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

作者：Scheibye Knudsen Morten; Mitchell Sarah J; Fang Evandro F; Iyama Teruaki; Ward Theresa; Wang James; Dunn Christopher A; Singh Nagendra; Veith Sebastian; Hasan Olive Md Mahdi; Mangerich Aswin; Wilson Mark A; Mattson Mark P; Bergersen Linda H; Cogger Victoria C; Warren Alessandra; Le Couteur David G; Moaddel Ruin; Wilson David M III; Croteau Deborah L; de Cabo Rafael^*; Bohr Vilhelm A

来源：Cell Metabolism, 2014, 20(5): 840-855.

DOI：10.1016/j.cmet.2014.10.005

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, beta-hydroxybutyrate levels are increased by the high-fat diet, and beta-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, beta-hydroxybutyrate and NAD(+), through the deacetylase SIRT1 and suggests possible interventions for CS.

• 出版日期2014-11-4