The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing

Abstract

Ageing is associated with a variety of pathophysiological changes, including development of insulin resistance, progressive decline in β-cell function and chronic inflammation, all of which affect metabolic homeostasis in response to nutritional and environmental stimuli. SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD biosynthetic enzyme, together comprise a novel systemic regulatory network, named the 'NAD World', that orchestrates physiological responses to internal and external perturbations and maintains the robustness of the physiological system in mammals. In the past decade, an accumulating body of evidence has demonstrated that SIRT1 and NAMPT, two essential components in the NAD World, play a critical role in regulating insulin sensitivity and insulin secretion throughout the body. In this article, we will summarize the physiological significance of SIRT1 and NAMPT-mediated NAD biosynthesis in metabolic regulation and discuss the ideas of functional hierarchy and frailty in determining the robustness of the system. We will also discuss the potential of key NAD intermediates as effective nutriceuticals for the prevention and the treatment of age-associated metabolic complications, such as type 2 diabetes.

Keywords: NAD; NAD World; NAMPT; SIRT1; inflammation; insulin secretion; insulin sensitivity.

Figure 1. The function of SIRT1 as a key mediator that coordinates metabolic responses to nutritional and environmental cues and maintains physiological robustness in mammals

Major roles of SIRT1 in the liver, adipose tissue, skeletal muscle, pancreatic β cells, and the brain are summarized in this scheme. Through these functions illustrated here, SIRT1 regulates the balance between insulin sensitivity and insulin secretion throughout the body and provides protection against nutritional and environmental perturbations, such as high-fat diet (HFD) and chronic inflammation. More details are given in the text.

Figure 2. NAMPT-mediated NAD biosynthetic pathways in mammals

In mammals, nicotinamide (NIC) is converted to nicotinamide mononucleotide (NMN) by the rate-limiting enzyme, nicotinamide phosphoribosyltranferase (NAMPT). There are two forms of NAMPT: intracellular and extracellular NAMPT (iNampt and eNampt, respectively). eNAMPT has significantly higher enzymatic activity than iNAMPT and likely synthesizes NMN in blood circulation. Extracellular NMN might be directly transferred into tissues/cells or is first converted to nicotinamide riboside (NR) and then transferred into tissues/cells. NR is re-converted to NMN by nioctinamide riboside kinase and utilized for NAD biosynthesis. NAD is generated from NMN by nicotinamide/nicotinic acid mononucleotide adenylyltransferase (NMNAT) and consumed by sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38.

Figure 3. The concept of the NAD World and the possible effect of chronic inflammation

Pancreatic β-cells and neurons (the brain) are two major frailty points in the NAD World because these two cell types have very low levels of iNAMPT. These particular cell types likely depend on extracellular NMN, which is speculated to be synthesized by eNAMPT secreted by adipose tissue, and maintain optimal NAD levels for their functions. Chronic inflammation, which is caused by inflammatory cytokines and oxidative stress, decreases NAMPT and NAD levels in multiple tissues, contributing to the pathogenesis of age-associated metabolic complications, such as type 2 diabetes. It still remains unclear whether chronic inflammation in adipose tissue also decreases plasma eNAMPT levels and remotely affects the functions of “frailty” cell types. More details for the concept of the NAD World are given in the text.

Figure 4. Therapeutic potential of key NAD intermediates against age-associated diseases

Supplementation of key NAD intermediates, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), improves insulin secretion, insulin action, energy expenditure, and cognitive function and prevents inflammatory reactions in mice. These NAD intermediates are expected to be translatable as effective anti-aging nutriceuticals into humans in the near future.