If you have spent any time reading NAD+ forums, you have probably seen the same argument on loop: NMN is “one step closer” to NAD+, so it must be better than NR. Or the opposite camp, which insists NR is the only precursor with proper human pharmacokinetic data, so NMN is essentially expensive NR. Both claims are oversimplifications, and the truth lives in the actual enzymology of the salvage pathway.
This article walks through the biochemistry slowly. By the end, you will understand why both molecules raise NAD+, why they do not necessarily do so in the same tissues, and why the heated debate between the Imai and Brenner labs is not just academic posturing.
The salvage pathway, briefly
Mammalian cells make NAD+ through three routes: de novo synthesis from tryptophan, the Preiss-Handler pathway from nicotinic acid, and the salvage pathway, which recycles nicotinamide (NAM) released by NAD+-consuming enzymes such as sirtuins, PARPs, and CD38. The salvage pathway is the dominant route in most tissues.
The salvage pathway has two key enzymatic steps. NAM to NMN is catalysed by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme. NMN to NAD+ is catalysed by nicotinamide mononucleotide adenylyltransferase (NMNAT1, 2, or 3, depending on subcellular location).
NR enters the pathway differently. Nicotinamide riboside kinase (NRK1 or NRK2) phosphorylates NR to produce NMN, which then feeds into the same NMNAT step. So both molecules converge on NMN before becoming NAD+. This is the seed of the “one step closer” argument, and also why it is misleading.
Why “one step closer” oversimplifies
The claim assumes that exogenous NMN bypasses NAMPT and enters cells directly as NMN. The reality, established by Trammell and Brenner in 2016, is that orally administered NR appears in blood as NR, while orally administered NMN is largely dephosphorylated to NR in the gut and liver before entering circulation in many studies. By this reading, oral NMN and oral NR deliver largely overlapping pools of circulating precursors.
The Imai lab disputes this. In 2019, Grozio and colleagues identified Slc12a8 as a putative NMN-specific transporter in the small intestine, arguing that NMN can enter certain cells intact. This finding remains contested. Independent groups have struggled to replicate the transporter’s specificity, and Brenner’s group has published rebuttals questioning the experimental design.
The honest summary is this: in some tissues, under some conditions, NMN may enter cells without dephosphorylation. In others, it almost certainly does not. The “one step closer” framing is marketing, not biochemistry. For more on how the precursor actually behaves in the body, see our science guide.
What human evidence shows
NR has the longer human pharmacokinetic record. Trammell’s 2016 work in healthy adults established that oral NR raises whole-blood NAD+ in a dose-dependent manner, with a clear time course and metabolite signature. Subsequent trials have replicated this across age groups and dosing schedules.
NMN human data caught up later. Yoshino’s 2021 trial in postmenopausal women with prediabetes showed that 250 mg oral NMN for ten weeks improved muscle insulin sensitivity, a functional readout rather than just a NAD+ number. Earlier Japanese pharmacokinetic work confirmed NMN is bioavailable in humans, though the absorption pathway remains debated.
Animal evidence is broader for both. Mills’ 2016 long-term mouse study showed NMN supplementation across the lifespan mitigated age-related physiological decline. Yoshino’s 2018 review summarised the parallel mouse work for both precursors.
Tissue distribution differs
This is where the two molecules genuinely diverge. NR appears to favour liver and certain peripheral tissues. NMN, particularly if Slc12a8 turns out to be real and tissue-specific, may favour intestinal epithelium and possibly other tissues expressing the transporter. Rajman’s 2018 review catalogued these distribution patterns and flagged that “raises NAD+” is too coarse a description for either molecule.
For practical dosage decisions, the tissue question matters less than people assume, because both precursors raise systemic NAD+ enough to drive sirtuin-dependent processes in measurable ways.
The Imai-Brenner debate, plainly
Shin-ichiro Imai (Washington University) and Charles Brenner (City of Hope) lead the two competing camps. Imai’s group emphasises NMN’s direct transport and tissue-specific uptake. Brenner’s group emphasises NR’s superior pharmacokinetic record and questions whether oral NMN delivers anything NR does not. Both camps publish in top journals. Both have commercial entanglements. Neither is wrong on every point.
The reasonable Malaysian consumer position is to recognise that this is an active scientific dispute, not a settled question. If you want a head-to-head framework, our compare guide walks through the practical trade-offs.
Bottom line for Malaysian readers
NMN and NR both raise NAD+ through the salvage pathway, but they enter at different points and may favour different tissues. The “one step closer” claim is a simplification of a contested transport question. Human evidence exists for both. If you are choosing between them, weight cost, third-party testing, and consistency of supply more heavily than the biochemistry slogans.