Few molecules have moved from biochemistry textbooks to supplement shelves as fast as NAD+. It is a coenzyme present in every living cell, its levels fall in some tissues with age, and two of its building blocks, NMN and nicotinamide riboside, are now widely sold as “NAD boosters”. This guide explains what NAD+ actually does, how its precursors feed it, what human trials have and have not shown, and how researchers measure it.
The short answer
- NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that shuttles electrons in energy metabolism and is consumed as a substrate by enzymes including sirtuins, PARPs, which help repair DNA, and CD38.
- Cells make most of their NAD+ by recycling nicotinamide through the salvage pathway, in which NMN (nicotinamide mononucleotide) is the direct precursor. Nicotinamide riboside (NR) feeds the same pathway by being converted to NMN.
- In rodents, and in some human tissues, NAD+ declines with age. In mice, the NAD+-consuming enzyme CD38, which rises with age, is a major driver.
- Human trials show NR and NMN can raise NAD+-related molecules in blood and are generally well tolerated, but clinical benefits so far have been modest and inconsistent.
- NAD+ is not a peptide, but it sits at the centre of the metabolism and ageing research in which peptides such as MOTS-c and SS-31 are studied.
What NAD+ does
NAD+ has two jobs. The first is as an electron carrier: in glycolysis, the citric acid cycle and the mitochondria’s energy-producing machinery, NAD+ picks up electrons to become NADH, then hands them on so the cell can make ATP. In that role it is recycled, not used up.
The second job consumes it. Several enzyme families break NAD+ apart to do their work: sirtuins, which remove acetyl tags from proteins and help regulate metabolism and stress responses; PARPs, which flag and help repair damaged DNA; and CD38, an enzyme on immune and other cells that degrades NAD+. Because these enzymes use NAD+ up, cells must constantly rebuild it.
From yeast to pellagra: a short history
- 1906Arthur Harden and William Young find a heat-stable factor in yeast extracts that is needed for fermentation, later identified as NAD.
- 1929Harden and Hans von Euler-Chelpin share the Nobel Prize in Chemistry for work on sugar fermentation and its enzymes.
- 1937Conrad Elvehjem shows that nicotinic acid, a form of niacin, cures black tongue in dogs, the canine version of pellagra, linking an NAD+ building block to a deficiency disease.
- 2010sWork in mice links falling NAD+ to ageing, and NMN and NR enter human trials.
How cells make NAD+
Cells can build NAD+ from the amino acid tryptophan or from niacin, but most of it comes from the salvage loop above, which recycles the nicotinamide released each time an enzyme uses NAD+ up. How NMN gets into cells is still debated: much of it appears to be converted to NR outside the cell first, and a dedicated NMN transporter reported in mouse gut in 2019 remains contested.
NAD+ and ageing
In mice, NAD+ levels fall in several tissues with age, and restoring them with precursors has improved a range of age-related measures in animal studies. A 2016 study in Cell Metabolism identified CD38, whose levels rise with age, as a major cause of that decline in mice.
The human picture is more variable. Declines have been reported in some tissues and blood measures, but their size depends on the tissue, the population and the measurement method, and it is not established that low NAD+ is a cause of human ageing rather than one of its markers.
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View NAD+What the human trials show
| Study | Precursor and participants | Main findings |
|---|---|---|
| Martens et al., 2018 | NR, healthy middle-aged and older adults | Well tolerated; raised NAD+ in blood. Effects on physiological measures were exploratory. |
| Yoshino et al., 2021 | NMN, 25 postmenopausal women with prediabetes, 10 weeks, placebo-controlled | Muscle insulin sensitivity improved by about 25%; liver insulin sensitivity did not change; muscle NAD+ itself did not measurably rise. |
| Igarashi et al., 2022 | NMN, healthy older men | Raised blood NAD+; some muscle function measures changed. |
The pattern across trials is consistent: the precursors reliably raise NAD+-related molecules in blood, and they have been well tolerated in the short term, but clinical effects have been small, specific to particular measures and not always replicated. Raising a number in blood is not the same as showing a health benefit; our guide on how to read a study explains the difference between surrogate and clinical outcomes.
Reasonably well established
- NAD+ is essential for energy metabolism and is consumed by sirtuins, PARPs and CD38.
- NR and NMN raise NAD+-related molecules in human blood.
- NAD+ declines with age in several mouse tissues, driven partly by CD38.
Open questions
- Whether raising NAD+ produces meaningful health benefits in people.
- How much NAD+ declines in different human tissues with age.
- Long-term safety of sustained supplementation.
How NAD+ is measured
NAD+ is tricky to measure. Its reduced partner, NADH, is unstable, so samples must be handled and extracted quickly and consistently. Laboratories use enzymatic cycling assays or, increasingly, liquid chromatography with mass spectrometry, which can measure NAD+ and its related metabolites together. Results also differ between whole blood, blood cells and tissue biopsies, which is one reason studies are hard to compare. Our guides to reading an HPLC chromatogram and reading a mass spectrum explain the two halves of LC-MS.
Where peptides fit in
- MOTS-c, a mitochondrial-derived peptide, acts on the energy sensor AMPK; see our MOTS-c guide.
- SS-31 binds a lipid in the inner mitochondrial membrane, where NADH hands over its electrons; see the mitochondrial peptides.
- 5-Amino-1MQ blocks NNMT, an enzyme that uses up nicotinamide, the raw material of the salvage loop; see our 5-Amino-1MQ guide.
Research use only. Pure Peptides Canada products are laboratory reagents, not for human or veterinary use. This article summarizes published research for education and is not medical or nutritional advice.
Frequently asked questions
What is NAD+?
NAD+ (nicotinamide adenine dinucleotide) is a coenzyme found in every living cell. It carries electrons in energy metabolism and is consumed by enzymes such as sirtuins, PARPs and CD38, so cells must continually rebuild it.
What is NMN?
NMN (nicotinamide mononucleotide) is the molecule one step before NAD+ in the salvage pathway. It is made from nicotinamide by the enzyme NAMPT and converted to NAD+ by NMNAT enzymes.
What is nicotinamide riboside?
Nicotinamide riboside (NR) is a form of vitamin B3 that cells convert to NMN using NRK enzymes, and then to NAD+. It has been tested in several small human trials.
Do NAD+ levels decline with age?
In mice, NAD+ falls in several tissues with age, partly because the NAD+-consuming enzyme CD38 rises. In people, declines have been reported in some tissues, but their size varies with the tissue and measurement method.
Do NMN or NR supplements work?
Trials show they raise NAD+-related molecules in blood and are generally well tolerated in the short term. Clinical benefits have been modest and specific, such as improved muscle insulin sensitivity in one 2021 trial of prediabetic women, and are not yet established.
What is the difference between NMN and NR?
Both feed the NAD+ salvage pathway. NR is converted to NMN inside cells by NRK enzymes, while NMN is one step closer to NAD+; much NMN may be converted to NR before entering cells.
Metabolism research, with the evidence in view
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References
- Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9:1286.
- Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224–1229.
- Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016;23(6):1127–1139.
- Igarashi M, et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj Aging. 2022;8:5.
- Harden A, Young WJ. The alcoholic ferment of yeast-juice. Proc R Soc Lond B. 1906;77:405–420.
For laboratory research use only. Not for human or veterinary use. This article is educational and is not medical advice.