期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13172-8
关键词
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资金
- Intramural Research Program of the NIH
- National Institute on Aging
- NIH
- HELSE SoR-OST [2017056]
- Research Council of Norway [262175]
- Rosa Sloyfe & Norwegian Breast Cancer Society [207819]
- 2017 AACR NextGen Grant for Transformative Cancer Research [17-20-01-LYSS]
- German Research Foundation (DFG) [INST 38/537-1 FUGG]
- Japan AMED [JP18bm0804016h0002, JP17gm5010002h0001]
- South East Norway Regional Health Authority [2015029]
- NIH [DK097153]
Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD(+), a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD(+) biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). 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 extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD(+) levels counteracts WS phenotypes.
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