NAD + Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair

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 an...

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Published in:	Cell metabolism Vol. 24; no. 4; p. 566
Main Authors:	Fang, Evandro Fei, Kassahun, Henok, Croteau, Deborah L, Scheibye-Knudsen, Morten, Marosi, Krisztina, Lu, Huiming, Shamanna, Raghavendra A, Kalyanasundaram, Sumana, Bollineni, Ravi Chand, Wilson, Mark A, Iser, Wendy B, Wollman, Bradley N, Morevati, Marya, Li, Jun, Kerr, Jesse S, Lu, Qiping, Waltz, Tyler B, Tian, Jane, Sinclair, David A, Mattson, Mark P, Nilsen, Hilde, Bohr, Vilhelm A
Format:	Journal Article
Language:	English
Published:	United States 11.10.2016
Subjects:	Animals Ataxia Telangiectasia - pathology Ataxia Telangiectasia Mutated Proteins - deficiency Ataxia Telangiectasia Mutated Proteins - metabolism Behavior, Animal Caenorhabditis elegans - metabolism Caenorhabditis elegans - ultrastructure Cells, Cultured Disease Models, Animal DNA Repair - drug effects Gene Knockdown Techniques Health Homeostasis - drug effects Longevity - drug effects Metabolomics Mice Mitophagy - drug effects NAD - pharmacology Neurons - drug effects Neurons - metabolism Phenotype Phthalazines - pharmacology Piperazines - pharmacology Proteomics Rats, Sprague-Dawley Signal Transduction - drug effects Sirtuin 1 - metabolism
ISSN:	1932-7420, 1932-7420
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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.
AbstractList	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.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. 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.
Author	Shamanna, Raghavendra A Tian, Jane Mattson, Mark P Fang, Evandro Fei Lu, Qiping Croteau, Deborah L Sinclair, David A Marosi, Krisztina Wollman, Bradley N Wilson, Mark A Scheibye-Knudsen, Morten Bohr, Vilhelm A Kassahun, Henok Li, Jun Morevati, Marya Kerr, Jesse S Bollineni, Ravi Chand Lu, Huiming Nilsen, Hilde Iser, Wendy B Waltz, Tyler B Kalyanasundaram, Sumana
Author_xml	– sequence: 1 givenname: Evandro Fei surname: Fang fullname: Fang, Evandro Fei organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 2 givenname: Henok surname: Kassahun fullname: Kassahun, Henok organization: Institute of Clinical Medicine, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway – sequence: 3 givenname: Deborah L surname: Croteau fullname: Croteau, Deborah L organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 4 givenname: Morten surname: Scheibye-Knudsen fullname: Scheibye-Knudsen, Morten organization: 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 – sequence: 5 givenname: Krisztina surname: Marosi fullname: Marosi, Krisztina organization: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 6 givenname: Huiming surname: Lu fullname: Lu, Huiming organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 7 givenname: Raghavendra A surname: Shamanna fullname: Shamanna, Raghavendra A organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 8 givenname: Sumana surname: Kalyanasundaram fullname: Kalyanasundaram, Sumana organization: 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 – sequence: 9 givenname: Ravi Chand surname: Bollineni fullname: Bollineni, Ravi Chand organization: Department of Biosciences, University of Oslo, 0316 Oslo, Norway – sequence: 10 givenname: Mark A surname: Wilson fullname: Wilson, Mark A organization: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 11 givenname: Wendy B surname: Iser fullname: Iser, Wendy B organization: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 12 givenname: Bradley N surname: Wollman fullname: Wollman, Bradley N organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 13 givenname: Marya surname: Morevati fullname: Morevati, Marya organization: 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 – sequence: 14 givenname: Jun surname: Li fullname: Li, Jun organization: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA – sequence: 15 givenname: Jesse S surname: Kerr fullname: Kerr, Jesse S organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 16 givenname: Qiping surname: Lu fullname: Lu, Qiping organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 17 givenname: Tyler B surname: Waltz fullname: Waltz, Tyler B organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 18 givenname: Jane surname: Tian fullname: Tian, Jane organization: Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA – sequence: 19 givenname: David A surname: Sinclair fullname: Sinclair, David A organization: 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 – sequence: 20 givenname: Mark P surname: Mattson fullname: Mattson, Mark P organization: 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 – sequence: 21 givenname: Hilde surname: Nilsen fullname: Nilsen, Hilde organization: Institute of Clinical Medicine, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway – sequence: 22 givenname: Vilhelm A surname: Bohr fullname: Bohr, Vilhelm A email: vbohr@nih.gov organization: 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
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27732836$$D View this record in MEDLINE/PubMed
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References	27732834 - Cell Metab. 2016 Oct 11;24(4):526-528. doi: 10.1016/j.cmet.2016.09.019
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Snippet	Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked...
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SubjectTerms	Animals Ataxia Telangiectasia - pathology Ataxia Telangiectasia Mutated Proteins - deficiency Ataxia Telangiectasia Mutated Proteins - metabolism Behavior, Animal Caenorhabditis elegans - metabolism Caenorhabditis elegans - ultrastructure Cells, Cultured Disease Models, Animal DNA Repair - drug effects Gene Knockdown Techniques Health Homeostasis - drug effects Longevity - drug effects Metabolomics Mice Mitophagy - drug effects NAD - pharmacology Neurons - drug effects Neurons - metabolism Phenotype Phthalazines - pharmacology Piperazines - pharmacology Proteomics Rats, Sprague-Dawley Signal Transduction - drug effects Sirtuin 1 - metabolism
Title	NAD + Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair
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