NMN (Nicotinamide Mononucleotide) — The NAD+ Precursor
NMN is a direct precursor to NAD+, a coenzyme central to energy metabolism, DNA repair, and sirtuin activation. NAD+ levels decline ~50% between age 20 and 60, and NMN supplementation has been shown to restore them in multiple human trials.
Mechanism of Action
NMN is phosphorylated to NMN-AMP (NMNAT pathway) and then to NAD+. Elevated NAD+ activates sirtuins (SIRT1, SIRT3, SIRT6) and PARP1, driving DNA repair, mitochondrial biogenesis, and metabolic regulation. It also activates NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway.
Human Trial Evidence
A 2020 Keio University trial (Irie et al., Endocrine Journal) showed 250 mg/day NMN safely elevated blood NAD+ metabolites in healthy men. A 2021 JISSN trial (Liao et al.) demonstrated improved aerobic capacity in amateur runners at 600 mg/day over 6 weeks. A 2023 Washington University trial showed 250 mg/day improved muscle insulin sensitivity in postmenopausal women.
Dosing Protocol
250–500 mg/day is the most studied range in humans. Some practitioners use 1,000 mg/day (Sinclair protocol). Best taken in the morning with food. Sublingual or liposomal forms may improve bioavailability.
Safety & Contraindications
No serious adverse events reported in human trials up to 1,200 mg/day over 12 weeks. Mild GI effects (nausea, loose stools) reported at higher doses. Theoretical concern: NAD+ fuels PARP1 which can support cancer cell survival — no clinical evidence of harm, but caution is warranted in active cancer.