NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair
Evandro Fei Fang, Henok Kassahun, Deborah L Croteau, Morten Scheibye-Knudsen, Krisztina Marosi, Huiming Lu, Raghavendra A Shamanna, Sumana Kalyanasundaram, Ravi Chand Bollineni, Mark A Wilson, Wendy B Iser, Bradley N Wollman, Marya Morevati, Jun Li, Jesse S Kerr, Qiping Lu, Tyler B Waltz, Jane Tian, David A Sinclair, Mark P Mattson, Hilde Nilsen, Vilhelm A Bohr, Evandro Fei Fang, Henok Kassahun, Deborah L Croteau, Morten Scheibye-Knudsen, Krisztina Marosi, Huiming Lu, Raghavendra A Shamanna, Sumana Kalyanasundaram, Ravi Chand Bollineni, Mark A Wilson, Wendy B Iser, Bradley N Wollman, Marya Morevati, Jun Li, Jesse S Kerr, Qiping Lu, Tyler B Waltz, Jane Tian, David A Sinclair, Mark P Mattson, Hilde Nilsen, Vilhelm A Bohr
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.
Conflict of interest statement
Competing interests statement
The Bohr laboratory has CRADA arrangements with ChromaDex and GlaxoSmithKline. DAS is a consultant for GSK, Ovascience and Metrobiotech.
Published by Elsevier Inc.
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Source: PubMed