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. MattsonHilde Nilsen, Vilhelm A. Bohr

Research output: Contribution to journalArticle

97 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)566-581
Number of pages16
JournalCell Metabolism
Volume24
Issue number4
DOIs
StatePublished - Oct 11 2016
Externally publishedYes

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Mitochondrial Degradation
Ataxia Telangiectasia
DNA Repair
NAD
DNA Damage
Premature Aging
Cerebellar Ataxia
Double-Stranded DNA Breaks
Memory Disorders
Atrophy
Therapeutics
Animal Models
Neurons

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Fang, E. F., Kassahun, H., Croteau, D. L., Scheibye-Knudsen, M., Marosi, K., Lu, H., ... Bohr, V. A. (2016). NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metabolism, 24(4), 566-581. https://doi.org/10.1016/j.cmet.2016.09.004

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

In: Cell Metabolism, Vol. 24, No. 4, 11.10.2016, p. 566-581.

Research output: Contribution to journalArticle

Fang, EF, Kassahun, H, Croteau, DL, Scheibye-Knudsen, M, Marosi, K, Lu, H, Shamanna, RA, Kalyanasundaram, S, Bollineni, RC, Wilson, MA, Iser, WB, Wollman, BN, Morevati, M, Li, J, Kerr, JS, Lu, Q, Waltz, TB, Tian, J, Sinclair, DA, Mattson, MP, Nilsen, H & Bohr, VA 2016, 'NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair', Cell Metabolism, vol. 24, no. 4, pp. 566-581. https://doi.org/10.1016/j.cmet.2016.09.004
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. / NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. In: Cell Metabolism. 2016 ; Vol. 24, No. 4. pp. 566-581.
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