The NAD World: a new systemic regulatory network for metabolism and aging--Sirt1, systemic NAD biosynthesis, and their importance

Abstract

For the past several years, it has been demonstrated that the NAD-dependent protein deacetylase Sirt1 and nicotinamide phosphoribosyltransferase (Nampt)-mediated systemic NAD biosynthesis together play a critical role in the regulation of metabolism and possibly aging in mammals. Based on our recent studies on these two critical components, we have developed a hypothesis of a novel systemic regulatory network, named "NAD World", for mammalian aging. Conceptually, in the NAD World, systemic NAD biosynthesis mediated by intra- and extracellular Nampt functions as a driver that keeps up the pace of metabolism in multiple tissues/organs, and the NAD-dependent deacetylase Sirt1 serves as a universal mediator that executes metabolic effects in a tissue-dependent manner in response to changes in systemic NAD biosynthesis. This new concept of the NAD World provides important insights into a systemic regulatory mechanism that fundamentally connects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of metabolic robustness and aging in mammals.

Figure 1

Mammalian Sirt1 as a key mediator that coordinates metabolic responses to nutritional availability in various tissues and organs. Sirt1 regulates the activity of key metabolic transcription factors, such as PGC-1α, LXRα, PPARγ, and FOXO1, and the expression of important effecter genes, such as PTP1B and Ucp2, and mediates diverse metabolic responses in organ/tissue-dependent manners.

Figure 2

Major NAD biosynthetic pathways in lower eukaryotes and invertebrates vs. mammals and the enzymatic reaction of nicotinamide phosphoribosyltransferase (Nampt). (A) The NAD biosynthetic pathway in the budding yeast Saccharomyces cerevisiae and invertebrates, such as C. elegans and Drosophila. The de novo pathway from tryptophan is not shown in this scheme. Pnc1, nicotinamidase; Npt1, nicotinic acid phosphoribosyltransferase; Nma1 and Nma2, nicotinic acid mononucleotide adenylyltransferase 1 and 2; Qns1, NAD synthetase; Sir2, silencing information regulator 2; Nic, nicotinamide; Na, nicotinic acid; NaMN, nicotinic acid mononucleotide. (B) The NAD biosynthetic pathway from nicotinamide in mammals. The pathways from tryptophan and nicotinic acid are not shown in this scheme. Sirt1 and other mammalian sirtuins are representative enzymes that catalyze NAD for their enzymatic activities. Nampt, nicotinamide phosphoribosyltransferase; Nmnat, nicotinamide mononucleotide adenylyltransferase; NMN, nicotinamide mononucleotide. (C) The reaction catalyzed by Nampt. PRPP, 5-phosphoribosyl 1-pyrophosphate; PPi, inorganic pyrophosphate.

Figure 3

Systemic NAD biosynthesis mediated by intra- and extracellular Nampt. See texts for details. NMN, nicotinamide mononucleotide; iNampt and eNampt, intra- and extracellular nicotinamide phosphoribosyltransferase; Nmnat, nicotinamide/nicotinic acid mononucleotide adenylyltransferase.

Figure 4

A conceptual scheme of the NAD World. The NAD World is a novel systemic regulatory network for metabolism and aging that is comprised of two critical components: Nampt-mediated systemic NAD biosynthesis (see Figure 3) as a driver that keeps up the pace of metabolism in tissues/organs and the NAD-dependent deacetylase Sirt1 (see Figure 1) as a universal mediator that executes metabolic effects in various tissues in response to changes in systemic NAD biosynthesis. See texts for details.

Figure 5

A model of mammalian aging as the process of robustness breakdown triggered by a decline in systemic NAD biosynthesis. Pancreatic β cells and neurons are likely the most critical frailty points in the NAD World due to their very low levels of iNampt and systemic impacts on many other tissues/organs. When systemic NAD biosynthesis levels decline and reach frailty thresholds for pancreatic β cells and neurons, these two cell types start having functional problems, which eventually spread to other peripheral tissues/organs through insulin secretion and central metabolic regulation. This cascade of robustness breakdown might be the central process of aging that causes a variety of age-associated diseases, including impaired glucose tolerance (IGT), type 2 diabetes, dementia, and many others. See texts for details.