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Cell Metab. 2016 Oct 11;24(4):566-581. doi: 10.1016/j.cmet.2016.09.004.

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

Author information

1
Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
2
Institute of Clinical Medicine, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway.
3
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.
4
Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
5
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.
6
Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
7
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
8
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.
9
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.
10
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.

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.

PMID:
27732836
PMCID:
PMC5777858
DOI:
10.1016/j.cmet.2016.09.004
[Indexed for MEDLINE]
Free PMC Article

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