Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline

Abstract

Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD⁺) catabolism primarily feeds systemic organs for NAD⁺ synthesis. We surprisingly found that, despite blunted hepatic NAD⁺ and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs’ NAD⁺ are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5′-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD⁺ through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD⁺, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD⁺ homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD⁺ decline and kidney dysfunction.