| First Author | Scheibye-Knudsen M | Year | 2014 |
| Journal | Cell Metab | Volume | 20 |
| Issue | 5 | Pages | 840-55 |
| PubMed ID | 25440059 | Mgi Jnum | J:218788 |
| Mgi Id | MGI:5618387 | Doi | 10.1016/j.cmet.2014.10.005 |
| Citation | Scheibye-Knudsen M, et al. (2014) A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab 20(5):840-55 |
| abstractText | 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. |
