Abstract
Nicotinamide riboside (NR) is one of the orally bioavailable NAD+ precursors and has been demonstrated to exhibit beneficial effects against aging and aging-associated diseases. However, the metabolic pathway of NR in vivo is not yet fully understood. Here, we demonstrate that orally administered NR increases NAD+ level via two different pathways. In the early phase, NR was directly absorbed and contributed to NAD+ generation through the NR salvage pathway, while in the late phase, NR was hydrolyzed to nicotinamide (NAM) by bone marrow stromal cell antigen 1 (BST1), and was further metabolized by the gut microbiota to nicotinic acid, contributing to generate NAD+ through the Preiss–Handler pathway. Furthermore, we report BST1 has a base-exchange activity against both NR and nicotinic acid riboside (NAR) to generate NAR and NR, respectively, connecting amidated and deamidated pathways. Thus, we conclude that BST1 plays a dual role as glycohydrolase and base-exchange enzyme during oral NR supplementation.
Highlights
Nicotinamide riboside (NR) is one of the orally bioavailable NAD+ precursors and has been demonstrated to exhibit beneficial effects against aging and aging-associated diseases
It has been reported that NR supplementation resulted in a significant increase of deamidated NAD+ intermediates and that gut microbiota is involved in generating NAD+ and deamidated NAD+ intermediates[33]
The present study demonstrated that orally administered NR increased NAD+ levels in a diphasic manner (Fig. 10)
Summary
Nicotinamide riboside (NR) is one of the orally bioavailable NAD+ precursors and has been demonstrated to exhibit beneficial effects against aging and aging-associated diseases. Oral administration of amidated NAD+ precursors, NAM, NR, and NMN, has been demonstrated to be as an effective and practical approach to elevate NAD+ levels in vivo. This study raises a question whether orally administered NR uses the conventional amidated pathway to elevate NAD+ levels How these deamidated NAD+ intermediates generated by gut microbiota contribute to NAD+ generation after NR oral administration is still unclear. We have discovered that BST1 has a baseexchange activity between NR and nicotinic acid riboside (NAR) using NA and NAM This base-exchange activity is important in the small intestine to bypass the deamidated NAD+ precursors into the amidated pathway following the accumulation of deamidated metabolites. We concluded that NR metabolism is more complicated than originally thought, and it is important to consider the role of BST1 in NR supplementation therapy to protect from aging and aging-related diseases
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