirtuins as evolutionarily conserved regulators of lifespan. In mammals, it has been established that sirtuins regulate physiological responses to metabolism and stress, two key factors that affect the process of aging. Further investigation into the intimate connection among sirtuins, metabolism, and aging has implicated the activation of SIRT1 as both preventative and therapeutic measures against multiple age-associated disorders including type 2 diabetes and Alzheimer's disease. SIRT1 activation has clear potential to not only prevent age-associated diseases but also to extend healthspan and perhaps lifespan. Sirtuin activating compounds and NAD intermediates are two promising ways to achieve these elusive goals.

Fig. 1

The deacetylation reaction of sirtuins. Upon the binding of both an acetylated lysine substrate and NAD, sirtuins cleave the glycosidic bond separating NAD into its nicotinamide and ribose moieties, producing nicotinamide, 2′-O-acetyl-ADP-ribose, and a deacetylated substrate

Fig. 2

The metabolic regulation of SIRT1 in the liver, skeletal muscle, white adipose tissue (WAT), and hypothalamus. In the liver, SIRT1 regulates gluconeogenesis by deacetylating PGC-1α, TORC2, FOXO1, and STAT3. SIRT1 promotes fatty acid oxidation by deacetylating PGC-1α, promoting an interaction between SIRT1 and PPARα. SIRT1 also regulates cholesterol homeostasis by positively regulating the function of LXRα. In skeletal muscle, SIRT1 enhances mitochondrial fatty acid oxidation by deacetylating PGC-1α and MyoD. SIRT1 also improves insulin sensitivity by inhibiting the transcription of PTP1B. In WAT, SIRT1 enhances fatty acid mobilization by repressing the transcriptional activation of PPARγ by binding to NCoR/SMRT complex. SIRT1 regulates the production/secretion of adiponectin by deacetylating FOXO1, and possibly by inhibiting PPARγ. In pancreatic β-cells, SIRT1 enhances glucose-stimulated insulin secretion and improves glucose tolerance, at least in part, by repressing the expression of UCP-2. In the hypothalamus, SIRT1 in POMC neurons prevents the pathology of diet-induced obesity by reducing sympathetic nerve activity and BAT-like remodeling of perigonadal WAT. SIRT1 also regulates food intake and feeding behavior by decreasing and increasing the protein levels of AgRP and POMC, respectively

Fig. 3

Regulation of SIRT1. SIRT1 activity is regulated by (A) NAD levels, (B) protein–protein interactions and posttranslational modifications, (C) factors that modulate its transcription, and (D) factors that modulate its translation. (A) SIRT1 activity is primarily regulated by NAD levels. NAD levels are regulated by AMPK-mediated up-regulation of NAMPT expression. AMPK can be activated by FGF21 and adiponectin. FGF21 induces LKB1, one of two major AMPK activators, to phosphorylate AMPK. Adiponectin induces calcium influx through its receptor adiponectin receptor 1 (adipoR1) and this calcium activates the other major AMPK kinase, calcium/calmodulin-dependent protein kinase kinase β (CaMKK β). (B) SIRT1 is activated by direct binding of AROS and sumoylation at Lysine734. Conversely, SIRT1 is inhibited by direct binding of DBC1. (C) p53 and HIC1 repress transcription of SIRT1 while C/EBPα and E2F1 enhance it. (D) Binding of HuR to SIRT1 mRNA increases its half-life. In contrast, binding of miR-34a, miR-132, or miR-217 results in translational repression of SIRT1 mRNA

Fig. 4

Pathways of mammalian NAD biosynthesis. Four dietary metabolites can be used to generate NAD: tryptophan (Trp), nicotinamide (NAM), nicotinic acid (NA), and nicotinamide riboside (NR). De novo NAD biosynthesis occurs from Trp via the eight-step Kynurenine pathway. The first and rate-limiting step in this pathway is shared by tryptophan dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO), with TDO acting in the liver and the brain and IDO acting in the immune system. NA generates NAD through the Preiss–Handler pathway (PHP). In this pathway, nicotinic acid phosphoribosyltransferase (NAPRT1) forms nicotinic acid mononucleotide (NaMN), which is converted to NAD by the sequential actions of glutamine-dependent NAD synthetase (NADSYN1) and Nmnat. In the salvage pathway, homodimeric nicotinamide phosphoribosyltransferase (NAMPT) converts NAM to nicotinamide mononucleotide (NMN) and nicotinamide nucleotide adenylyltransferase (Nmnat) converts NMN to NAD. NR generates NAD by way of nicotinamide riboside kinase (Nrk) or purine nucleoside phosphorylase (Pnp) and nicotinamide salvage

Fig. 5

Manipulation of SIRT1 function. Caloric restriction (CR), genetic manipulation, NAD biosynthesis, and sirtuin activating compounds (STACs) increase the dosage/activity of SIRT1, providing beneficial metabolic responses against numerous age-associated physiology and thereby promoting longevity