Nicotinamide, Nicotinamide Riboside and Nicotinic Acid-Emerging Roles in Replicative and Chronological Aging in Yeast

Abstract

Nicotinamide, nicotinic acid and nicotinamide riboside are vitamin B3 precursors of NAD⁺ in the human diet. NAD⁺ has a fundamental importance for cellular biology, that derives from its essential role as a cofactor of various metabolic redox reactions, as well as an obligate co-substrate for NAD⁺-consuming enzymes which are involved in many fundamental cellular processes including aging/longevity. During aging, a systemic decrease in NAD⁺ levels takes place, exposing the organism to the risk of a progressive inefficiency of those processes in which NAD⁺ is required and, consequently, contributing to the age-associated physiological/functional decline. In this context, dietary supplementation with NAD⁺ precursors is considered a promising strategy to prevent NAD⁺ decrease and attenuate in such a way several metabolic defects common to the aging process. The metabolism of NAD⁺ precursors and its impact on cell longevity have benefited greatly from studies performed in the yeast Saccharomyces cerevisiae, which is one of the most established model systems used to study the aging processes of both proliferating (replicative aging) and non-proliferating cells (chronological aging). In this review we summarize important aspects of the role played by nicotinamide, nicotinic acid and nicotinamide riboside in NAD⁺ metabolism and how each of these NAD⁺ precursors contribute to the different aspects that influence both replicative and chronological aging. Taken as a whole, the findings provided by the studies carried out in S. cerevisiae are informative for the understanding of the complex dynamic flexibility of NAD⁺ metabolism, which is essential for the maintenance of cellular fitness and for the development of dietary supplements based on NAD⁺ precursors.

Keywords: NAD+ metabolism; Sir2; aging; vitamin B3; yeast.

Figure 1

NAD⁺ synthesis in yeast. A schematic view of the pathways involved in NAD⁺ biosynthesis. In yeast NAD⁺ can be obtained through the de novo pathway starting from tryptophan or through salvage pathways from nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR) evidenced in yellow boxes. Abbreviations of enzyme names, that catalyze each step of NAD⁺ biosynthesis, are reported. The Preiss-Handler pathway is indicated by red arrows while NR utilization is indicated by green ones.

Figure 2

Simplified scheme of NA and NR metabolism in yeast. NA and NR are constitutively produced, released in the growth medium and retrieved by yeast cells. Uptake of NA and NR depends on Tna1 and Nrt1, respectively. NA fuels the Preiss-Handler pathway and NR enters the Nrk1-dependent and Urh1/Pnp1-dependent salvage routes. NA is synthesized intracellularly from NAM, while NR from NMN. Abbreviations of enzyme names are reported. See text for details.

Figure 3

Scheme of NaR metabolism in yeast. NaR can be utilized for NAD⁺ synthesis through two salvage routes that rely on Nrk1 and Urh1 and produce NaMN and NA respectively. NaR is generated intracellularly from NaMN by Isn1 and Sdt1. Abbreviations of enzyme names are reported.

Figure 4

Scheme of main biosynthetic routes for NAD⁺. (a) Hst1 negatively controls the transcription of BNA genes required for de novo NAD⁺ synthesis in yeast. The inactivation of NPT1 prevents NA and NAM recycling through salvage pathways. (b) Cells lacking Nrk1, Pnp1 and Urh1 cannot utilize NR for NAD⁺ synthesis. Abbreviations of enzyme names are reported.