NAD+ is required not only for life but for a long life. In this issue, Camacho-Pereira et al. (2016) implicate CD38 in the decline of NAD+ during aging, with implications for combating age-related diseases.
In this issue, Eduardo Chini and col- leagues address an open question in bio- gerontology: why do NAD+ levels fall as we age? They show that the major culprit is an NADase called CD38 whose levels rise during aging. Their results also add to the body of evidence indicating that loss of SIRT3 activity in mitochondria is a cause of age-related metabolic decline (Camacho-Pereira et al., 2016) (Figure 1).
Finally, the authors addressed how CD38 may affect therapies designed to raise NAD+ levels. Currently, the favored approach in mouse and humans is to treat with NAD+ precursors, such as nicotinamide riboside (NR) or nicotin- amide mononucleotide (NMN).
Interest- ingly, CD38 not only degrades NAD+ in vivo, but also NMN. When CD38 knockout mice were given injections of NAD+, NMN, or NR (which is converted to NMN), circulating levels of NAD metab- olites remained stable after 150 min, long after they began to fall in the wild-type animals. Furthermore, when compared to the wild-type, CD38 knockout mice on a high-fat diet exhibited a much larger improvement in glucose tolerance when given NR.
These findings suggest that the efficacy of NAD+ precursors may be enhanced by co-supplementation with CD38 inhibitors, which have been recently identified (Escande et al., 2013; Haffner et al., 2015).
Michael B. Schultz1 and David A. Sinclair