The NMN question: when a moving biomarker is not the same as slower ageing

Few molecules in the longevity conversation have travelled as far, as fast, as NMN. An entire category grew up around a single, genuinely interesting observation, that a key cellular molecule declines as we age and that this decline can be slowed or reversed by supplementation. The observation is sound. The leap that often follows it, from a biomarker moving on a chart to a person ageing more slowly, is where the reasoning gets ahead of the evidence. This article is about that gap, and how to read claims about NMN and longevity with the care they deserve.

The observation that built the category

The starting point is NAD+, a coenzyme present in every cell that participates in energy metabolism and a wide range of repair and signalling processes. Levels of NAD+ fall with age across many tissues, and this decline has been linked, in laboratory and animal work, to several of the changes we associate with growing older. A 2021 review in Nature Reviews Molecular Cell Biology sets out this picture in detail, describing how NAD+ metabolism shifts during ageing and why that shift attracted so much attention. NMN is one of the molecules the body uses to make NAD+, a precursor, and the logic that launched the category is simple to state. If NAD+ falls with age, and NMN helps build NAD+, then supplying more NMN might restore what time takes away. It is a clean story, and clean stories sell.

What precursors can and cannot do

The first part of that story holds up reasonably well. Precursor supplementation can raise measurable NAD+ in the blood. A 2018 trial in Nature Communications showed that chronic supplementation with a related NAD+ precursor was well tolerated in healthy middle-aged and older adults and raised blood NAD+ levels. That is a real, repeatable effect, and it is the foundation on which the category rests. Raising the number is achievable.

What is far less settled is what that raised number does. A broader review in Endocrine Reviews in 2023 examined NAD+ precursors and ageing and found a recurring pattern, that precursors reliably move the biomarker but that evidence for meaningful changes in health or function in humans is thin and inconsistent. A 2021 review in Mechanisms of Ageing and Development drew a similar contrast between encouraging preclinical findings and more modest, harder-to-interpret clinical results. The honest position is that precursors can do one thing well, raise circulating NAD+, and that everything beyond that remains an open question.

The surrogate-marker-versus-outcome problem

This is the heart of the matter, and it is not unique to NMN. In medicine, a surrogate marker is something measurable that is hoped to stand in for an outcome that actually matters. Blood NAD+ is a surrogate. The outcomes that matter, slower ageing, better function, a longer healthy life, are far harder to measure and take far longer to observe. The trouble is that surrogates and outcomes do not always move together. The history of medicine is full of markers that improved on cue while the outcome they were meant to predict did not budge, or moved the wrong way. A biomarker shifting tells you the intervention is doing something. It does not, by itself, tell you that the something is good, lasting, or relevant to how long or how well a person lives.

Applied to NMN, the problem is plain. Raising blood NAD+ demonstrates that the precursor is being absorbed and used. It does not demonstrate that ageing has slowed, because the link between the blood number and the outcomes people actually care about has not been established in humans. A 2024 review in Aging and Disease covering NAD+ in ageing and disease is careful on exactly this point, treating restored NAD+ as a plausible mechanism under investigation rather than a proven route to better outcomes.

How to read longevity claims critically

A few habits make these claims easier to assess. The first is to ask what was actually measured. If a study or a piece of marketing reports that a marker rose, note that and nothing more, the marker rose. The second is to ask whether the result came from cells, animals, or people, because effects seen in a dish or a mouse frequently fail to carry over to humans. The third is to watch for the quiet substitution of language, where a measured change in a biomarker is described using the vocabulary of outcomes, so that raising NAD+ becomes slowing ageing without any step in between to justify the change. A 2024 article in Cell Metabolism reviewing human trials of anti-ageing interventions is a useful model of the right tone, cataloguing what has been tried and remaining frank about how preliminary most of the human evidence still is. Reading that way is not cynicism. It is simply keeping the claim and the evidence in the same frame.

What the evidence does and does not show

Pulling the threads together gives a measured picture. The evidence does show that NAD+ declines with age, that this decline is biologically meaningful, and that precursor supplementation can raise circulating NAD+ in humans. Those points are reasonably well supported. The evidence does not show that raising blood NAD+ slows ageing in people, lengthens life, or produces reliable improvements in how the body functions over time. The gap between the first set of claims and the second is the conceptual gap that the category was built on, often without acknowledging it. NMN is not a fraud, and the underlying biology is genuinely worth studying. The fair summary is that a powerful and verifiable effect on a biomarker has been mistaken, in much of the surrounding conversation, for a proven effect on ageing itself. Those are different things, and keeping them apart is the single most useful move a reader can make.

Further reading

Continue reading from the journal: What is NAD+? A plain-English guide to the cell’s busiest coenzyme and NMN clinical trials: a sober reading of the human evidence.

Sources

• Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 2021. doi:10.1038/s41580-020-00313-x
• Bhasin S, Seals D, Migaud M, et al. Nicotinamide adenine dinucleotide in ageing biology: a review. Endocrine Reviews, 2023. doi:10.1210/endrev/bnad019
• Reiten OK, Wilvang MA, Mitchell SJ, Hu Z, Fang EF. Preclinical and clinical evidence of NAD+ precursors in health, disease and ageing. Mechanisms of Ageing and Development, 2021. doi:10.1016/j.mad.2021.111567
• Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 2018. doi:10.1038/s41467-018-03421-7
• Guarente L, Sinclair DA, Kroemer G. Human trials exploring anti-aging medicines. Cell Metabolism, 2024. doi:10.1016/j.cmet.2023.12.007
• Rahman MM, Sharma G, Rahman MS, et al. NAD+ in ageing and disease. Aging and Disease, 2024. doi:10.14336/AD.2023.0519-1