Age-Dependent Decline of NAD+-Universal Truth or Confounded Consensus?

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD⁺-dependent enzymes. In the early 2000s, reports that NAD⁺ declines with aging introduced the notion that NAD⁺ metabolism is globally and progressively impaired with age. Since then, NAD⁺ became an attractive target for potential pharmacological therapies aiming to increase NAD⁺ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD⁺ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD⁺ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD⁺ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD⁺ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD⁺ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

Keywords: C. elegans; NAD+; aging; human; monkey; mouse; rat; yeast.

Figure 1

NAD⁺ biosynthesis pathways in mammalian cells. ACMS: 2-amino-3-carboxymuconate, NA: nicotinic acid, NAD⁺: nicotinamide adenine dinucleotide, NAM: nicotinamide, NAMN: nicotinic acid mononucleotide, NAR: nicotinic acid riboside, NMN: nicotinamide mononucleotide, NAAD: nicotinic acid adenine dinucleotide, NR: nicotinamide riboside, QA: quinolinic acid, TRP: tryptophan, IDO: indoleamine-2,3-dioxygenase, NADSYN1: NAD synthetase, NAMPT: nicotinamide phosphoribosyltransferase, NAPRT: nicotinic acid phosphoribosyltransferase, NMNAT: nicotinamide mononucleotide adenylyl transferase, NRK: NR Kinase, QPRT: quinolinic acid phosphoribosyltransferase, TDO: tryptophan-2,3-dioxygenase, ARTs: ADP-ribosyltransferases, CD38: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1, SARM1: NAD⁺ hydroxylase SARM1, ATP: adenosine triphosphate, PPi: inorganic pyrophosphate, PRPP: 5-phosphoribosyl-1-pyrophosphate.

Figure 2

This review discusses the scientific robustness of the claim that NAD⁺ levels decline with age.