A high-fat diet and NAD+ activate sirt1 to rescue premature aging in cockayne syndrome

Research output: Contribution to journalJournal articleResearchpeer-review

  • Sarah J. Mitchell
  • Evandro F. Fang
  • Teruaki Iyama
  • Theresa Ward
  • James Wang
  • Christopher A. Dunn
  • Nagendra Singh
  • Sebastian Veith
  • Md Mahdi Hasan-Olive
  • Aswin Mangerich
  • Mark A. Wilson
  • Mark P. Mattson
  • Victoria C. Cogger
  • Alessandra Warren
  • David G. Le Couteur
  • Ruin Moaddel
  • David M. Wilson
  • Deborah L. Croteau
  • Rafael De Cabo

Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csbm/m mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csbm/m mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet, and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS.

Original languageEnglish
JournalCell Metabolism
Issue number5
Pages (from-to)840-855
Number of pages16
Publication statusPublished - 4 Nov 2014

ID: 172128793