A High-Fat Diet and NAD + Activate Sirt1 to Rescue Premature Aging in Cockayne Syndrome

• DOI: 10.1016/j.cmet.2014.10.005
• Publication Date: 2014-11-04T21:46:04Z
• Authors: Morten Scheibye-K...; 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; Linda H. Bergersen; Victoria C. Cogger; Alessandra Warren; David G. Le Couteur; Ruin Moaddel; David M. Wilson; Deborah L. Croteau; Rafael de Cabo; Vilhelm A. Bohr
• Keywords: Cockayne syndrome; Premature aging

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, Csb(m/m) mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csb(m/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.