NMN and NR Supplements: What the Human Evidence Actually Shows

Over the last decade, NMN and NAD+ supplements were hyped as groundbreaking tools in the fight against aging. 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.

This article traces the rise—and fall—of NAD+ precursors like NMN and NR, and examines 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.

Starving humans isn't exactly ideal, so the scientific question became: if the molecular mechanisms behind calorie restriction's benefits could be identified, perhaps those effects could be mimicked without the restriction itself.

This was the problem 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 lifespan 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 lifespan 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 lifespan gains.

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

This pointed to an obvious question. What if NAD+ levels could be boosted to counteract the natural decline? Could aging be delayed?

In a crucial study published in 2016, the theory was put to the test in mice. Researchers needed a way 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
• Supplementing with precursors can increase levels
• In mice, this led to cellular rejuvenation and extended lifespan

What About Humans?

If NR and NMN could work in mice, why not in humans?

That was the obvious next question. But not everyone waited for the experimental evidence needed to answer it.

On Joe Rogan's podcast in 2019, David Sinclair—one of the top figures in the anti-aging supplement field—described his personal use of NMN, another NAD+ precursor. He gave a strong impression that there was a good scientific basis for what he was doing—and that impression reached 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.

Headlines like “Scientists may have found the key to reversing aging!” appear regularly—only for the underlying findings to fail replication in subsequent, more rigorous testing. In most cases, the miracle cure didn't pan out.

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 physically active individuals.

The New COVID Study

A newly published study has profound implications for how NMN and NR supplements should be evaluated. The evidence it provides represents a significant challenge to the NAD+ precursor hypothesis.

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.

Researchers proposed a straightforward 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]

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.

What remains is a litany of failed human trials for NR and NMN. Yes, blood NAD+ levels increase. But so far, that's all the evidence shows.

The Role of TMG

Despite the failed trials, there are still plenty of anecdotal reports online. People say they feel better when taking NMN or NR.

Could that be real? Possibly. But what's actually going on?

The placebo effect is one explanation. But there may be something else worth noting.

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].

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.

What the evidence does support with confidence right now is this: there is no strong evidence that NAD+ precursors help combat aging in humans. TMG, by contrast, has a growing evidence base for exercise performance and metabolic support.

Conclusion

Despite years of hype, the evidence for NMN and NAD+ supplements as aging interventions is not holding up to scrutiny.

The early science was promising. But the more rigorous the studies became—especially in humans—the less support emerged.

NAD+ levels can be increased through supplementation. But does that translate into improved lifespan or human function?

Based on the current evidence, the answer appears to be no.

If NMN or NR is part of a supplement routine, it's worth considering whether TMG—often taken alongside—is the ingredient actually doing the work. TMG has a more robust human evidence base and may be a more evidence-supported choice for those seeking supplements to pair with an active lifestyle.

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