Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.
| Title: | Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. |
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| Authors: | Vermeij WP; Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Dollé ME; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.; Reiling E; 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.; Jaarsma D; Department of Neuroscience, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Payan-Gomez C; 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.; Bombardieri CR; Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Wu H; Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Roks AJ; Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Botter SM; 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.; van der Eerden BC; Department of Internal Medicine, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Youssef SA; Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80125, 3508 TC Utrecht, The Netherlands.; Kuiper RV; Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80125, 3508 TC Utrecht, The Netherlands.; Nagarajah B; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.; van Oostrom CT; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.; Brandt RM; Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Barnhoorn S; Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Imholz S; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.; Pennings JL; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.; de Bruin A; 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.; Gyenis Á; Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Pothof J; Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands.; Vijg J; Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.; van Steeg H; 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.; Hoeijmakers JH; 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. |
| Source: | Nature [Nature] 2016 Sep 15; Vol. 537 (7620), pp. 427-431. Date of Electronic Publication: 2016 Aug 24. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| Imprint Name(s): | Publication: Basingstoke : Nature Publishing Group; Original Publication: London, Macmillan Journals ltd. |
| MeSH Terms: | Caloric Restriction* ; Diet, Reducing* ; Genomic Instability*; Aging/*genetics ; DNA Repair/*genetics; Brain/physiology ; DNA-Binding Proteins/deficiency ; DNA-Binding Proteins/genetics ; Endonucleases/deficiency ; Endonucleases/genetics ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/prevention & control ; Nuclear Proteins/deficiency ; Nuclear Proteins/genetics ; Transcription Factors/deficiency ; Transcription Factors/genetics ; Animals ; DNA Damage ; Female ; Male ; Mice ; Transcriptome ; DNA Excision Repair Protein ERCC-5 |
| 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. |
| Competing Interests: | The authors declare no competing financial interests. |
| Comments: | Comment in: Nature. 2016 Sep 15;537(7620):316-317. doi: 10.1038/nature19427.. (PMID: 27556941); Comment in: Nat Rev Endocrinol. 2016 Nov;12(11):623. doi: 10.1038/nrendo.2016.161.. (PMID: 27636726) |
| References: | Nat Cell Biol. 2009 May;11(5):604-15. (PMID: 19363488); Annu Rev Pathol. 2010;5:99-118. (PMID: 20078217); PLoS Genet. 2008 Aug 15;4(8):e1000161. (PMID: 18704162); Nature. 2006 Dec 21;444(7122):1038-43. (PMID: 17183314); N Engl J Med. 2009 Oct 8;361(15):1475-85. (PMID: 19812404); Science. 2003 Sep 19;301(5640):1731-3. (PMID: 14500985); J Alzheimers Dis. 2012;30 Suppl 2:S5-13. (PMID: 22045480); Nature. 2007 Nov 8;450(7167):165-7. (PMID: 17994065); DNA Repair (Amst). 2005 Nov 21;4(11):1314-24. (PMID: 16115803); Acta Neuropathol. 2010 Oct;120(4):461-75. (PMID: 20602234); Chem Res Toxicol. 2009 Nov;22(11):1747-60. (PMID: 19757819); Mech Ageing Dev. 2013 May-Jun;134(5-6):180-95. (PMID: 23591128); PLoS Genet. 2014 Oct 09;10(10):e1004686. (PMID: 25299392); PLoS Biol. 2007 Jan;5(1):e2. (PMID: 17326724); Nat Genet. 1993 Nov;5(3):217-24. (PMID: 8275084); Genet Med. 2016 May;18(5):483-93. (PMID: 26204423); Pathobiol Aging Age Relat Dis. 2011;1:null. (PMID: 22953029); Mol Cell Proteomics. 2013 May;12(5):1350-62. (PMID: 23399551); Diabetes. 2012 Jun;61(6):1315-22. (PMID: 22618766); Annu Rev Pharmacol Toxicol. 2016;56:427-45. (PMID: 26514200); Am J Hum Genet. 2013 May 2;92(5):800-6. (PMID: 23623386); Cell. 2013 Jun 6;153(6):1194-217. (PMID: 23746838); Nat Rev Mol Cell Biol. 2014 Jul;15(7):465-81. (PMID: 24954209); Nature. 2007 Jun 28;447(7148):1130-4. (PMID: 17554337); PLoS One. 2015 Jul 15;10(7):e0132767. (PMID: 26177460); Neurobiol Dis. 2007 Apr;26(1):212-20. (PMID: 17306982); Curr Biol. 1997 Jun 1;7(6):427-39. (PMID: 9197240); Nat Biotechnol. 2008 Mar;26(3):303-4. (PMID: 18327243); BMC Genomics. 2009 Dec 07;10:585. (PMID: 19968875); Nature. 2010 Oct 7;467(7316):707-10. (PMID: 20861837); Am J Hum Genet. 2013 May 2;92(5):807-19. (PMID: 23623389); Nat Protoc. 2009;4(8):1184-91. (PMID: 19617889); Science. 2010 Apr 16;328(5976):321-6. (PMID: 20395504); Physiol Rev. 2013 Apr;93(2):571-98. (PMID: 23589828); Osteoarthritis Cartilage. 2009 May;17 (5):636-45. (PMID: 19010693); Interdiscip Top Gerontol. 2014;39:45-61. (PMID: 24862014); J Neurosci. 2011 Aug 31;31(35):12543-53. (PMID: 21880916); Circulation. 2012 Jul 24;126(4):468-78. (PMID: 22705887); Neurobiol Aging. 2014 Sep;35(9):2147-60. (PMID: 24799273); Science. 2009 Jul 10;325(5937):201-4. (PMID: 19590001); Mol Aspects Med. 2011 Jun;32(3):159-221. (PMID: 21840335); RNA Biol. 2015;12(1):30-42. (PMID: 25826412); Toxicol Sci. 2011 Mar;120 Suppl 1:S130-45. (PMID: 21163908); Aging Cell. 2013 Oct;12(5):901-9. (PMID: 23795901); J Bone Miner Res. 2004 Oct;19(10 ):1640-50. (PMID: 15355559) |
| Grant Information: | P01 AG017242 United States AG NIA NIH HHS; P30 CA013330 United States CA NCI NIH HHS |
| Substance Nomenclature: | 0 (DNA-Binding Proteins); EC 3.1.- (Endonucleases); 0 (Nuclear Proteins); 0 (Transcription Factors); EC 3.1.- (DNA Excision Repair Protein ERCC-5); EC 3.1.- (Ercc1 protein, mouse) |
| Entry Date(s): | Date Created: 20160825 Date Completed: 20170220 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5161687 |
| DOI: | 10.1038/nature19329 |
| PMID: | 27556946 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural