NAD+ metabolism and the control of energy homeostasis: A balancing act between mitochondria and the nucleus

This high-impact review, published in Cell Metabolism by Johan Auwerx's group at EPFL, provided a comprehensive analysis of the role of NAD+ (nicotinamide adenine dinucleotide) as a central molecule in the regulation of cellular energy metabolism. The article examined how NAD+ acts as an essential substrate for key enzymes that control metabolic homeostasis.

The authors detailed the multiple roles of NAD+ beyond its classical function as a redox cofactor:

• Substrate for sirtuins (SIRT1-7), NAD+-dependent deacetylases that regulate gene expression, DNA repair, and metabolism
• Substrate for PARPs (poly-ADP-ribose polymerases), essential for DNA damage repair
• Substrate for CD38/CD157, ectoenzymes that regulate calcium signaling
• Mediator of mitochondria-nucleus communication through the NAD+/NADH ratio

The review explored how the decline of NAD+ with aging compromises sirtuin function and mitochondrial capacity, creating a vicious cycle of metabolic dysfunction. The competition between sirtuins and PARPs for available NAD+ becomes particularly relevant in aging, when DNA damage increases and PARP activation consumes more NAD+.

The authors discussed strategies to elevate NAD+ levels, including precursors such as NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside), CD38 inhibitors, and activation of de novo biosynthesis. This review was fundamental in establishing the field of "NAD+ supplementation" as an anti-aging strategy.