title: A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome.
abstract: Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csb(m/m) mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csb(m/m) mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet, and β-hydroxybutyrate, PARP inhibition, or NAD(+) supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD(+), through the deacetylase SIRT1 and suggests possible interventions for CS.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mitchell
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Evandro F
authors.initials: EF
authors.lastname: Fang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Iyama
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Ward
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: James
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Dunn
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.affiliation: Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Veith
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Md Mahdi
authors.initials: MM
authors.lastname: Hasan-Olive
authors.affiliation: Molecular Toxicology Group, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Aswin
authors.initials: A
authors.lastname: Mangerich
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: The Brain and Muscle Energy Group - Synaptic Neurochemistry Laboratory, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway; Danish Center for Healthy Aging, ICMM, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Bergersen
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney, NSW 2139, Australia.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.affiliation: Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney, NSW 2139, Australia.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Warren
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney, NSW 2139, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: decabora@grc.nia.nih.gov.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA; Danish Center for Healthy Aging, ICMM, University of Copenhagen, Copenhagen, Denmark. Electronic address: vbohr@nih.gov.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D019588:Aging, Premature / Q000178:diet therapy* / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002460:Cell Line; D003057:Cockayne Syndrome / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D009243:NAD; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D020155:3-Hydroxybutyric Acid