Who Found NAD+, and When Did NMN and NR Reach Human Trials?

Arthur Harden and W. J. Young reported the factor in 1906, while they studied how yeast juice ferments sugar. Today that factor is called NAD+. Yeast and worm studies linked it to lifespan in 2000 and 2001. The first human study of NR, a form of vitamin B3, came in 2016. The earliest human NMN study we verified came in 2019.

The short answer

Arthur Harden and W. J. Young found the factor in 1906, while they studied how yeast juice ferments sugar. Today that molecule is called NAD+.

The first human study of nicotinamide riboside (NR), a form of vitamin B3, came in 2016. The earliest human study of nicotinamide mononucleotide (NMN) that we verified came in 2019. Both tested single doses between 100 and 1,000 mg.

Check the milligrams on any label against those doses. The NAD+ pillar covers the aging science.

Who found NAD+, and what did they call it?

The surprise comes early. Researchers expected heat to destroy the enzymes in yeast juice. Harden showed that boiled yeast extract could still boost fermentation, because it held a heat-stable co-enzyme containing phosphate. Adding potassium phosphate set off vigorous fermentation (Nature, 1965).

Harden and his team pushed Buchner's yeast juice through a gelatine ultrafilter. The juice split into two fractions, and neither could ferment on its own. Recombined, they fermented again. Harden explained that a large enzyme, zymase proper, stayed on the filter while a small partner passed through. The 1929 Nobel committee wrote that this partner was called co-enzyme or co-zymase, "for the sake of brevity" (Nobel Prize, 1929).

The 1906 discovery is credited to Harden with W. J. Young. The Spektrum lexicon lists zymase and, as a component of yeast enzymes, cozymase, whose current designation is NAD (Spektrum, Kompaktlexikon der Biologie). Buchner had won the 1907 Nobel Prize for non-cellular fermentation. Harden shared the 1929 prize with Hans von Euler-Chelpin, who went on to purify the co-enzyme (Nature, 1965).

The name changed. The molecule did not. Harden and Young reported the factor, and it is now called NAD+.

What did Warburg show about the molecule?

Otto Warburg won the 1931 Nobel Prize in Physiology or Medicine for work on the respiratory enzyme of living cells. That enzyme was an iron-containing heme group, a different molecule from the coenzymes. The Neue Deutsche Biographie says it corresponds to what was later described as cytochrome c oxidase (NDB, Warburg, Otto Heinrich).

The part that matters here came in the 1930s. Warburg identified two coenzymes that remove hydrogen during cell respiration. The NDB lists them as the molecules now known as NAD and NADP. It also says he was nominated for the Nobel Prize again in 1944 for those results.

The sources we checked do not tie those coenzymes to aging. That connection came decades later, through the yeast and worm work below.

When did scientists link NAD+ levels to aging?

The link ran through yeast. In 2000, Lin, Defossez and Guarente showed that yeast lived longer on a restricted diet, and that the extension vanished in strains lacking the SIR2 gene or NPT1, a gene in the NAD+ synthesis pathway (Lin et al., Science, 2000). They concluded that the longer life appears to require NAD+ to activate Sir2.

In 2011, Yoshino and colleagues reported that levels of NAD+, and of NAMPT (the rate-limiting enzyme in mammalian NAD+ synthesis), fell in several organs as mice aged (Yoshino et al., Cell Metabolism, 2011). That paper returns in the NMN section below.

For the human side of NAD+ and age, read the NAD+ pillar. This page stays with the history.

How did sirtuins connect NAD+ to aging research?

Sirtuins are enzymes that remove acetyl groups from histones, the proteins DNA wraps around, and they need NAD+ to do it. In 2000, Imai and colleagues showed that yeast and mouse Sir2 proteins are NAD-dependent histone deacetylases. They argued that this activity connects metabolism, gene silencing and aging in yeast and, perhaps, in higher organisms (Imai et al., Nature, 2000).

A year later, Tissenbaum and Guarente tested the idea in worms. An extra copy of sir-2.1, the worm gene closest to yeast SIR2, extended lifespan by up to 50 percent in Caenorhabditis elegans (Tissenbaum and Guarente, Nature, 2001).

Neither study tested a supplement. They explain why researchers wanted to raise NAD+ in the first place.

When was NMN first shown to raise NAD+ in animals, and when did human trials start?

NMN was in the biochemistry literature by 1963. That year, Chambon, Weill and Mandel reported that nicotinamide mononucleotide (NMN) activated a nuclear enzyme that makes polyadenylic acid (Chambon et al., 1963). The PubMed record has no abstract, so that claim rests on the title and on a 2015 review. The review calls the Mandel group's 1960s work a milestone in ADP-ribosylation research, a family of reactions that add ADP-ribose units to proteins. It places the experiment in rat liver nuclear extracts (Faraone-Mennella, 2015).

In the papers we checked, the first NMN study to raise NAD+ in animals is from 2011. Yoshino and colleagues reported that NMN restored NAD+ levels in mice fed a high-fat diet and improved their glucose tolerance, meaning how quickly blood sugar clears after a sugar load (Yoshino et al., 2011). It is the earliest animal NMN study this page cites.

The first human pharmacokinetic study of nicotinamide riboside (NR) came in 2016. Pharmacokinetic means how the body absorbs, spreads and clears a compound. The authors describe it as the first clinical trial of NR pharmacokinetics in humans. Trammell and colleagues gave single oral doses of 100, 300 and 1,000 mg and found blood NAD+ metabolites rising with dose. In a pilot in one person, blood NAD+ rose as much as 2.7-fold (Trammell et al., Nature Communications, 2016). Two co-authors list ChromaDex as their affiliation. ChromaDex makes NIAGEN, the NR ingredient used in the 2018 trial below.

The earliest human NMN study we verified was published online in 2019. Irie and colleagues gave 10 healthy Japanese men single oral doses of 100, 250 and 500 mg. The design had no placebo arm. The team tracked clinical measures and plasma levels of two nicotinamide metabolites for five hours, and reported no significant clinical symptoms and dose-dependent rises in those metabolites (Irie et al., Endocrine Journal, 2019). The abstract does not report NAD+ itself. This was an absorption and safety study, not a test of NAD+ levels.

Randomized human trials followed. In 2018, Martens and colleagues enrolled 30 healthy adults aged 55 to 79. In a crossover design, each person took 500 mg of NR twice a day for six weeks and placebo for six weeks, in random order. Crossover means everyone receives both treatments, one after the other. NAD+ in peripheral blood mononuclear cells, the white blood cells drawn in a blood sample, was about 60 percent higher on NR than on placebo. Seven of the 30 reported mild side effects, including nausea (Martens et al., Nature Communications, 2018).

In 2021, Yoshino and colleagues ran a 10-week, randomized, double-blind, placebo-controlled trial in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, measured with a clamp (a test that holds insulin high and infuses glucose to see how fast the body clears it), rose after NMN and did not change on placebo (Yoshino et al., Science, 2021). A published comment argued that the groups differed in liver fat at baseline, and that the trial was not effectively randomized. The authors replied that muscle insulin sensitivity was identical in both groups at the start (Brenner, 2021; Klein and Yoshino, 2021).

Grades, per outcome. NR and blood NAD+ markers: Moderate, on the strength of the 2018 trial alone. NMN and insulin-stimulated glucose disposal: Preliminary, because it is one trial of 25 women with a disputed baseline. NMN absorption and safety: Preliminary, because it used single doses in 10 men with no placebo. Animal and yeast results: Insufficient for people.

Why does the history matter for buying NMN or NR today?

The record is young, and the studies are small and short. The NR studies we verified used single doses or six-week periods. The one NMN trial with a placebo arm that we verified ran ten weeks. Those are the lengths to hold a label against.

How do you check a claim before you buy?

1. Find the species. A yeast, worm or mouse result is a starting point. It is not a human result.
2. Find the dose. Put the milligrams on the label beside the dose in the human study. Note whether that study used one dose or weeks of daily dosing.
3. Match the form. NMN and NR were tested in different studies, so a result for one does not carry over automatically to the other.
4. Match the outcome. A blood NAD+ marker, a plasma metabolite and a clamp test each measure something different from how you feel.
5. Check the lot. The certificate for the exact lot is the closest match to the bottle in your hand.

The label checklist covers how to confirm the amounts, the lot certificate and which tests an outside lab ran.

When should you ask a clinician first?

Ask a clinician before you start NMN or NR if you are pregnant or nursing, take prescription medicines, or are treating a medical condition. Most human studies here were short and small, so information on interactions with medicines is thin. If you notice an unexpected reaction, stop and talk to your clinician before you restart.

Where does one product fit?

Mt. Angel Vitamins sells a two-capsule NMN and NR serving in a 60-capsule bottle. Each serving lists 500 mg NMN and 200 mg NR. It also lists 250 mg resveratrol, 50 mg TMG, 50 mg black pepper extract and 10 mg zinc, which this article does not cover. The bottle holds 30 servings and costs $59.99, about $2.00 a day. The product page links a lot-level certificate of analysis.

The NMN amount sits at the top of the single-dose range in the 2019 study. The NR amount sits between the 100 mg and 300 mg doses in the 2016 study. Those are single-dose comparisons, so they do not show what a daily product does over time. See the product page.

Next reads

• The NAD+ pillar for the full aging science and the human data on NAD+ levels.
• Where a two-capsule serving sits in the trials, with the dose question worked through study by study.
• The NMN monograph, with its evidence record and safety section, if you want the NMN detail in one place.

Related reading

• Is NMN legal in US supplements? The FDA timeline from 2022
• Epigenetic clocks and NAD precursors
• where niacin fits in the NAD timeline

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