A century after the identification of a coenzymatic activity for NAD(+), NAD(+) metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite.

In fact, the actions of NAD(+) have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD(+)-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions.

Through these effects, NAD(+) provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD(+)-dependent pathways may have a major contribution to oxidative metabolism and life span extension.

In this review, we will provide an integrated view on:
1) the pathways that control NAD(+) production and cycling, as well as its cellular compartmentalization;
2) the signaling and transcriptional pathways controlled by NAD(+); and
3) novel data that show how modulation of NAD(+)-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.

About the Authors

Houtkooper RH, Cantó C, Wanders RJ, Auwerx J. (2010) The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev. 2010 Apr;31(2):194-223. Ecole Polytechnique Fédérale de Lausanne, Laboratory for Integrative and Systems Physiology, Building AI, Station 15, CH-1015 Lausanne, Switzerland.