NAD+: research overview

Nicotinamide riboside is an NAD+ precursor whose oral bioavailability and capacity to raise the NAD+ metabolome have been characterised in randomised, placebo-controlled human trials. Martens et al. (Nature Communications 2018) reported that chronic NR supplementation was well tolerated and elevated whole-blood NAD+ in middle-aged and older adults. When NR is co-formulated with the SIRT1 activator pterostilbene (NRPT), the combination has been reported in a randomised, double-blind, placebo-controlled trial to raise NAD+ approximately 40-90 percent in healthy older adults (Dellinger et al., NPJ Aging Mech Dis 2017), and in NAFLD subjects to lower ALT and GGT (Dellinger et al., Hepatology 2023). NR is the most direct mechanistic complement to exogenous NAD+ approaches.

NMN is the immediate metabolic precursor of NAD+ via NMNAT enzymes. A randomised, double-blind, placebo-controlled safety study reported that 1250 mg/day oral beta-NMN for up to 4 weeks in 31 healthy adults aged 20-65 was well tolerated, with no severe adverse events and no changes outside physiological variation across haematology, biochemistry, urine, and body composition (Fukamizu et al., Sci Rep 2022). NMN is the precursor most often discussed alongside NAD+ itself when the goal is to load the salvage pathway. The two are best regarded as mechanistic alternatives rather than additive partners.

Pterostilbene is a methoxylated stilbene structurally related to resveratrol and reported as a SIRT1-activating polyphenol with greater oral bioavailability than resveratrol. In a randomised, double-blind, placebo-controlled trial in 120 adults aged 60-80, the combination of nicotinamide riboside plus pterostilbene (NRPT) raised whole-blood NAD+ approximately 40% at the 1x dose and 90% at the 2x dose, sustained over 8 weeks (Dellinger et al., 2017). A subsequent NAFLD trial reported time-dependent reductions in ALT and GGT and lower circulating ceramide 14:0 in the NRPT arm (Dellinger et al., Hepatology 2023). Pterostilbene is the most rigorously co-trialed SIRT1 activator in the NAD+ stack.

Apigenin is a flavone reported to inhibit CD38, the principal NAD+-degrading ectoenzyme. Escande et al. (Diabetes 2013) characterised apigenin as a CD38 inhibitor and reported that treatment of cells with apigenin raised intracellular NAD+ and reduced global protein acetylation, while apigenin administration to obese mice raised tissue NAD+, lowered acetylation, and improved glucose and lipid handling. Quercetin was profiled in the same study with similar CD38-inhibitory activity. The mechanistic complement to NAD+ loading is reducing NAD+ degradation, which is the niche apigenin occupies in this stack.

NAD+ turnover produces nicotinamide (NAM), which is methylated by nicotinamide N-methyltransferase (NNMT) for excretion; NNMT uses S-adenosylmethionine (SAM) as the methyl donor. Komatsu et al. (Sci Rep 2018) reported that NNMT directly interacts with methionine-cycle enzymes (BHMT, MAT1A, AHCY) and that NNMT over-expression lowered SAM and the SAM/SAH ratio in vivo and in vitro. TMG is a one-carbon methyl donor that feeds the BHMT-driven remethylation of homocysteine to methionine, regenerating SAM. The mechanistic argument for pairing TMG with high-dose NAD+ precursors is therefore documented at the enzymological level, even though no published RCT has yet measured whether TMG co-administration preserves SAM status in NAD+ supplemented humans.