One hundred and twenty years of the coenzyme

1906Harden & Young find the co-zymase

At the Lister Institute in London, Arthur Harden and William John Young show that yeast fermentation needs two things: the enzyme fraction and a small, heat-stable factor they call the co-zymase. That factor is nicotinamide adenine dinucleotide. Harden shares the 1929 Nobel Prize in Chemistry (with Hans von Euler-Chelpin, who went on to purify and characterize the coenzyme) for the fermentation work that began here.

Nicotinamide adenine dinucleotide — history

1930sWarburg puts it in the redox engine

Otto Warburg and Walter Christian demonstrate the pyridine coenzymes' role in hydride transfer — NAD+ and its phosphate cousin NADP+ become the recognized electron currency of metabolism. For half a century, NAD+ is biochemistry's workhorse: essential, everywhere, and — it is assumed — fully understood.

2000Imai, Armstrong, Kaeberlein & Guarente — the sirtuin connection

At MIT, Shin-ichiro Imai, Christopher Armstrong, Matt Kaeberlein and Leonard Guarente publish "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase" in Nature. Sir2 — tied to lifespan in yeast — does not just need NAD+ nearby; it cleaves it to function. Metabolism and gene regulation turn out to share a molecule, and NAD+ becomes a longevity target.

Imai S. et al., Nature 403, 795 (2000) — abstract

2004Bieganowski & Brenner discover nicotinamide riboside

Paul Bieganowski and Charles Brenner (then at Dartmouth) identify nicotinamide riboside — NR — as a nutrient and map the NRK genes as a Preiss-Handler-independent route to NAD+ in fungi and humans. The first modern NAD+ precursor vitamin enters the record.

Bieganowski P., Brenner C., Cell 117, 495 (2004) — abstract

2012Massudi and colleagues measure the decline

Hassan Massudi, Ross Grant, Nady Braidy and colleagues (University of New South Wales / Sydney research community) report age-associated changes in oxidative stress and NAD+ metabolism in human tissue: NAD+ declines with age. The observation converts NAD+ from housekeeping chemistry into a restoration hypothesis.

Massudi H. et al., PLoS ONE 7, e42357 (2012) — abstract

2014The PARP ledger is written down

Elise Fouquerel and Robert Sobol review how PARP1 activation consumes NAD+ during DNA repair — enough, under heavy damage, to collapse cellular NAD+ and drive cell death. Every repair event is a withdrawal from the same account sirtuins draw on.

Fouquerel E., Sobol R.W., DNA Repair 23, 39 (2014) — abstract

2016The Imai lab's NMN mouse study

Kathryn Mills, Sho Yoshida, Liana Stein and colleagues in Shin-ichiro Imai's laboratory at Washington University School of Medicine in St. Louis show long-term NMN administration mitigates age-associated physiological decline in mice — the precursor strategy's flagship animal result.

Mills K.F. et al., Cell Metabolism 24, 795 (2016) — abstract

2018Humans enter the data; Sinclair's lab tallies the evidence

Christopher Martens and colleagues (University of Colorado Boulder) publish the first rigorous chronic NR supplementation trial in healthy middle-aged and older adults: NR raises NAD+ and is well tolerated (Nature Communications). The same year, Luis Rajman, Karolina Chwalek and David Sinclair (Harvard Medical School) review the in-vivo evidence for NAD-boosting molecules — the field's reference assessment, including its open questions.

Martens C.R. et al., Nat Commun 9, 1286 (2018) — abstract · Rajman L. et al., Cell Metab 27, 529 (2018) — abstract

2019–20A transporter, and the first human NMN data

Alessia Grozio, Mills, Jun Yoshino and colleagues identify Slc12a8 as an NMN transporter (Nature Metabolism, 2019) — cells have a dedicated door for the precursor. In 2020, Junichiro Irie and colleagues at Keio University report the first clinical-parameter study of oral NMN in healthy Japanese men: NMN is tolerated and raises NAD+ metabolites.

Grozio A. et al., Nat Metab 1, 47 (2019) — abstract · Irie J. et al., Endocr J 67, 153 (2020) — abstract