NAD+

NAD+ has been understood as an electron carrier since the 1930s — glycolysis, the citric acid cycle and oxidative phosphorylation all depend on the NAD+/NADH couple. In that role it is recycled, not used up.

The modern interest comes from the discovery that two enzyme families consume it. Sirtuins use NAD+ as a co-substrate for protein deacetylation, and PARPs cleave it during DNA repair. Both destroy the molecule, which means cellular NAD+ is a finite pool depleted by activity.

• Sirtuin activity, which is NAD+-dependent and central to the metabolic ageing literature

• PARP-mediated DNA repair and the NAD+ cost it imposes

• Age-related decline in tissue NAD+, a repeatedly measured observation

• Salvage pathway precursors — NMN and NR — and whether raising precursors raises the pool

• Mitochondrial function and oxidative metabolism generally

NAD+ itself is a large, charged molecule that crosses membranes poorly, so much of the field works with precursors rather than the coenzyme. Whether precursor administration measurably raises NAD+ in a given tissue, and whether that changes anything downstream, is the open question the literature is organised around.

Glutathione is the companion redox molecule with a parallel delivery problem. MOTS-c and AICAR act on AMPK, which sits alongside sirtuins in energy sensing.