NAD+, NMN & NR: An Honest Assessment

NAD+ (nicotinamide adenine dinucleotide) is a coenzyme found in every cell of your body. It's essential for:

• Energy metabolism: NAD+ is crucial for converting food into cellular energy (ATP)
• DNA repair: Enzymes called sirtuins and PARPs require NAD+ to function
• Cellular signaling: NAD+ influences hundreds of cellular processes

Here's the key observation that sparked the NAD+ supplement industry: NAD+ levels decline with age. In some tissues, NAD+ may drop by 50% or more between young adulthood and old age.

The reasoning seemed straightforward: if low NAD+ is associated with aging, maybe boosting NAD+ could slow aging. This hypothesis launched a billion-dollar supplement category.

But there's a critical question that's often glossed over: Is declining NAD+ a cause of aging, or a consequence of it? This distinction matters enormously for whether supplementation makes sense.

Since you can't effectively supplement NAD+ directly (it's poorly absorbed), people take precursors—molecules your body converts into NAD+:

Nicotinamide Riboside (NR)

• Brand names: Tru Niagen (by ChromaDex), Elysium Basis
• More research history, FDA GRAS status
• Typical dose: 250-500mg/day
• Cost: $40-80/month

Nicotinamide Mononucleotide (NMN)

• Promoted heavily by David Sinclair and others
• Claims of better bioavailability (controversial)
• Typical dose: 250-1000mg/day
• Cost: $30-100/month
• FDA status has been uncertain (drug vs. supplement dispute)

Do they raise NAD+ levels? Yes. Both NR and NMN reliably increase blood NAD+ levels in humans. Studies show increases of 40-90% in NAD+ metabolites.

But here's the crucial point: raising NAD+ levels doesn't automatically mean health benefits. You can raise many blood markers without affecting outcomes that actually matter. The question is whether these increases translate to functional improvements.

The Interventions Testing Program (ITP) is the gold standard for testing anti-aging compounds in mice. Run by the National Institute on Aging across three independent sites, it's specifically designed to identify interventions that extend lifespan. Rapamycin, for instance, showed consistent lifespan extension in ITP trials.

What happened when they tested NR?

Nicotinamide riboside was tested in the ITP and published in 2021. The results:

• No lifespan extension in either sex
• No effect at either of the two doses tested (1000 ppm and 3000 ppm)
• Results were consistent across all three testing sites

This is a significant negative result. The ITP is rigorous, well-powered, and has successfully identified compounds that do extend lifespan (rapamycin, acarbose, 17α-estradiol). NR simply didn't work.

But what about NMN?

NMN has not been tested by the ITP as of late 2024. Some advocates argue NMN might work even though NR didn't—perhaps due to different bioavailability or cellular uptake. However, since both are converted to NAD+ through similar pathways, this seems like motivated reasoning. If boosting NAD+ extended lifespan in mice, NR should have shown something.

Several human trials have been conducted with NR and NMN. Here's an honest summary:

What The Trials Show:

NAD+ levels increase: Consistent finding across studies. Blood NAD+ metabolites go up 40-90%.

Generally safe and well-tolerated: Side effects are minimal in most trials—some flushing, mild GI effects.

What The Trials Don't Show (Yet):

Functional benefits in healthy people: Most trials in healthy adults show no improvement in:

• Exercise performance or aerobic capacity
• Muscle strength or endurance
• Cognitive function
• Metabolic markers (in healthy individuals)

A 2022 study in Nature Communications of NR in healthy middle-aged adults found that despite significantly raising NAD+ levels, there were no improvements in physical function, muscle strength, or metabolic health.

A 2021 NMN trial showed improved muscle insulin sensitivity in prediabetic women—but this was a specific population, not healthy adults.

The Honest Assessment:

If you're a healthy person, the current evidence does not show meaningful functional benefits from NR or NMN supplementation. The supplements successfully raise NAD+ levels, but that elevated NAD+ doesn't seem to translate into measurable improvements in outcomes that matter.

There may be benefits in specific populations (older adults with metabolic dysfunction, certain disease states), but the broad anti-aging claims remain unproven in humans.

No discussion of NAD+ supplements is complete without addressing David Sinclair. The Harvard geneticist has been the most prominent promoter of NAD+ precursors, particularly NMN. His book "Lifespan" and frequent media appearances have significantly shaped public perception.

Important context about Sinclair:

• Significant financial interests: Sinclair has been involved with multiple companies in the NAD+ space, including serving on the board of Metro International Biotech (working on NMN drugs) and Life Biosciences. He has directly profited from NMN popularity.
• Scientific controversies: Sinclair's earlier work on resveratrol (another "longevity compound" he promoted) largely failed to replicate in rigorous testing. GlaxoSmithKline paid $720 million for a resveratrol company based partly on his work; the drug never panned out.
• Claims vs. evidence: Some of Sinclair's public claims about his personal regimen and "biological age reversal" have been criticized by other researchers as going far beyond what the data supports.

What other longevity researchers say:

Peter Attia, MD, who hosts the most popular longevity podcast and has no financial interest in discrediting NAD+ supplements, has been notably skeptical. He has described the NAD+ precursor data as "mostly noise" and has expressed disappointment in the lack of convincing human data despite years of research.

Matt Kaeberlein, a well-respected aging researcher at the University of Washington, has been critical of the hype around NAD+ precursors, noting the discrepancy between marketing claims and actual evidence.

This doesn't mean Sinclair is wrong about everything—he's a legitimate scientist who has contributed to the field. But his financial interests and track record warrant healthy skepticism when he promotes specific supplements.

Here's the fundamental scientific question that rarely gets discussed in supplement marketing:

Is declining NAD+ a driver of aging, or a downstream effect of other aging processes?

The supplement industry assumes the former: low NAD+ → aging → boost NAD+ → slow aging.

But the relationship might be more like: aging → cellular damage → increased NAD+ consumption → low NAD+.

In the second scenario, NAD+ decline is a symptom of aging, not a cause. Boosting NAD+ levels would be like treating a fever with ice—you're addressing the thermometer, not the infection.

Evidence for the "consequence" theory:

• NAD+ is consumed by DNA repair enzymes (PARPs) that become more active with age due to accumulated DNA damage
• Inflammation, which increases with age, drives NAD+ consumption
• The ITP failure with NR suggests that even substantially raising NAD+ doesn't address underlying aging processes

The honest answer: NAD+ decline is probably both cause and consequence—a complex feedback loop. But the failure of NR to extend lifespan in mice, and the lack of functional benefits in healthy humans, suggests that simply supplementing precursors doesn't break this cycle in a meaningful way.

Despite the skeptical tone of this article, there are some situations where NAD+ precursors might provide genuine benefit:

1. Specific Disease States

Some research suggests benefits in conditions characterized by metabolic dysfunction or NAD+ depletion:

• Heart failure (early research, not definitive)
• Some neurodegenerative conditions (being studied)
• Metabolic syndrome / prediabetes (limited evidence)
• Post-acute COVID symptoms (very preliminary)

2. Skin Health and Cancer Prevention

One of the more interesting findings: nicotinamide (plain niacin) has been shown to reduce skin cancer risk in high-risk individuals. This isn't NMN or NR specifically, but it suggests some NAD+ pathway effects on skin health are real.

3. Alcoholism and Liver Stress

Alcohol metabolism depletes NAD+. There's some logic to supplementation during recovery, though this isn't a replacement for medical treatment.

4. Extreme Age or Frailty

NAD+ decline is most pronounced in very old or frail individuals. Supplementation might provide more benefit in this population than in healthy middle-aged adults—though we don't have strong trials proving this yet.

Before spending $50-100/month on supplements, consider that several well-established behaviors increase NAD+ levels naturally:

Exercise

Physical activity, especially aerobic exercise, upregulates NAD+ biosynthesis. Regular exercisers have higher NAD+ levels than sedentary individuals.

Caloric Restriction / Fasting

Energy restriction activates the NAD+ synthesis pathway. Time-restricted eating may provide some of this benefit.

Sleep

NAD+ follows circadian rhythms. Poor sleep disrupts NAD+ metabolism. Fixing sleep may be more impactful than supplementation.

Avoiding Excessive Alcohol

Alcohol metabolism consumes NAD+. Reducing alcohol intake preserves NAD+ levels.

Reducing Inflammation

Chronic inflammation drives NAD+ consumption. Anti-inflammatory lifestyle factors (exercise, omega-3s, avoiding processed foods) may help preserve NAD+.

The irony: The lifestyle interventions that boost NAD+ naturally are the same ones with strong evidence for longevity benefits. Meanwhile, NR supplementation raises NAD+ but hasn't shown lifespan or functional benefits. This suggests NAD+ levels might be a marker of metabolic health rather than a master switch you can flip with a pill.

Here's our honest assessment:

If you're a healthy adult hoping for longevity benefits:

• The evidence does not currently support NMN or NR for this purpose
• NR failed to extend lifespan in rigorous mouse studies
• Human trials don't show functional benefits in healthy people
• Your money is probably better spent on proven interventions: gym membership, better food, sleep optimization

If you have specific health conditions:

• There may be benefits in certain metabolic or cardiovascular conditions
• Discuss with a doctor who understands the evidence
• Don't expect miracles—effects, if any, are likely modest

If you're very old or frail:

• This is where NAD+ precursors might make the most theoretical sense
• Still no strong evidence, but the risk-benefit calculation is different
• Low risk of harm if you want to try it

If you just want to try it:

• They appear safe for most people
• Keep expectations low
• Don't substitute supplements for the fundamentals
• Be skeptical of dramatic claims from anyone with financial interests

The NAD+ story is a reminder that biology is complex. A compelling hypothesis (NAD+ declines with age → boosting it slows aging) doesn't always survive contact with rigorous testing. The supplements successfully raise NAD+ levels—they just don't seem to do much with that increase, at least in healthy people.

Future research might identify specific contexts where NAD+ precursors provide meaningful benefits. But right now, the hype significantly exceeds the evidence.