NAD+ research often moves through three claims too quickly: NAD+ is important in cells; an intervention changes NAD-related measurements; therefore the intervention slows human ageing. The first two statements can be investigated directly. The third requires its own clinical evidence.
Another distinction matters before any result is discussed: NAD+ is a coenzyme, not a peptide. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are different molecules used in NAD metabolism. A study of one is not automatically a study of the others.
Biological importance is a starting point
NAD participates in cellular energy-related reactions and is used by enzymes involved in other cellular processes. Cells maintain it through interconnected synthesis and recycling pathways. Research on NR in mice and humans showed changes in NAD-related metabolites after oral exposure, establishing that this pathway can be affected experimentally. The study did not establish longer human life. Trammell and colleagues, 2016.
A concentration measured in blood is also not a direct map of every organ. The sample type, assay and timing matter. Whole blood, particular blood cells and muscle tissue can provide different views of metabolism; an increase in one compartment should not be presented as proof of an equivalent change everywhere.
Human trials show a biomarker–outcome gap
In a placebo-controlled crossover study involving 24 middle-aged and older adults, Martens and colleagues found that NR affected NAD metabolism. The study explored physiological outcomes but was not a demonstration that NR extends life or prevents age-related disease. Its findings were a basis for further testing, not a general anti-ageing verdict. Martens et al., 2018.
Another randomised trial studied forty men with obesity and insulin resistance over twelve weeks. NR did not improve insulin sensitivity, whole-body glucose measures or body composition in that population. This negative result matters alongside biomarker-positive reports; it illustrates why a proposed mechanism cannot substitute for the outcome measurement. Dollerup et al., 2018.
In a separate crossover experiment in twelve older men, NR altered the muscle NAD-related metabolome and some molecular signatures, while muscle mitochondrial bioenergetics remained unchanged. The researchers measured tissue directly, yet a metabolic signal still did not automatically become a functional improvement. Elhassan et al., 2019.
A positive finding can still be narrow
A ten-week NMN study in 25 postmenopausal women with prediabetes and overweight or obesity reported improved muscle insulin sensitivity. That is a specific physiological finding in a defined population. It should not be expanded into a claim that all adults gain the same effect or that NMN reverses ageing. The paper also reported that measured muscle NAD+ concentrations did not increase, illustrating the difference between concentration, turnover and downstream response. Yoshino et al., 2021.
Differences between trials can arise from the molecule, participants, duration and chosen measurement. It is more informative to preserve those details than to count positive and negative papers as if every experiment asked the same question.
The 2026 evidence still separates markers from function
A 24-week randomised NMN trial in adults aged 65 and older was published as an early accepted article in September 2026. Its abstract reported increased circulating NAD-related metabolites, but no significant improvement in the primary auditory-function endpoint or physical-performance measures. Some nominal findings did not survive adjustment for multiple testing and were described as exploratory. Igarashi and colleagues, 2026.
This longer study strengthens the need to read the endpoint rather than the headline. A sustained biochemical change and a demonstrated benefit to daily function remain separate findings. The report’s early-publication status should also be retained when citing it, rather than treating an accepted manuscript as a different or additional trial.
Direct NAD+ infusion is a separate evidence question
A 2019 pilot examined direct NAD+ infusion in eleven men: eight in the intervention group and three controls. It tracked plasma and urine metabolites over hours. That design can describe short-term metabolic handling; it cannot establish durable improvements in cognition, energy, addiction outcomes, lifespan or healthy ageing. Grant and colleagues.
It is therefore inappropriate to use an oral NR or NMN trial as direct evidence for an NAD+ infusion. The molecule and route have changed. The small direct-infusion pilot does not bridge every remaining question about exposure, benefit or uncommon adverse effects.
What to look for next
A convincing ageing claim would need meaningful, prespecified outcomes and sufficient follow-up, not merely a laboratory marker moving in the expected direction. Look for a suitable comparison group, transparent handling of multiple outcomes, information on withdrawals and harms, and replication in the population of interest.
None of the studies described here establishes that an NAD-related intervention extends human lifespan or broadly reverses ageing. They offer useful, sometimes mixed evidence about particular molecules and measurements. Those mixed findings call for more precise research questions and clinical outcomes.
Continue with How to read a clinical trial for a closer look at interpreting research evidence.
Sources and further reading
- Trammell et al.: NR metabolism in mice and humans — Original animal and human pharmacokinetic research; 2016-10-10.
- Martens et al.: placebo-controlled NR crossover trial — Original randomised human trial; 2018-03-29.
- Dollerup et al.: NR trial in men with obesity — Original randomised human trial; 2018-08-01.
- Yoshino et al.: NMN and muscle insulin sensitivity — Original randomised human trial; 2021-04-22.
- Elhassan et al.: NR and the older human muscle metabolome — Original randomised human trial; 2019-08-13.
- Igarashi et al.: 24-week NMN trial in older adults — Original randomised human trial; early accepted article; 2026-09-25.
- Grant et al.: pilot study of directly infused NAD+ — Original human metabolomic pilot; 2019-09-12.
