NAD homeostasis in health and disease
Authors: Johan Auwerx
Dina Hofer
Mario Romani
Elena Katsyuba
Journal: Nature metabolism (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: NAD+; metabolism; sirtuin; longevity; ageing
Affiliations: Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Nagi Bioscience, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Thermo Fisher Scientific, Zug, Switzerland., Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. .

Abstract:  The conceptual evolution of nicotinamide adenine dinucleotide (NAD+) from being seen as a simple metabolic cofactor to a pivotal cosubstrate for proteins regulating metabolism and longevity, including the sirtuin family of protein deacylases, has led to a new wave of scientific interest in NAD+. NAD+ levels decline during ageing, and alterations in NAD+ homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes and cancer. In preclinical settings, various strategies to increase NAD+ levels have shown beneficial effects, thus starting a competitive race to discover marketable NAD+ boosters to improve healthspan and lifespan. Here, we review the basics of NAD+ biochemistry and metabolism, and its roles in health and disease, and we discuss current challenges and the future translational potential of NAD+ research. 

Retracted: No

PubPeer comments:
 In this recent excellent review, Katsyuba et al. discuss NAD+ metabolism and pharmacological strategies to manipulate NAD+ tissue levels in experimental models and humans. The authors include acipimox, a well-known lipolysis inhibitor acting via the HCAR2 receptor mainly in adipose tissue, in their table of u201cNAD+ boostersu201d (see part of Table 5 as an example). I would like to draw the attention of the authors to my earlier comment (see quote below) on Pubpeer regarding the publication (cited in the current review) van de Weijer, T. et al. Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans. Diabetes 64, 1193u20131201 (2015) to which the authors have not responded. I would be happy if the authors would now clarify this. Also, they may want to consider correcting the title of Table 5 to u201cTherapeutic potential of NAD+ boosters and niacin analogs in humansu201d Quote from my earlier comment: u201cIn this interesting study, the authors state in the title  ... effects of the NAD+ precursor acipimox... , in the Introduction  However, besides the known effects of acipimox on lipolysis, acipimox is also an NAD+ precursor. and in Discussion  ...a standard clinical dosage of acipimox, an NAD+ precursor... and  Future research is needed to investigate the safety and efficacy of NAD+ precursors... However, these sentences and the rest of the paper don t cite studies showing how acipimox (mainly thought to act via the HCAR2 receptor to inhibit lipolysis) is metabolized to NAD+. Specifically, I had difficulty understanding which enzyme(s) in the mammalian NAD+ biosynthesis pathway(s) convert the pyrazine ring of acipimox to the pyridine ring of NAD+ and its related natural metabolites. The authors also don t report experimental data (e.g. using radioactively labelled acipimox) to show such conversion. I would be happy if the authors could clarify this.u201d ![file] ![file] ,