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

Abstract

Summary 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.

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

“…One recent study has proposed the use of HFD to rescue another model of progeria, Cockayne Syndrome, highlighting a dysregulated PARP1/Sirt1-dependent pathway that drives the premature aging phenotype (30). An important distinction between this study and the one described in this manuscript is that the benefits induced by HFD for Cockayne Syndrome appear to be independent of thermogenesis or increased metabolism of the diet.…”

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

“…Some experimental studies support the notion that HFD‐induced obesity exacerbates cerebral pathological alterations and the accompanying cognitive deficit in APP transgenic mice (Ho et al, 2004). In wild‐type mice, some studies suggest that HFD impairs cognition (Winocur & Greenwood, 2005) while other claim for no effect (Kesby et al, 2015) or even improvement of memory (Coscina et al, 1986) and protection from age‐related cognitive decline (Scheibye‐Knudsen et al, 2014). Thus, we next tested the effect of HFD on behavior.…”

DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade

“…DNA repair deficiency sensitizes lung cancer cells to NAD + biosynthesis blockade Mehdi Touat, 1,2,3 Tony Sourisseau, 1 Nicolas Dorvault, 1,4 Roman M. Chabanon, 1,4 Marlène Garrido, 1,4 Daphné Morel, 1,4 Dragomir B. Krastev, 5 Ludovic Bigot, 1 Julien Adam, 1,6 Jessica R. Frankum, 5 Sylvère Durand, 7 Clement Pontoizeau, 8,9,10 Sylvie Souquère, 11 Mei-Shiue Kuo, 1 Sylvie Sauvaigo, 12 Faraz Mardakheh, 13 Alain Sarasin, 14 Ken A. Olaussen, 1,15 Luc Friboulet, 1 Frédéric Bouillaud, 16 Gérard Pierron, 11 Alan Ashworth, 17 Anne Lombès, 16 Christopher J. Lord,5 Jean-Charles Soria, 1,2,15 and Sophie Postel-Vinay (8,9).…”

“…Lord,5 Jean-Charles Soria, 1,2,15 and Sophie Postel-Vinay (8,9). NAD + acts as ratelimiting cofactor for the DNA repair enzyme PARPs (12).…”