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

Evandro F. Fang (), Yujun Hou, Sofie Lautrup, Martin Borch Jensen, Beimeng Yang, Tanima SenGupta, Domenica Caponio, Rojyar Khezri, Tyler G. Demarest, Yahyah Aman, David Figueroa, Marya Morevati, Ho-Joon Lee, Hisaya Kato, Henok Kassahun, Jong-Hyuk Lee, Deborah Filippelli, Mustafa Nazir Okur, Aswin Mangerich, Deborah L. Croteau, Yoshiro Maezawa, Costas A. Lyssiotis, Jun Tao, Koutaro Yokote, Tor Erik Rusten, Mark P. Mattson, Heinrich Jasper, Hilde Nilsen and Vilhelm A. Bohr ()
Additional contact information
Evandro F. Fang: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Yujun Hou: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Sofie Lautrup: University of Oslo and Akershus University Hospital
Martin Borch Jensen: Buck Institute for Research on Aging
Beimeng Yang: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Tanima SenGupta: University of Oslo and Akershus University Hospital
Domenica Caponio: University of Oslo and Akershus University Hospital
Rojyar Khezri: Oslo University Hospital
Tyler G. Demarest: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Yahyah Aman: University of Oslo and Akershus University Hospital
David Figueroa: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Marya Morevati: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Ho-Joon Lee: University of Michigan Medical School
Hisaya Kato: Chiba University Graduate School of Medicine
Henok Kassahun: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Jong-Hyuk Lee: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Deborah Filippelli: University of Konstanz
Mustafa Nazir Okur: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Aswin Mangerich: University of Konstanz
Deborah L. Croteau: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health
Yoshiro Maezawa: Chiba University Graduate School of Medicine
Costas A. Lyssiotis: University of Michigan Medical School
Jun Tao: the First Affiliated Hospital, Sun Yat-Sen University
Koutaro Yokote: Chiba University Graduate School of Medicine
Tor Erik Rusten: Oslo University Hospital
Mark P. Mattson: Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health
Heinrich Jasper: Buck Institute for Research on Aging
Hilde Nilsen: University of Oslo and Akershus University Hospital
Vilhelm A. Bohr: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13172-8

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