NAD+ — Published Research

NAD+ is synthesized through three main pathways: (1) de novo synthesis from tryptophan via the kynurenine pathway, (2) the Preiss-Handler pathway from nicotinic acid (niacin), and (3) the salvage pathway from nicotinamide (NAM) via nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) can also be converted to NAD+ through salvage pathway enzymes. NAMPT expression varies by tissue and decreases with age in some tissue models.

Verdin E. “NAD+ in aging, metabolism, and neurodegeneration.” Science. 2015. PubMed

Sirtuins (SIRT1-7) are NAD+-dependent protein deacylases that use NAD+ as a co-substrate, cleaving it to produce nicotinamide and O-acetyl-ADP-ribose during the deacetylation reaction. SIRT1 deacetylates targets including PGC-1α, FOXO transcription factors, and p53. SIRT3, localized to mitochondria, deacetylates metabolic enzymes involved in fatty acid oxidation and the TCA cycle. Sirtuin activity is limited by intracellular NAD+ availability, creating a link between cellular NAD+ levels and sirtuin-mediated metabolic regulation.

Imai S, Guarente L. “NAD+ and sirtuins in aging and disease.” Trends Cell Biol. 2014. PubMed

NAD+ is consumed by poly(ADP-ribose) polymerases (PARPs), which use NAD+ for ADP-ribosylation during DNA repair. PARP1 is the major NAD+ consumer during genotoxic stress, and excessive PARP activation can deplete cellular NAD+ pools. CD38, an ectoenzyme, is another major NAD+ consumer that increases with age in some tissues. CD38 catalyzes the hydrolysis of NAD+ to nicotinamide and ADP-ribose (or cyclic ADP-ribose). Research has characterized the competition between sirtuins, PARPs, and CD38 for the cellular NAD+ pool.

Camacho-Pereira J et al. “CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism.” Cell Metab. 2016. PubMed

Clinical studies have examined oral supplementation with NAD+ precursors (NR and NMN) and measured changes in blood NAD+ levels. A systematic review of human trials found that NR supplementation increased whole blood NAD+ by 40–142% depending on duration. NMN studies have similarly shown increases in blood NAD+ metabolites. These studies characterized pharmacokinetics, tolerability, and safety profiles, establishing that oral precursors can elevate circulating NAD+ levels in humans.

Reiten OK et al. “Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing.” Mech Ageing Dev. 2021. PMC