NAD+ repletion inhibits accelerated aging in Werner syndrome through the restoration of mitophagy

Metabolic dysfunction is a primary feature of the premature aging Werner syndrome (WS), a heritable human disease caused by mutations in the gene encoding the DNA helicase Werner (WRN). However, the relationship between WRN mutation and its severe metabolic phenotypes is unclear. Here we report mitochondrial dysfunction and depletion of NAD+, a fundamental ubiquitous cofactor, in WS patient samples and WS animal models. NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably delays accelerated aging, including stem cell dysfunction in both C. elegans and Drosophila models of WS. Mechanistically, WRN physically binds to a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) and facilitates its NAD+ production. Our findings reveal an unprecedented anti-aging mechanism of WRN that integrates its new function of NAD+ synthesis to coordinate mitochondrial maintenance and energy expenditure, and suggest therapeutic potential. Two C. elegans strains were used: the N2: wild type Bristol isolate was from Caenorhabditis Genetics Center (CGC) and the wrn-1(gk99), a C. elegans model of WS with a 196bp deletion mutation resulting in the complete absence of the WRN-1 protein, was a gift from Dr. Hyeon-Sook Koo (Yonsei University, Korea). Both strains were treated with vehicle control, NAD+ precursor nicotinamide riboside (NR, 1 mM), a SIRT1 activator (SRT1720, 10 µM), or a PARP inhibitor (Olaparib, 500 nM) from the L4 stage, followed by changing to fresh drug plate on adult Day 4, and collection for transcriptomic analysis on adult D7. Approximately 500 worms were used for each experiment, with four biological repeats per condition. (N=4 per group, total N=32 microarray samples)