The coenzyme NAD was first discovered by the British biochemists Arthur Harden and William John Young in 1906. They noticed that adding boiled and filtered yeast extract greatly accelerated alcoholic fermentation in unboiled yeast extracts. They called the unidentified factor responsible for this effect a coferment. Through a long and difficult purification from yeast extracts, this heat-stable factor was identified as a nucleotide sugar phosphate by Hans von Euler-Chelpin. In 1936, the German scientist Otto Heinrich Warburg showed the function of the nucleotide coenzyme in hydride transfer and identified the nicotinamide portion as the site of redox reactions.
Vitamin precursors of NAD were first identified in 1938, when Conrad Elvehjem showed that liver has an "anti-black tongue" activity in the form of nicotinamide. Then, in 1939, he provided the first strong evidence that niacin is used to synthesize NAD. In the early 1940s, Arthur Kornberg was the first to detect an enzyme in the biosynthetic pathway. In 1949, the American biochemists Morris Friedkin and Albert L. Lehninger proved that NADH linked metabolic pathways such as the citric acid cycle with the synthesis of ATP in oxidative phosphorylation. In 1958, Jack Preiss and Philip Handler discovered the intermediates and enzymes involved in the biosynthesis of NAD; salvage synthesis from nicotinic acid is termed the Preiss-Handler pathway. In 2004, Charles Brenner and co-workers uncovered the nicotinamide riboside kinase pathway to NAD.
The non-redox roles of NAD(P) were discovered later. The first to be identified was the use of NAD as the ADP-ribose donor in ADP-ribosylation reactions, observed in the early 1960s. Studies in the 1980s and 1990s revealed the activities of NAD and NADP metabolites in cell signaling – such as the action of cyclic ADP-ribose, which was discovered in 1987.
The metabolism of NAD remained an area of intense research into the 21st century, with interest heightened after the discovery of the NAD-dependent protein deacetylases called sirtuins in 2000, by Shin-ichiro Imai and coworkers in the laboratory of Leonard P. Guarente. In 2009 Imai proposed the "NAD World" hypothesis that key regulators of aging and longevity in mammals are sirtuin 1 and the primary NAD synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). In 2016 Imai expanded his hypothesis to "NAD World 2.0", which postulates that extracellular NAMPT from adipose tissue maintains NAD in the hypothalamus (the control center) in conjunction with myokines from skeletal muscle cells. In 2018, Napa Therapeutics was formed to develop drugs against a novel aging related target based on the research in NAD metabolism conducted in the lab of Eric Verdin.