Science Corner 67 | NAD+ – Seven Cohorts. No Decline. Now What?
A new study in Nature Metabolism may be the most careful challenge yet to one of the longevity supplement world's core assumptions. The finding is worth understanding clearly, because it changes some things while leaving others intact.
The premise behind NR and NMN supplements has been straightforward: aging often depletes NAD+ and improving those levels can help with long-term health. Researchers at Amsterdam UMC tested that premise across seven independent human cohorts. Whole-blood NAD+ did not vary with age. The authors also conclude that NAD+ levels did not respond to changes in different lifestyle factors.
It stayed, in the authors' own words, remarkably stable.
Blood NAD+ may be so tightly regulated that it tells us almost nothing about what's happening inside the cells where aging actually occurs.
Seven Cohorts, One Very Consistent Answer
The study measured NAD+ in over 300 people. The groups were diverse: young adults under 30, elderly people including those in their 80s, elite athletes, frail older adults, cardiovascular patients, and long-lived families from a Dutch longevity study. Some groups just had their blood drawn once. Others went through months of exercise programs, protein-rich diets, or multi-part nutrition and fitness interventions.
Across six of those seven cohorts, blood NAD+ showed no link to age and no meaningful response to any intervention. The one cohort where blood NAD+ did change was a twin study where participants took escalating doses of NR, a form of vitamin B3 that the body uses to make NAD+, starting at 250 mg per day and reaching 1 gram per day over four weeks with a four month maintenance period. That produced a clear increase. Now we have real clinical evidence suggesting the supplement raises blood NAD+. That part holds.
What the data do not support is what that NAD+ blood number means. For example, we cannot use it as evidence of a deficit, or as a window into what's happening in your muscles, liver, brain, or mitochondria.
The Measurement Problem Buried in Earlier Studies
Before getting to the biology, the methods found here deserve their own attention.
The research team built and validated a careful measurement system that only needs 10 microliters of blood, roughly a small droplet, to quantify NAD+. In doing so, they found something important: NAD+ breaks down quickly when blood is handled carelessly. A single freeze-thaw cycle, freezing a sample and then thawing it for analysis, introduced enough measurement noise, about 3.5 nmol/mL of random variation, that had nothing to do with biology. Repeated freeze-thaw cycles made it worse. Some samples even lost up to 70% of their apparent NAD+ content by the third cycle.
Most earlier studies froze blood samples conventionally before analysis. That means some of the age-related NAD+ declines reported in earlier work may have been picking up sample degradation, not a real biological signal. The Amsterdam team's power analysis showed that with a rigorous method and 20 people per group, they could reliably detect a true difference of at least 7 nmol/mL between groups. No such difference appeared between younger and older adults.
Why Blood May Be the Wrong Window
NAD+ lives mostly inside cells, not floating in blood. Whole blood carries NAD+ in at concentrations 50 to 100 times higher than plasma. The body appears to hold blood NAD+ steady regardless of age or behavior, similar to how serum magnesium can appear normal even when the body's cellular magnesium stores are running low.
That stability in blood does not mean nothing is changing with age. It may mean blood is the wrong place to look.
The original case for NAD+ supplements was built largely on animal studies measuring NAD+ directly in muscle and liver tissue. Those tissue levels did decline in aging mice, and restoring them was associated with measurable improvements. The assumption was that the same thing happens in aging humans, and that blood levels would reflect it. This paper suggests they do not. Whether tissue NAD+ declines with age in humans the way it does in mice remains an open question, one that requires muscle biopsies and more advanced imaging, not blood draws.
What the Data Do and Don't Change
The basic biology of NAD+ is not in question. It plays real roles in energy production, DNA repair, and cellular stress responses. The animal evidence is strong. NR reaches the bloodstream effectively, as the twin study confirms.
What shifts is the rationale for supplementation in healthy adults with no known metabolic problems. A few specific findings worth noting:
Elite athletes had blood NAD+ levels similar to sedentary controls. Years of intense training did not move the number. Whatever exercise does for NAD+ metabolism inside cells, it does not show up in blood.
Niacin status markers also stayed stable. The researchers looked at two additional measures of niacin adequacy, the niacin index and the niacin number, across all cohorts. Neither changed meaningfully with age or intervention.
Some NAD+-related metabolites did shift modestly in certain cohorts even when NAD+ itself did not, which suggests the underlying biology is more complex than a single blood number can capture.
Where the Research Goes From Here
The next phase of NAD+ research will be more targeted. Tissue-specific measurement, using muscle biopsies and imaging that can detect NAD+ directly in relevant compartments, is already underway in several ongoing trials. The populations being studied are more defined: older adults with significant muscle loss, people with mitochondrial disease, patients with specific metabolic conditions where NAD+ metabolism is already known to be impaired.
That narrowing is a sign the field is getting more rigorous, not giving up. Broad claims about universal NAD+ depletion are giving way to more specific, testable questions about who benefits and under what conditions. Those are better questions, and they will produce more useful answers.
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Personal note from Jordan
The longevity space moves faster than the science does. Every few months something new arrives with compelling mechanistic rationale, promising animal data, and a price tag to match the enthusiasm. For most of it right now, including NAD+ precursors, the data are still evolving. We are watching a field figure itself out in real time.
Taking any longevity supplement at this stage is a calculated bet (I am personally a Urolithin A user). You are saying the biology makes sense, the safety profile looks reasonable, and you are willing to act on early evidence because waiting for certainty means waiting a very long time. That is a very defensible position. But the bet only makes sense if you are clear-eyed about what you are buying. Plausibility and potential. Not a proven outcome.
This paper adds a harder question to the NAD+ bet specifically: we may not know whether blood NAD+ is even the right thing to measure. The athlete data is interesting to me. If years of extreme physical stress do not move blood NAD+, the body is working hard to keep that number where it wants it regardless of what we do.
None of this makes NAD+ a bad bet. It just means it’s not a guarantee.