NAD+ (Nicotinamide Riboside)

Nicotinamide riboside enters cells via equilibrative nucleoside transporters (ENTs) and is phosphorylated by NR kinases (NRK1 and NRK2) to form NMN, which is then converted to NAD+ by NMNAT enzymes. This two-step pathway bypasses the rate-limiting NAMPT enzyme in the NAD+ salvage pathway, providing a more efficient route to NAD+ restoration than nicotinamide alone. Once converted, NAD+ fuels sirtuin-dependent deacetylation reactions (SIRT1–7) that regulate mitochondrial biogenesis (via PGC-1α deacetylation), DNA repair (via PARP activation), circadian rhythm maintenance, and inflammatory gene suppression. NR also activates the NRK pathway independently of the salvage pathway, which may be particularly important in tissues where NAMPT is low or inhibited. Unlike niacin, NR does not activate GPR109A (the niacin receptor), avoiding the characteristic flushing. NR supplementation has been shown to increase NAD+ metabolome components including NAAD, a biomarker confirming de novo NAD+ synthesis activation.

Martens et al. (Nature Communications, 2018) demonstrated that NR at 1000 mg/day for 6 weeks was well tolerated and effectively raised NAD+ levels by 60% in healthy middle-aged and older adults, with trends toward reduced systolic blood pressure and arterial stiffness. Trammell et al. (Nature Communications, 2016) established NR's pharmacokinetics in the first human study, showing dose-dependent NAD+ metabolome changes. Dollerup et al. (American Journal of Clinical Nutrition, 2018) found NR at 1000 mg twice daily for 12 weeks was safe in obese men, with increases in NAD+ and changes in skeletal muscle mitochondrial function. Elhassan et al. (Cell Reports, 2019) showed NR supplementation in aged men increased skeletal muscle NAD+ metabolome and improved anti-inflammatory gene expression. A large systematic review by Mehmel et al. (Nutrients, 2020) confirmed NR's safety profile across multiple human studies.

Nicotinamide riboside (NIAGEN), nicotinamide riboside chloride

NR is orally bioavailable and raises blood NAD+ levels within 2–8 hours of ingestion. Peak blood NAD+ occurs at approximately 8 hours. Unlike niacin, NR does not undergo significant first-pass conversion to nicotinamide, allowing more efficient NAD+ pathway utilization. The NRK pathway is the primary route of NR metabolism.