NAD+ supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy

Research output: Contribution to journalJournal articleResearchpeer-review

  • Beimeng Yang
  • Xiuli Dan
  • Yujun Hou
  • Jong Hyuk Lee
  • Noah Wechter
  • Sudarshan Krishnamurthy
  • Risako Kimura
  • Mansi Babbar
  • Tyler Demarest
  • Ross McDevitt
  • Shiliang Zhang
  • Yongqing Zhang
  • Mark P. Mattson
  • Deborah L. Croteau
  • Bohr, Vilhelm

Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A-T). Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in A-T patient fibroblasts, and in ATM-deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1-dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm−/− mice. Our findings suggest a central role for mitochondrial dysfunction-induced senescence in A-T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention.

Original languageEnglish
Article numbere13329
JournalAging Cell
Volume20
Issue number4
Number of pages14
ISSN1474-9718
DOIs
Publication statusPublished - 2021

Bibliographical note

Publisher Copyright:
Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

    Research areas

  • Ataxia Telangiectasia, mitophagy, Nicotinamide riboside, SASP, senescence

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