Resveratrol Increases Intracellular NAD+ Levels Through Up regulation of The NAD+ Synthetic Enzyme Nicotinamide Mononucleotide Adenylyltransferase

Abstract

Resveratrol is a polyphenol with major health benefits that is thought to operate through direct activation of the 'anti-aging' enzyme SIRT1. However recent reports have challenged this 'direct-activation' hypothesis, suggesting the mechanism by which resveratrol increases SIRT1 function is still unknown. We report for the first time that resveratrol induces a dose dependent increase in activity of the NAD+ synthetic enzyme nicotinamide mononucleotide adenylyl transferase (NMNAT1). Activation of NMNAT1 by resveratrol in cultured primary human astrocytes and neurons increased NAD+ levels by up to 5 fold. As SIRT1 requires NAD+ as a substrate to perform its gene silencing function, higher NAD+ levels will enhance SIRT1 activity. This finding suggests that resveratrol may promote SIRT1 function by enhancing NAD+ synthesis in whole cell systems without requiring direct activation.