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.
A n 80-year-old male with a history of valve replacement for severe aortic stenosis and aortocoronary bypass presented to the emergency department of the Pontevedra Hospital, having experienced asthenia for almost 1 week and morning fever without shivering for the past 48 h. The initial examination showed a good general state. He had neither a headache nor focal neurological signs. No urinary or digestive symptoms were observed. A chest X ray and transthoracic echocardiography ruled out pleuropulmonary pathology and acute endocarditis. The urinary sediment analysis results were normal, and biochemical markers did not indicate heart damage (cardiac troponin I Ͻ 0.04 ng/ml). In the presence of fever (38.4°C), leukocytosis (12,600 cells/mm 3 with 76.2% neutrophils), and a high C-reactive protein level (12.1 mg/dl), empirical antibiotic treatment was initiated with intravenous levofloxacin and the patient was admitted to the hospital to assess his progress. Blood and urine cultures, serologic testing, and an abdominal ultrasound scan were requested. During the following days, the patient remained asymptomatic and hemodynamically stable, with a persistent low-grade fever. The urine culture was negative, and the abdominal ultrasound scan results were normal. The serology results were negative for hepatitis B virus, hepatitis C virus, HIV, Treponema pallidum, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae and showed past infection with cytomegalovirus and Epstein-Barr virus. The two sets of blood cultures were incubated in the BD Bactec FX system (Becton Dickinson Biosciences), which detected bacterial growth in all bottles (BD Bactec Plus Aerobic/F and Plus Anaerobic/F media) in less than 4 h. The initial Gram stain revealed Gram-positive coccobacilli. The blood culture broth was subcultured in blood agar, chocolate agar,
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