Journal
CELL METABOLISM
Volume 20, Issue 5, Pages 840-855Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2014.10.005
Keywords
-
Categories
Funding
- National Medical Health and Research Council of Australia CJ Martin Early Career Fellowship (RGMS) [ID 2010-01671]
- DFG [1331]
- Zukunftskolleg Konstanz
- NIA/NIH
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available