title: Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.
abstract: Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1∆/-) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg-/-(also known as Ercc5-/-) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1∆/-mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1∆/-mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1∆/-mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: W P
authors.initials: WP
authors.lastname: Vermeij
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: M E T
authors.initials: ME
authors.lastname: Dollé
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.|Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Reiling
authors.affiliation: Department of Neuroscience, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Jaarsma
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.|Facultad de Ciencias Naturales y Matemáticas, Universidad del Rosario, Carrera 24, 63C-69 Bogotá, Colombia.
authors.forename: C
authors.initials: C
authors.lastname: Payan-Gomez
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: C R
authors.initials: CR
authors.lastname: Bombardieri
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: A J M
authors.initials: AJ
authors.lastname: Roks
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.|Laboratory for Orthopedic Research, Balgrist University Hospital, Forchstrasse 340, 8008, Zürich, Switzerland.
authors.forename: S M
authors.initials: SM
authors.lastname: Botter
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: B C
authors.initials: BC
authors.lastname: van der Eerden
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80125, 3508 TC Utrecht, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Youssef
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80125, 3508 TC Utrecht, The Netherlands.
authors.forename: R V
authors.initials: RV
authors.lastname: Kuiper
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Nagarajah
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: C T
authors.initials: CT
authors.lastname: van Oostrom
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: R M C
authors.initials: RM
authors.lastname: Brandt
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Barnhoorn
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Imholz
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: J L A
authors.initials: JL
authors.lastname: Pennings
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80125, 3508 TC Utrecht, The Netherlands.|Department of Pediatrics, Division Molecular Genetics, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Á
authors.initials: Á
authors.lastname: Gyenis
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Pothof
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: J
authors.initials: J
authors.lastname: Vijg
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.|CECAD Forschungszentrum, Universität zu Köln, Joseph-Stelzmann-Straße 26, 50931 Köln, Germany.
authors.forename: J H J
authors.initials: JH
authors.lastname: Hoeijmakers
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000502:physiology; D031204:Caloric Restriction; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004038:Diet, Reducing; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics; D005260:Female; D042822:Genomic Instability; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000517:prevention & control; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D059467:Transcriptome; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C499360:Ercc1 protein, mouse