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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Evandro Fei Fang
  • Henok Kassahun
  • Deborah L Croteau
  • 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

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.

Original languageEnglish
JournalCell Metabolism
Issue number4
Pages (from-to)566-581
Number of pages16
Publication statusPublished - 11 Oct 2016

ID: 169440364