The formal history of NAD+ begins in 1906 with the pioneering work of Arthur Harden and William John Young, whose research built directly upon the foundation laid by Louis Pasteur a few decades earlier. Pasteur had demonstrated that yeast cells were responsible for fermentation, the process in which yeast cells consume sugars and convert them to alcohol and other products. Fermentation in yeast is the same as one of the metabolic processes that occurs in animals and humans to generate energy (lactic acid fermentation). 

In their groundbreaking work, Arthur Harden and William John Young sought to learn more about how yeast perform fermentation.¹ They tried to reproduce the process outside of the yeast cells. Using laboratory techniques, they were able to break open yeast cells and separate their contents into two fractions. They observed that one fraction was heat-sensitive, losing its ability to catalyze fermentation when exposed to elevated temperatures, while another fraction was heat-stable, retaining its activity despite heat treatment.

By separating and then recombining the fractions, Harden and Young were able to show that the fermentation activity of the heat-sensitive fraction depended critically on the presence of the heat-stable one. They surmised that the heat-sensitive fraction contained proteins responsible for fermentation, and the heat-stable fraction contained cofactors and other stable molecules that helped the proteins perform the reactions. Among these was the molecule now known as NAD+.

Originally a student of art, Hans von Euler-Chelpin shifted his focus to chemistry and continued Harden and Young’s work by studying the details of the reactions that occur in the fermentation process. 

In this work, von Euler-Chelpin was able to further separate components of the heat-stable fraction of the yeast cells. In doing so, he purified the NAD+ molecule. von Euler-Chelpin is credited with uncovering the first information about the chemical shape and properties of the cofactor that allowed fermentation reactions to proceed.²

Otto Heinrich Warburg studied the chemical processes of fermentation reactions and discovered that NAD+ is needed for a certain type of chemical reaction, called a hydride transfer. In these reactions, a hydrogen atom along with its electrons is transferred from one molecule to another. These types of reactions are essential to cellular metabolism and many other chemical processes that are required to sustain life. 

Warburg’s work showed that, during fermentation, the nicotinamide portion of NAD+ accepts the hydride to become NADH and allows the reaction to proceed.³

In the early 1900s, pellagra was a common disease that caused symptoms such as diarrhea, dermatitis, and dementia. Joseph Goldberger conducted the first studies linking pellagra to a nutritional deficiency. However, some of his human experiments were controversial and ethically problematic, as they involved deliberately inducing the disease in institutionalized individuals by withholding certain nutritious foods from their diets. 

Conrad Elvehjem furthered this work by performing controlled experiments in dogs. Elvehem observed that when dogs get pellagra, due to a poor diet, their tongues turn black. This model animal system allowed Elvehjem to give dogs different food extracts and see which ones helped dogs recover from the “black tongue” disease. Through careful purification of the food extracts,⁴ Elvehjem discovered that niacin, also known as nicotinic acid, cured pellagra, or “black tongue” disease, in dogs, establishing it as the first identified vitamin precursor of NAD+.⁵

After Hans von Euler-Chelpin’s early purification of NAD+ and Conrad Elvehjem’s discovery of niacin as the nutrient that prevented pellagra, Arthur Kornberg studied the way that NAD+ is made in the body. 

By this time, methods for the purification of proteins and coenzymes had advanced to the point that scientists could purify all the components they thought would be needed for a reaction. They could then test their theories by combining the purified components and looking for evidence that the reaction had happened. 

Kornberg purified the components needed for the NAD-generating reaction from yeast cells and combined them in an experimental setup to demonstrate that they were responsible for creating NAD+. His experiments were the first to demonstrate the chemical reaction cells use to create NAD+ from the precursor molecule nicotinamide mononucleotide (NMN).⁶

While Conrad Elvehjem had shown that nicotinic acid prevents pellagra, and Arthur Kornberg had demonstrated how cells synthesize NAD+ from NMN, the connection between niacin and NAD+ production remained unclear.

Jack Preiss and Philip Handler addressed this gap, demonstrating that niacin is converted into NAD+ through a three-step process and identifying the enzymes responsible for each step. This metabolic route is now known as the Preiss-Handler pathway.⁷'⁸

By this time, researchers had established that NAD+ was essential for fermentation in yeast and for health in humans and animals, and they had elucidated various pathways by which cells synthesize NAD+. However, no studies had yet demonstrated how NAD could be chemically broken down. 

Mandel and colleagues identified a reaction in which NAD+ is cleaved into two components: nicotinamide and ADP-ribose.⁹

Sirtuin enzymes were first identified in yeast for their remarkable ability to extend lifespan. Biochemical studies investigating how yeast sirtuins influence longevity revealed that these enzymes use NAD+ to regulate gene activity by keeping certain genes “silent”  so they cannot function. 

To do this, the sirtuin enzymes break NAD+ and use its components to “deacetylate” other proteins in the cell. Deacetylating histone proteins associated with DNA, for example, can change how the cell accesses nearby genes in the DNA.¹⁰

Similar to the discoveries of niacin by Conrad Elvehjem and the work of Preiss and Handler, Brenner and colleagues identified a new NAD+ precursor called nicotinamide riboside (NR). They also characterized the enzymes that eukaryotic cells use to convert NR into NAD+. 

Their studies uncovered a two-step pathway for this conversion, and follow-up work showed that feeding cells with NR increased NAD+ levels and extended yeast lifespan.¹¹'¹²

During the 2010s, research on NAD+ accelerated dramatically, driven by growing evidence that NAD+ levels decline with age.¹³

The decade also saw the emergence of translational research, with clinical studies investigating NAD+ precursors, such as NR and NMN, as potential therapeutics for metabolic, neurodegenerative, and cardiovascular disorders. 

Collectively, the 2010s established NAD+ as a central target in age-related health and disease.

Research on NAD+ has entered an exciting new era, with scientists worldwide uncovering its broad therapeutic potential, including applications for neurodegenerative diseases such as Parkinson’s¹⁴ and Alzheimer’s disease.¹⁵ Recent studies have expanded our understanding of NAD+ beyond its essential role in cellular energy metabolism, highlighting its significance for brain health,¹⁴ cognition,¹⁶ and heart health.¹⁷

Researchers are actively investigating strategies to boost NAD+, with studies on precursors like NR and NMN appearing almost weekly. Human clinical trials at various stages are shedding light on how NAD+ impacts cardiovascular and neurological health, as well as broader areas such as muscle function and overall wellness. 

Reflecting this growing scientific and public interest, NAD+ supplementation is gaining traction in the consumer space, from intravenous therapies and injectables to oral supplements and liposomal formulations, as more people seek evidence-based ways to support long-term health.