Controlling lifespan with NAD+

Nicotinamide adenine dinucleotide (NAD+) is a substrate for sirtuins, enzymes implicated in metabolism and lifespan control, and a donor molecule for polyADP ribose polymerases (PARPs), which have also been linked to metabolism. Auwerx and colleagues now report that NAD+ controls lifespan by activating stress responses, including FOXO signalling and the mitochondrial unfolded protein response (UPR^mt) (Cell 154, 430–441; 2013).

The authors observed that ageing mice and Ceanorhabditis elegans had increased PARP activity and lower NAD+ levels. Inhibiting PARP activity or providing NAD+ precursors extended worm lifespan, which was dependent on the presence of the sir-2.1 sirtuin. Treatment with PARP inhibitors or NAD+ precursors also enhanced mitochondrial activity, as shown by increased respiration, mitochondrial abundance and gene expression of metabolic pathway components. Moreover, elevating NAD+ levels in worms induced an early-phase activation of the UPR^mt and a late-phase activation of the FOXO pathway, which is known to act as a defence response to increased reactive oxygen species. Further C. elegans lifespan analyses demonstrated that sir-2.1 expression is epistatically linked to the UPR^mt. Finally, the authors showed that increased NAD+ levels and sirtuin activity also induced UPR^mt and FOXO-dependent responses in mammalian cells.

Future studies will determine whether this evolutionarily conserved NAD+–sirtuin–UPR^mt–FOXO pathway could be manipulated for the treatment of ageing-related disorders.