A molecule called NAD+ sits at the center of one of the best-selling ideas in longevity: that its levels fall as people age, and that pills or infusions that raise it might help. A study published in the journal Nature Metabolism tested the first half of that idea in human blood and did not find the expected drop1. The paper, by Trętowicz and colleagues, is titled “Human whole-blood NAD+ levels do not vary with age or lifestyle interventions”1.
NAD+ is a helper molecule found in every cell. It shuttles energy during the chemical reactions that turn food into fuel, and it is needed by sirtuins and by PARP enzymes, which help repair damaged DNA2. Studies in animals, mostly mice, showed tissue levels falling with age, and that finding became the rationale for a multibillion-dollar supplement industry built around NAD+ “precursors” such as NR and NMN, which the body turns into NAD+2.
What the researchers found
The team measured NAD+ in whole blood from seven separate groups of people, more than 300 adults in total2. The groups ranged from people in their twenties to people in their late eighties2. They used a mass spectrometry test, a precise lab method for weighing molecules, that they had checked for accuracy, and they ran calculations in advance on how many people they would need to detect a difference1.
Blood NAD+ did not fall with age in any of the groups2. When levels were plotted against age, the lines were close to flat, and age accounted for about 1% of the differences between people2. In a subset of the Leiden Longevity Study, with people aged 63 to 87, there was no age trend at all1.
The researchers also looked at whether lifestyle changed blood NAD+:
- Elite athletes had the same blood NAD+ levels as people who did not exercise, though some related molecules differed modestly2.
- In frail older adults, three months of resistance exercise, a protein-rich diet, and a six-month combined exercise and nutrition program did not measurably change blood NAD+2.
- A supplement, nicotinamide riboside (NR), did raise blood NAD+12.
That last result matters for how the others are read. Because the test picked up the rise from NR, the flat results elsewhere are less likely to be due to a test that was not sensitive enough2.
Why earlier studies may have seen a drop
The paper offers a possible explanation for older reports of declining blood NAD+. Freezing blood before testing caused NAD+ to break down by 21 to 27%, according to the study, as red blood cells burst and expose the molecule to enzymes that consume it, including one called CD382. Because this breakdown varies from sample to sample, it can create differences between groups that are not biological2. Salim Hayek, who summarized the paper on LinkedIn, wrote that a single freeze-thaw cycle “introduces enough variance to swamp the age effects most prior studies have reported”1.
The authors also argue many earlier studies were too small. With the variation typical of frozen samples, groups of 20 people could reliably detect only differences larger than 7 nanomoles per milliliter, and several studies that reported age-related declines used smaller groups and reported smaller effects2.
Earlier results were genuinely mixed. A 2022 paper noted that a drop in blood NAD+ with age had been reported in about half of human studies but not in the other half3. That 2022 study, of 1,518 adults in a community in China with no heart disease or cancer, found an average level of 33.0 micromoles per liter3. Men had higher levels than women (34.5 versus 31.3)3. Overall, levels trended down before age 50 and the trend disappeared after 50; in men, the drop compared with the youngest group was significant only at age 60 and over, and in women there was no significant difference across age groups3. One of that study’s authors was affiliated with the BYHEALTH Institute of Nutrition & Health3.
What the study does not show
The study measured blood, not organs. According to Hayek, the authors note that NAD+ inside cells of specific tissues may still decline, and they do not claim NR is useless1. Their claim is narrower: that whole-blood NAD+ is unlikely to work as a marker of how the whole body is aging1.
The study also does not test whether raising NAD+ improves health. It shows that a supplement can raise the blood level, not what that rise does2.
The criticism
AboutNAD, a website devoted to NAD+, published a detailed critique calling the paper “a refinement of the NAD+ aging hypothesis, not a refutation of it”4. Its main points:
- Blood is not tissue. Direct human measurements in skin, brain, skeletal muscle and liver show age-related NAD+ decline, the site wrote, and stable blood levels do not contradict that4.
- Red blood cells. Red blood cells make up roughly 40 to 45% of blood volume and carry much of its NAD+, and their counts tend to fall with age and be lower in women4. The study did not adjust for this. The authors ran exploratory checks in two smaller sub-groups and found no link, but acknowledged these “were not designed to formally test this relationship” and recommended future studies record red cell levels at blood draw4.
- Pooled small studies. Combining several smaller studies adds variation and can hide modest real effects, the site argued4.
The site quoted Howard Sesso of Harvard Medical School:
Their finding that NAD+ levels do not vary with age is provocative, but it is very difficult to make a definitive conclusion when combining several smaller underpowered observational studies and clinical trials.4
The critique also pointed to the 2022 study of 1,518 adults as one that found a decline in blood4. As described above, that decline was limited to certain age ranges and to men3.
Who is behind the coverage
The sources available to Biohack do not say who funded the Nature Metabolism study or whether its authors have ties to supplement makers. The two longer write-ups come from sites in the NAD and longevity space: AboutNAD, which focuses on NAD+, and Healthspan, a longevity site42. Readers should weigh both the praise and the criticism with that in mind.
How it fits the field
The finding lands on a busy market. Hayek wrote that clinics sell NAD+ infusions and that direct-to-consumer NAD+ blood tests sell the idea of blood NAD+ as a measure of aging, which is the use this study questions1. Healthspan’s summary made a related point: using blood NAD+ to judge whether a supplement is affecting aging may be measuring the wrong thing2.
The two sides agree on more than the headlines suggest. Both accept that blood NAD+ alone is a poor gauge of age42. They differ on how much the result should change belief in an age-related decline across the body. AboutNAD put the open question as “where, in whom, and with what consequences” NAD+ declines4.
What to watch next
- Larger single studies that measure blood NAD+ carefully, without freezing problems, and record red blood cell counts at the time of the blood draw, as the authors recommended4.
- Studies that measure NAD+ directly in muscle, liver, brain and skin in people of different ages4.
- Whether companies selling NAD+ blood tests or infusions respond to the finding1.
