A possibility of nutriceuticals as an anti-aging intervention: activation of sirtuins by promoting mammalian NAD biosynthesis

Abstract

Aging science has recently drawn much attention, and discussions on the possibility of anti-aging medicine have multiplied. One potential target for the development of anti-aging drugs is the SIR2 (silent information regulator 2) family of NAD-dependent deacetylases/ADP-ribosyltransferases, called "sirtuins." Sirtuins regulate many fundamental biological processes in response to a variety of environmental and nutritional stimuli. In mammals, the mammalian SIR2 ortholog SIRT1 has been most studied, and small molecule SIRT1 activators (STACs), including a plant-derived polyphenolic compound resveratrol, have been developed. On the other hand, sirtuin activity is regulated by NAD biosynthetic pathways, and nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role in the regulation of mammalian sirtuin activity. Recent studies have provided a proof of concept for the idea that nicotinamide mononucleotide (NMN), the NAMPT reaction product, can be used as a nutriceutical to activate SIRT1 activity. Based on these recent findings, the possibility of sirtuin-targeted nutriceutical development will be discussed.

Figure 1

The de novo and salvage NAD biosynthetic pathways in the budding yeast Saccharomyces cerevisiae. Pnc1, Npt1, Nma1 and Nma2, Qns1, and Qpt1 are nicotinamidase, nicotinic acid phosphoribosyltransferase, nicotinic acid mononucleotide adenylyltransferase 1 and 2, NAD synthetase, and quinolinic acid phosphoribosyltransfease, respectively. This pathway is also conserved in C. elegans, Drosophila and other invertebrates. Nic, nicotinamide; NA, nicotinic acid; NaMN, nicotinic acid mononucleotide.

Figure 2

NAD biosynthetic pathways from nicotinamide and nicotinic acid in mammals. The de novo pathway from tryptophan is not shown in this scheme. These pathways, are conserved throughout vertebrates. Nicotinamide is the main precursor for NAD biosynthesis in mammals. NPT, NAMPT, and NMNAT are nicotinic acid phosphoribosyltransferase, nicotinamide phosphoribosyltransferase, and nicotinamide/nicotinic acid mononucleotide adenylyltransferase, respectively. Multiple enzymes break NAD down to nicotinamide and ADP-ribose, but only sirtuins are shown in this scheme. Nic, nicotinamide; NA, nicotinic acid; NaMN, nicotinic acid mononucleotide; NMN, nicotinamide mononucleotide.

Figure 3

Sirtuin-targeted nutriceutical and pharmaceutical anti-aging interventions. Whereas small molecule sirtuin activators (STACs) aim to treat pathological aspects of aging as pharmaceutical drugs, key NAD intermediates, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), can be used to manage physiological aspects of aging and prevent functional declines in particular cell types, including pancreatic β cells and neurons, as nutriceuticals. See text for details.