Calorie restriction can extend lifespan by increasing intracellular nicotinamide adenine dinucleotide (NAD(+)), thereby upregulating the activity of sirtuins (Caenorhabditis elegans Sir-2.1; human SIRT1). Nicotinic acid (NA) can be metabolized to NAD(+); however, the calorie restriction mimetic (CRM) potential of NA is unclear. This study explored the ability and mechanism of NA to extend the lifespan of human Hs68 cells and C. elegans. We found that NA can efficiently increase the intracellular NAD(+) levels in Hs68 cells and C. elegans; however, NA was only able to extend the lifespan of C. elegans. The steady-state NAD(+) level in C. elegans was approximately 55 mu M. When intracellular NAD(+) was increased by a mutation of pme-1 (poly (ADP-ribose) metabolism enzyme 1) or by pretreatment with NAD(+) in the medium, the lifespan extension ability of NA disappeared. Additionally, the saturating concentration of NAD(+) required by SIRT1 was approximately 200 mu M; however, the steady-state concentration of NAD(+) in Hs68 cells reached up to 460 mu M. These results demonstrate that the lifespan extension ability of NA depends on whether the intracellular level of NAD(+) is lower than the sirtuin-saturating concentration in Hs68 cells and in C. elegans. Thus, the CRM potential of NA should be limited to individuals with lower intracellular NAD(+).
