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

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

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.

MeSH terms

  • Animals
  • Ataxia Telangiectasia / pathology*
  • Ataxia Telangiectasia Mutated Proteins / deficiency
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Behavior, Animal
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans / ultrastructure
  • Cells, Cultured
  • DNA Repair / drug effects*
  • Disease Models, Animal
  • 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

Substances

  • Phthalazines
  • Piperazines
  • NAD
  • Ataxia Telangiectasia Mutated Proteins
  • Sirtuin 1
  • olaparib