This is a response to Matt Kaeberlein's podcast, “Supplement Industry Secrets: What They Aren’t Telling You About NAD+ & NMN”, which can be seen here:
I'd like to respond to some of the points he makes in it.
Lifespan is not the only meaningful endpoint in biomedical research. Biomarkers and validated surrogate endpoints are routinely used when the ultimate outcome would take decades to measure. We use them throughout mainstream medicine: for example, lowering LDL cholesterol is accepted as a way of reducing cardiovascular risk without requiring every cholesterol-lowering drug to undergo a 40-year mortality trial.
Human clinical trials have demonstrated that oral NMN and NR can increase NAD+ levels and alter NAD+ metabolism in humans. NAD+ is an essential coenzyme involved in numerous cellular processes, including DNA repair through PARP enzymes and cellular regulation through sirtuins. It is therefore reasonable to investigate whether maintaining or increasing cellular NAD+ availability might support these processes, even though we do not yet have decades-long trials demonstrating an effect on human lifespan.
Matt points to population studies showing that whole-blood NAD+ levels do not decline dramatically with age. That's interesting, but blood NAD+ is not necessarily a good proxy for NAD+ availability within individual tissues.
There is human evidence that NAD+ metabolism can differ between tissues. For example, studies of skeletal muscle have found age-related differences in NAD+ levels, while exercise-trained older adults can have muscle NAD+ levels more similar to those of younger people.
This matters because a measurement of NAD+ in circulating blood doesn't necessarily tell us what is happening inside skeletal muscle, liver, brain, heart or other tissues. NAD+ metabolism is highly tissue-specific, and local demand can change with ageing, exercise, inflammation and metabolic stress.
So the observation that blood NAD+ remains relatively stable with age does not by itself establish that NAD+ availability is equally well maintained in every tissue.
Skeptics argue that there is no meaningful human efficacy data for NAD precursors. That is becoming increasingly difficult to sustain.
In a randomised, double-blind, placebo-controlled trial, 10 weeks of NMN supplementation increased skeletal-muscle insulin sensitivity by about 25% in postmenopausal women with prediabetes, together with increased insulin signalling in muscle. This is particularly interesting because the researchers measured effects in the target tissue itself rather than simply demonstrating an increase in a blood biomarker.
A randomised trial in recreational runners also found improvements in several measures of aerobic capacity and ventilatory threshold when NMN was combined with exercise training, although it did not find a significant improvement in VO₂max itself. That is a more modest finding than some promotional descriptions of the study suggest, but it is still evidence of a measurable physiological effect in humans.
There have also been human studies of NR reporting improvements in cardiovascular measures such as aortic stiffness and blood pressure in older adults. The overall human evidence is still preliminary and inconsistent, but “there is no evidence of functional effects” is no longer an accurate description of the field.
Matt discusses a study reporting molecular signatures associated with kidney injury following oral NAD-precursor supplementation. That is a legitimate finding that deserves investigation. But there is a significant difference between finding molecular signatures associated with injury and demonstrating that NMN causes clinically meaningful kidney damage.
There is also a strikingly different body of preclinical evidence. Other mouse studies have found NMN or NR to be protective against kidney injury, including reduced tubular injury and improved kidney function in models of cisplatin-induced kidney damage. Another mouse study found that NMN protected aged mice against acute kidney injury.
That doesn't prove that NMN is beneficial to human kidneys, any more than the concerning mouse study proves that NMN damages human kidneys. It demonstrates that the biology is considerably more complicated than either conclusion suggests.
I don't think the evidence currently justifies the more extravagant claims made by the NAD+ supplement industry. We don't know that NMN or NR extends human lifespan, and we don't yet have evidence that increasing NAD+ in otherwise healthy people produces major long-term health benefits.
But the opposite conclusion, that NAD precursors are essentially pointless because blood NAD+ doesn't fall dramatically with age, is also premature.
What we actually have is a fascinating and still developing area of research. NAD+ metabolism clearly matters to cellular function. NMN and NR can alter NAD+ metabolism in humans. Some human trials have reported measurable physiological benefits, while others have produced more modest or null results. Animal studies have produced both promising and concerning findings.
That is a long way from proving that NMN is a longevity drug. But it is also a long way from proving that it is useless.
For me, that is where the interesting question lies: not whether NMN has already been proven to extend human life, but whether manipulating NAD+ metabolism can produce specific health benefits in particular tissues and populations.
That question is still open and, to my mind, considerably more interesting than either the supplement industry's promises or the suggestion that the entire NAD+ hypothesis is collapsing.
