NAD+

NAD+ is not a peptide. It is nicotinamide adenine dinucleotide, the central redox cofactor of metabolism, and its biochemistry is settled science rather than an open research question. It carries electrons in glycolysis, the citric acid cycle and oxidative phosphorylation, and it is the obligatory cosubstrate for the sirtuin deacetylases and the PARP enzymes involved in DNA repair.

What is genuinely under research is the consequence of its decline. Tissue NAD+ falls with age across every species examined, and the mechanisms proposed include increased consumption by PARPs responding to accumulated DNA damage, increased activity of the NADase CD38, and reduced salvage synthesis. Because sirtuins require NAD+, falling levels reduce sirtuin activity, which connects the cofactor to a large literature on metabolic regulation and cellular ageing.

Rodent work on precursor supplementation — nicotinamide mononucleotide and nicotinamide riboside — reports raised tissue NAD+ and improvements across metabolic, vascular, muscular and cognitive endpoints in aged animals.

The human evidence concerns precursors far more than NAD+ itself, and this distinction is the crux of the entire field.

Controlled human trials of nicotinamide riboside and nicotinamide mononucleotide have consistently shown that oral precursor supplementation raises blood NAD+ measurably and is well tolerated at studied doses. That much is established. What those trials have not consistently shown is a corresponding functional benefit — results for insulin sensitivity, muscle function, cardiovascular measures and cognition have been mixed and generally modest, with several well-conducted trials reporting no significant effect on the primary endpoint.

Direct NAD+ administration, including by intravenous infusion, is widely offered commercially and has a much thinner evidence base. NAD+ is a large charged molecule with poor cell membrane permeability, and there is genuine scientific debate about whether administered NAD+ enters cells intact or is degraded extracellularly to precursors that are then taken up — which would make it an expensive route to the same place.

The claim that NAD+ declines with age is true and well documented. The claim that restoring it reverses ageing is not supported by human data, and the gap between those two statements is where most marketing operates.

The most specific unsupported claim concerns direct administration. Raising blood NAD+ is not the same as raising intracellular NAD+ in the tissues that matter, and the membrane permeability problem is a real biochemical obstacle rather than a quibble. The precursor route exists precisely because cells take up precursors more readily than the intact cofactor.

A second claim treats the strong rodent results as predictive. Mouse lifespan and healthspan studies have repeatedly failed to translate, and NAD+ biology involves species differences in salvage pathway enzymes that make extrapolation particularly unreliable.

The fair summary is that NAD+ biology is real and important, and that the intervention question in humans remains substantially unresolved after a decade of well-funded study.

Against 5-Amino-1MQ on the metabolic shelf, the relationship is elegantly opposite. NAD+ approaches add substrate to the pool; NNMT inhibition reduces the drain on it by preventing methylation of nicotinamide. Two routes to the same endpoint, neither demonstrated in humans to produce a functional outcome.

Against the precursors NMN and NR, the difference is the membrane permeability question — precursors are taken up readily, the intact cofactor much less so, and essentially all of the good human trial data belongs to the precursors rather than to NAD+ itself.

Against MOTS-c and SS-31 on the same shelf, NAD+ is substrate while those are signalling and structure respectively. SS-31 stabilises the membrane platform on which oxidative metabolism runs; MOTS-c modulates the signalling governing it; NAD+ is the cofactor the process consumes. Conceptually complementary, and none established in healthy human ageing.

NAD+ and its precursors are generally well tolerated in the doses used in published trials, and this is a genuine finding from real controlled studies rather than an absence of data.

The substantive concern is theoretical but not frivolous. NAD+ is required by PARP enzymes for DNA repair and by sirtuins for regulating cell survival pathways, and these processes matter to cancer biology in both directions. Some published work has raised the possibility that raising NAD+ availability could support the metabolic demands of existing malignant cells. No human study has demonstrated harm; equally, no study has adequately addressed the question, and it is raised in the scientific literature rather than only by critics.

High-dose nicotinamide can cause flushing and, at sustained high intake, hepatotoxicity has been reported. Methyl group depletion has been proposed as a consequence of high nicotinamide loads, since clearance proceeds by methylation — the same pathway NNMT inhibitors target from the other side.

Intravenous administration carries risks independent of the molecule, including infusion reactions and infection from non-sterile preparation.

NAD+ is a nucleotide cofactor rather than a peptide, and it is notably less stable in solution than the lyophilized peptides in this catalogue. It is sensitive to heat, to pH extremes, and hydrolyses over time in aqueous conditions.

Reconstitute only when needed and use promptly. Store reconstituted material at 2–8 °C protected from light, and treat the working window as shorter than for a typical peptide. Keep unopened lyophilized material frozen. Solutions should not be heated, and repeated freeze-thaw cycling should be avoided.