Manipulation of a Nuclear NAD⁺ Salvage Pathway Delays Aging without Altering Steady-state NAD⁺ Levels

Model for life span extension via increased flux through the NAD⁺ salvage pathway. Type III histone deacetylases such as Sir2 and Hst1–4 catalyze a key step in the salvage pathway by converting NAD⁺ to nicotinamide. Additional copies of PNC1, NPT1, NMA1, and NMA2 increase flux through the NAD⁺ salvage pathway, which stimulates Sir2 activity and increases life span. Additional copies of QNS1 fail to increase silencing. Unlike other steps in the pathway, its substrate cannot be supplied from a source outside the salvage pathway and is therefore limiting for the reaction. Abbreviations: NAD ⁺, nicotinamide adenine dinucleotide; NaMN, nicotinic acid mononucleotide; NaAD, desamido-NAD⁺.