NAD+

Overview

NAD+ (nicotinamide adenine dinucleotide) is not a peptide: it is a coenzyme made of two nucleotides, one carrying adenine and one carrying nicotinamide, joined through their phosphate groups. It appears in this index as a related compound because it is studied and discussed alongside longevity peptides.

Every living cell uses NAD+. It shuttles electrons in the reactions that turn food into usable energy, and it is consumed as a raw material by several enzyme families, including the sirtuins, the PARP enzymes involved in DNA repair, and CD38, an enzyme on immune and other cells.

Research interest comes from a consistent observation: NAD+ levels decline with age in rodents and, in the more limited data available, in human tissues. That has led to many studies of whether raising NAD+ affects aging biology. Most human work uses precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) rather than NAD+ itself, because NAD+ is a large molecule that is thought to be broken down largely outside cells before it can be used. For a full review of the precursor trials, see NAD+ precursors and cellular aging.

Research history

NAD+ was first identified in 1906 by Arthur Harden and William John Young, who found that a heat-stable factor in yeast extract was needed for fermentation. Its chemical structure and its role in carrying hydrogen in metabolic reactions were worked out over the following decades, with Otto Warburg and Hans von Euler-Chelpin among the key contributors.

For most of the twentieth century NAD+ was studied as a metabolic cofactor. The picture changed around 2000, when the sirtuin enzymes were found to require NAD+ to function, linking the molecule to research on calorie restriction and aging in yeast, worms and mice.

In 2016 Camacho-Pereira and colleagues showed in mice that the enzyme CD38 rises with age and is required for much of the age-related NAD+ decline. Around the same time, human trials of NR and NMN began, and clinics started offering intravenous NAD+ infusions well ahead of controlled data on that route.

What published studies have examined

Reviews and animal studies

• Reviews (2018 and 2021). Rajman, Chwalek and Sinclair reviewed in vivo evidence for NAD+-raising molecules, and Covarrubias and colleagues reviewed NAD+ metabolism in aging. Both describe strong and broad rodent evidence, with human evidence still early.
• CD38 and decline (2016). In mice, CD38 expression and activity increased with age, and animals lacking CD38 were protected from age-related NAD+ decline and mitochondrial dysfunction. CD38 was also the main enzyme breaking down NMN in the body.

Human studies with NAD+ itself

• Intravenous infusion pilot (2019). Grant and colleagues measured blood and urine in a small group of healthy volunteers during a six-hour intravenous NAD+ infusion. Plasma NAD+ did not rise for the first two hours, suggesting rapid removal and breakdown, and NAD+ and methylnicotinamide appeared in urine. This was a pharmacokinetic pilot without a control group and did not measure health outcomes.

Human studies with precursors

• NR in middle-aged and older adults (2018). Martens and colleagues ran a randomized, double-blind, placebo-controlled crossover trial and found NR was well tolerated and raised markers of NAD+ metabolism. Blood pressure and arterial stiffness signals were exploratory.
• NR in aged muscle (2019). Elhassan and colleagues gave 12 older men NR or placebo in a crossover trial. The muscle NAD+ metabolome rose and some circulating inflammatory cytokines fell, without changes in mitochondrial bioenergetics.
• NMN in prediabetes (2021). Yoshino and colleagues reported improved muscle insulin sensitivity after 10 weeks of NMN in a small randomized trial of postmenopausal women with prediabetes and overweight or obesity.

Open questions

• Does raising NAD+ matter clinically? Precursors reliably raise NAD+ markers in people, but functional benefits have been small and inconsistent, and no trial has shown slower aging or longer life.
• Direct NAD+ delivery. Evidence on what intravenous or injected NAD+ does in the body is limited to small pilot work. How much reaches cells intact, rather than being broken down to smaller molecules, is unclear.
• Which tissues decline, and by how much. Human measurements are sparse, and methods for measuring NAD+ in tissue vary between labs.
• Long-term safety. NAD+ supports the metabolism of all cells, including cancer cells. Whether chronically raising it carries risks has not been tested in long human trials.
• Industry funding. Several precursor trials have been funded wholly or in part by supplement manufacturers, which readers should weigh when judging the results.