Journal article
Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline
Cell metabolism, Vol.37(7), pp.1499-1514.e4
07/01/2025
DOI: 10.1016/j.cmet.2025.04.007
PMCID: PMC12328062
PMID: 40315855
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.
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•Liver produces and releases NaR when NaMN is accumulated•NT5C2 mediates liver NaR production•Kidneys use circulating NaR to produce NAD+ and circulating nicotinamide•NaR supplementation improves organ NAD+ levels and kidney dysfunction in aging
Song et al. identify an alternative pathway for maintaining NAD+ homeostasis through circulating NaR production and consumption by the liver-kidney axis, and boosting this pathway ameliorates aging-associated NAD+ decline and kidney dysfunction.
Details
- Title: Subtitle
- Nicotinic acid riboside maintains NAD+ homeostasis and ameliorates aging-associated NAD+ decline
- Creators
- Won-Suk Song - UC Irvine HealthXiyu Shen - University of California, IrvineKang Du - Department of Medicine, Physiology and Biophysics, University of California, Irvine, School of Medicine, Irvine, CA 92697, USACuauhtemoc B. Ramirez - University of California, IrvineSang Hee Park - University of California, IrvineYang Cao - Department of Medicine, Physiology and Biophysics, University of California, Irvine, School of Medicine, Irvine, CA 92697, USAJohnny Le - University of California, IrvineHosung Bae - University of Iowa, Internal MedicineJoohwan Kim - University of California, IrvineYujin Chun - University of California, IrvineNikki Joyce Khong - Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Irvine, CA 92697, USAMarie Kim - Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Irvine, CA 92697, USASunhee Jung - University of California, IrvineWonsuk Choi - University of California, IrvineMiranda L. Lopez - University of California, IrvineZaid Said - Department of Medicine, Physiology and Biophysics, University of California, Irvine, School of Medicine, Irvine, CA 92697, USAZehan Song - University of California, BerkeleySang-Guk Lee - Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Irvine, CA 92697, USADequina Nicholas - University of California, IrvineJeffrey Milbrandt - Washington University in St. LouisYo Sasaki - Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USADavid K. Imagawa - Division of Vascular and Endovascular Surgery, Department of Surgery, University of California, Irvine, Orange, CA 92868, USADorota Skowronska-Krawczyk - Department of Physiology and Biophysics, Department of Ophthalmology, University of California, Irvine, School of Medicine, Irvine, CA 92697, USADanica Chen - Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USAGina Lee - University of California, IrvineCholsoon Jang - University of California, IrvineQin Yang - University of California, Irvine
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.37(7), pp.1499-1514.e4
- DOI
- 10.1016/j.cmet.2025.04.007
- PMID
- 40315855
- PMCID
- PMC12328062
- NLM abbreviation
- Cell Metab
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 07/01/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217134102771
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