title: NAD+Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair.
abstract: Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD+, and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD+reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD+also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Evandro Fei
authors.initials: EF
authors.lastname: Fang
authors.affiliation: Institute of Clinical Medicine, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway.
authors.forename: Henok
authors.initials: H
authors.lastname: Kassahun
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Danish Center for Healthy Aging, University of Copenhagen, Copenhagen, Blegdamsvej 3B 2200, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Marosi
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Raghavendra A
authors.initials: RA
authors.lastname: Shamanna
authors.affiliation: Institute of Clinical Medicine, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway; Bioinformatics Core Facility, Department of Core Facilities, Institute of Cancer Research, Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway.
authors.forename: Sumana
authors.initials: S
authors.lastname: Kalyanasundaram
authors.affiliation: Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Ravi Chand
authors.initials: RC
authors.lastname: Bollineni
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Iser
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Wollman
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Danish Center for Healthy Aging, University of Copenhagen, Copenhagen, Blegdamsvej 3B 2200, Denmark.
authors.forename: Marya
authors.initials: M
authors.lastname: Morevati
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Kerr
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Qiping
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Waltz
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Institute of Clinical Medicine, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway.
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA; Danish Center for Healthy Aging, University of Copenhagen, Copenhagen, Blegdamsvej 3B 2200, Denmark. Electronic address: vbohr@nih.gov.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000473:pathology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000378:metabolism; D001522:Behavior, Animal; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006262:Health; D006706:Homeostasis / Q000187:drug effects; D008136:Longevity / Q000187:drug effects*; D055432:Metabolomics; D051379:Mice; D063306:Mitophagy / Q000187:drug effects*; D009243:NAD / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D040901:Proteomics; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D010793:Phthalazines; D010879:Piperazines; D009243:NAD; D064007:Ataxia Telangiectasia Mutated Proteins; D056564:Sirtuin 1; C531550:olaparib