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

ABSTRACT: Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high-fat, caloric-restricted or resveratrol-supplemented diet. The high-fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen 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 is able to 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. 4-month-old mice, WT and Csbm/m on a C57BL/6 background, were fed a standard AIN-93G diet (SD; carbohydrate:protein:fat ratio of 64:19:17 percent of kcal) ad libitum or at 40% CR, a SD supplemented with 100 mg/kgchow resveratrol ad libitum, or a high-fat diet ad libitum consisting of AIN-93G with 60% of calories from fat, primarily hydrogenated coconut oil (HFD; carbohydrate:protein:fat ratio of 16:23:61). Each group was on the specified diet for 8 months, after which the mice were sacrificed and the cerebellum was removed. For nicotinamide treatments, 4- or 18-month-old WT and Csbm/m mice were given daily injections of nicotinamide riboside (NR) (500 mg/kg/d, ip) or saline for one week, after which the mice were sacrificed and the cerebellum was removed. RNA was extracted from the cerebellums of all mice using Trizol, and RNA quality and quantity were tested using an Agilent 2100 BioAnalyzer with RNA 6000 nano chips. RNA was labeled using the standard Illumina protocol for Illumina TotalPrep RNA Amplification Kit. Labeled RNA was hybridized to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips (Illumina, San Diego, CA) overnight and washed, stained and scanned the next day.

ORGANISM(S): Mus musculus

SUBMITTER: Kevin Becker 

PROVIDER: E-GEOD-62194 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress