Over the last decade, NMN and NAD+ supplements were hyped as groundbreaking tools in the quest for longevity. Boost your NAD+ levels, the story went, and you might slow aging, boost energy, and even extend your life. But new evidence has called that entire narrative into question.
In this article, we’ll trace the rise—and fall—of NAD+ precursors like NMN and NR, and explore what the latest science really says about their effectiveness in humans.
Table of Contents
- A Surprising Discovery in Aging Research
- An Intriguing Aging Link
- Testing NAD Precursors
- What About Humans?
- The New COVID Study
- The Role of TMG
- Conclusion
- References
A Surprising Discovery in Aging Research
When scientists discovered one of the most counterintuitive dynamics related to aging back in 1935, it was thought that radical lifespan extension was just around the corner. When rats were starved, they lived much longer.
But starving humans isn’t exactly ideal, so if we can figure out, on a molecular level, why calorie restriction helps, then perhaps we could mimic the effect without calorie restriction.
And this was the problem the scientists in Leonard Guarente’s lab at MIT were wrestling with in the late 1990s. They were trying to gain a deeper understanding of the pathways linking calorie restriction and longevity benefits.
They were working with a very simple organism: yeast. They meticulously tracked different lines of yeast cells through time, carefully noting the molecular pathways connected to longer life.
As they pored through the data, they uncovered a subtle clue. It seemed the increased longevity generated by calorie restriction required the activation of a very specific protein: Sir2p. But that activation, in turn, depended upon a molecule called NAD [1].
Remove NAD, and Sir2p isn’t activated. And without that activation, there are no longevity gains.
So this research suggested NAD might be an essential player in the molecular process regulating aging and age-related diseases.
An Intriguing Aging Link
Another clue dropped a few years later.
Researchers took skin samples from newborn babies as well as from adults aged 15–77. They were exploring a link that had been found in rodents: NAD+ levels declined with age. And that decline was linked to age-related increases in cellular damage.
As they analyzed the human samples, the same pattern emerged. DNA damage correlated strongly with age, and crucially, NAD+ levels also dropped as age increased [2].
Statistically:
-
For DNA damage:
- Males: p = 0.029, r = 0.490
- Females: similar trend
-
For NAD+ levels:
- Males: p = 0.001, r = –0.706
- Females: p = 0.01, r = –0.537
The researchers’ conclusion was this: with age, accumulating DNA damage impairs NAD+ production. The decline in NAD+ might play a major role in the aging process. As levels drop, this could be limiting energy production, DNA repair, and important signaling pathways [2].
Testing NAD Precursors
So this pointed to an obvious question. What if we could boost NAD+ levels to counteract the natural decline? Could we delay aging?
In a crucial study published in 2016, the theory was put to the test in mice. First, researchers needed to boost NAD+ levels. Scientists had discovered this was possible through supplementing with nicotinamide riboside (NR)—a precursor the body uses to make NAD+ [3].
After six weeks of NR treatment, NAD+ concentration increased in muscle stem cells (MuSCs) from both young and old mice.
Then, the researchers looked specifically at how those stem cells behaved. The results were exhilarating: the treatment seemed to counteract some of the processes of aging. Cellular function was restored to a more youthful state. And the lifespans of the mice increased [3].
At this point, interest took off. The story was compelling:
- NAD+ is central to cellular health
- NAD+ declines with age
- If we supplement with precursors, we can increase levels
- In mice, this led to cellular rejuvenation and extended lifespan
What About Humans?
If it could work in mice, why not in humans?
That was the obvious next question. But not everyone waited for the experimental evidence we needed to answer it.
On Joe Rogan’s podcast in 2019, David Sinclair—one of the top figures in the anti-aging field—described his personal use of NMN, another NAD+ precursor. What he does privately is his own business, of course. But he gave a strong impression that there was a good scientific basis for what he was doing—and that impression was left with millions of viewers.
There was just one problem: at the time that episode aired, there wasn’t a single human clinical trial on the claimed benefits of NMN supplementation.
Worse still, the 2016 mouse study that initially sparked excitement has faced reproducibility issues—a widespread problem in science. It’s a depressingly common story: an initial study surfaces some amazing new discovery that generates huge hype… only for follow-up studies to fail to replicate the results.
You may have seen headlines like “Scientists may have found the key to reversing aging!”—only to wonder years later whatever happened to that miracle cure. In most cases, it didn’t replicate.
To combat this, the most robust program for testing lifespan-extending molecules in mice is the Interventions Testing Program (ITP). It’s run by three independent labs that run coordinated studies to ensure reproducibility.
Given the excitement, the ITP turned its attention to NAD+ precursors—specifically NR. And what they found was a serious blow to the hype. NR failed to increase lifespan in mice [4].
Despite raising blood NAD+ levels, there was no lifespan benefit or functional improvement. And since NMN works through the same NAD+ pathway, it’s unlikely it would perform differently.
Adding to the disappointment, the foundational idea—that NAD+ levels decline with age—has also been called into question.
In a study published in Nature Aging, researchers found that muscle biopsies of older adults who exercise had NAD+ levels similar to those of younger individuals [5].
This suggests that NAD+ decline may not be a universal feature of aging, especially in active individuals.
The New COVID Study
A newly published study has profound implications for how we think about NMN and NR supplements. To me, it’s a nail in the coffin for these compounds.
The study looked at long COVID.
Why does that matter here? Because one of the side effects of infection and its aftermath is a strain on NAD+ metabolism. Long COVID is associated with brain fog, immune issues, and mitochondrial dysfunction—all potentially connected to NAD+ depletion.
So researchers proposed a simple hypothesis: supporting NAD+ metabolism with NR supplementation might alleviate these symptoms.
In the study, 58 participants with long COVID were recruited. They were split into two groups:
- NR-NR group: took NR supplements for 20 weeks
- PBO-NR group: took a placebo for 10 weeks, then NR for the remaining 10 weeks [6]
As expected, NAD+ levels rose sharply with NR supplementation:
- In the NR-NR group: NAD+ increased 2.6- to 3.1-fold after 5–10 weeks and remained elevated at 20 weeks
- In the PBO-NR group: NAD+ levels stayed near baseline (0.93- to 1.0-fold) during placebo, then rose to 2.6-fold and 2.1-fold after switching to NR [6]
Here’s the crucial question: Did any of this improve symptoms?
Unfortunately, no. There were no significant differences between groups for any of the major metrics:
- Cognition (ECog, RBANS, TMT-B): p = 0.47–0.74
- Fatigue severity: p = 0.59
- Sleep quality: p = 0.69
- Anxiety: p = 0.84
- Depression: p = 0.20 [6]
If there was ever a scenario where NAD+ support might help, this was it. A population with strained NAD+ metabolism, elevated symptoms, and 20 weeks of treatment. And still—no benefit.
Instead, what we’re left with is a litany of failed human trials for NR and NMN. Yes, blood NAD+ levels increase. But so far, that’s all we’ve seen.
The Role of TMG
And yet, there are still plenty of anecdotal reports online. People say they feel better when taking NMN or NR.
Could they be?
Possibly. But what’s going on?
The placebo effect is one explanation. But there may be something else.
Many people who take NAD+ precursors also take TMG (trimethylglycine). And there’s study evidence that TMG may offer real benefits—especially when combined with exercise.
For example, a 2024 meta-analysis found that TMG supplements enhance strength and jumping performance [7]:
-
Maximal strength improvement (lower body):
- Standardized Mean Difference (SMD): 0.49, 95% CI: 0.01–0.98
-
Vertical jumping performance improvement:
- SMD: 0.36, 95% CI: 0.03–0.69
Another study found TMG boosted testosterone levels in young professional soccer players during a competitive season [8].
These potential benefits are the reason TMG is included in MicroVitamin.
So it’s entirely possible that people taking both NMN/NR and TMG are actually feeling the effects of the TMG—not the NAD+ precursors.
I can’t say for certain. But what we can say with confidence right now is this: we don’t have strong evidence that NAD+ precursors help combat aging in humans.
Conclusion
Despite years of hype, the collapse of the NMN and NAD+ supplement narrative seems complete.
The early science was promising. But the more rigorous the studies became—especially in humans—the less support emerged.
Yes, NAD+ levels can be increased. But does that improve lifespan or human function?
Right now, the answer appears to be no.
References
1. https://www.science.org/doi/10.1126/science.289.5487.2126
2. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042357
3. https://www.science.org/doi/10.1126/science.aaf2693
4. https://pmc.ncbi.nlm.nih.gov/articles/PMC8135004/
5. https://www.nature.com/articles/s43587-022-00174-3
6. https://www.sciencedirect.com/science/article/pii/S258953702500567X
7. https://pubmed.ncbi.nlm.nih.gov/39514262/
8. https://jissn.biomedcentral.com/articles/10.1186/s12970-021-00464-y
