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.
Highlights
The nicotinamide adenine dinucleotide (NAD) is an essential pyridine compound that is required for cellular bioenergetics and metabolism and is a critical regulator of key cellular processes including epigenetic modifications, DNA damage repair and aging/longevity [1,2,3]
NAD+ metabolism is tightly regulated as well as highly dynamic and flexible. These features result from the integration of the different NAD+ biosynthetic pathways in a complex network at the level of some key intermediates. This prevents NAD+ imbalance and ensures cells to cope with metabolic requirements according to changes in environmental/physiological conditions including aging
nicotinic acid (NA), NAM and nicotinamide riboside (NR), NAD+ precursors spanning from yeast to humans, fulfil such critical functions in supporting NAD+ metabolism/homeostasis and directly affect both replicative and chronological yeast aging, as evidenced by various aspects here presented
Summary
The nicotinamide adenine dinucleotide (NAD) is an essential pyridine compound that is required for cellular bioenergetics and metabolism and is a critical regulator of key cellular processes including epigenetic modifications, DNA damage repair and aging/longevity [1,2,3]. The balance between the activities of NMN adenylyltransferases and NMN nucleotidases seems to be a critical point to drive pyridine nucleotide metabolism “forward” to dinucleotides or “backward” to nucleosides depending on specific NAD+ requirements [60] In such a dynamic flexibility of homeostatic mechanisms regulating NAD+ levels, NR supplementation to npt mutants rescues Sir2-dependent silencing defects and extends RLS [35]. NR supplementation to cells grown in NA-free synthetic medium is sufficient for suppressing Sir2-dependent silencing defects and extends RLS This effect is dependent on NR salvage routes and is accompanied by an increase (from about 1 mM to about 2 mM) in intracellular NAD+ amount [35] that, as discussed above for NA supply, may provide support for an adequate Sir activity. This indicates that NR assimilation is able to prevent NAD+ reduction that physiologically takes place as cells age [61,62]
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