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Nat Commun. 2019 Nov 21;10(1):5284. doi: 10.1038/s41467-019-13172-8.

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome.

Author information

1
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA. e.f.fang@medisin.uio.no.
2
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478, Lørenskog, Norway. e.f.fang@medisin.uio.no.
3
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
4
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478, Lørenskog, Norway.
5
Buck Institute for Research on Aging, Novato, CA, 94945, USA.
6
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379, Oslo, Norway.
7
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379, Oslo, Norway.
8
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
9
Danish Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
10
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
11
Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
12
Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany.
13
Department of Molecular and Integrative Physiology, and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
14
Department of Hypertension and Vascular Disease, the First Affiliated Hospital, Sun Yat-Sen University, 510080, Guangzhou, China.
15
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
16
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA. bohrv@grc.nia.nih.gov.
17
Danish Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark. bohrv@grc.nia.nih.gov.

Abstract

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.

PMID:
31754102
PMCID:
PMC6872719
DOI:
10.1038/s41467-019-13172-8
[Indexed for MEDLINE]
Free PMC Article

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