Abstract

Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1∆/−) show numerous accelerated ageing features that limit their lifespan to 4-6 months1,2,3,4. 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)1,5. 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 syndrome6, 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.

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Primary accessions

Gene Expression Omnibus

Data deposits

The expression data have been deposited to the Gene Expression Omnibus database under accession number GSE77495.

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Acknowledgements

We thank P. de With, J. Rigters, E. Haasdijk, S. Gabriels, E. J. M. Stynenbosch, N. van Vliet, Y. van Loon, J. Baan and the animal caretakers for general assistance with mouse experiments. We thank A. H. J. Danser and J. P. van Leeuwen for support. We acknowledge financial support from the National Institute of Health (NIH)/National Institute of Ageing (NIA) (1PO1 AG-17242-02), the National Institute for Public Health and the Environment and the Ministry of Health, Welfare and Sport of The Netherlands (S/340005), European Research Council Advanced Grant DamAge and Proof of Concept Grant Dementia to J.H.J.H., the European commission FP7 Markage (FP7-Health-2008-200880), DNA Repair (LSHG-CT-2005-512113), EU ITN Address (GA-316390), the KWO Dutch Cancer Society (5030), the Dutch CAA Foundation and the Royal Academy of Arts and Sciences of the Netherlands (academia professorship to J.H.J.H.). The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number HEALTH-F2-2010-259893. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

    • W. P. Vermeij
    •  & M. E. T. Dollé

    These authors contributed equally to this work.

    • R. V. Kuiper

    Present address: Department of Laboratory Medicine, Karolinska Institute, SE 171, 77 Stockholm, Sweden.

Affiliations

  1. Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands

    • W. P. Vermeij
    • , E. Reiling
    • , C. Payan-Gomez
    • , C. R. Bombardieri
    • , S. M. Botter
    • , R. M. C. Brandt
    • , S. Barnhoorn
    • , Á. Gyenis
    • , J. Pothof
    •  & J. H. J. Hoeijmakers
  2. Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands

    • M. E. T. Dollé
    • , E. Reiling
    • , B. Nagarajah
    • , C. T. van Oostrom
    • , S. Imholz
    • , J. L. A. Pennings
    •  & H. van Steeg
  3. Department of Neuroscience, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands

    • D. Jaarsma
  4. Facultad de Ciencias Naturales y Matemáticas, Universidad del Rosario, Carrera 24, 63C-69 Bogotá, Colombia

    • C. Payan-Gomez
  5. Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands

    • H. Wu
    •  & A. J. M. Roks
  6. Laboratory for Orthopedic Research, Balgrist University Hospital, Forchstrasse 340, 8008, Zürich, Switzerland

    • S. M. Botter
  7. Department of Internal Medicine, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands

    • B. C. van der Eerden
  8. Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, PO Box 80125, 3508 TC Utrecht, The Netherlands

    • S. A. Youssef
    • , R. V. Kuiper
    •  & A. de Bruin
  9. Department of Pediatrics, Division Molecular Genetics, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands

    • A. de Bruin
  10. Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA

    • J. Vijg
  11. Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands

    • H. van Steeg
  12. CECAD Forschungszentrum, Universität zu Köln, Joseph-Stelzmann-Straße 26, 50931 Köln, Germany

    • J. H. J. Hoeijmakers

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Contributions

W.P.V., M.E.T.D., E.R., J.V., H.v.S., and J.H.J.H. designed the research and wrote the manuscript. D.J., C.P.-G., A.J.M.R., S.M.B., B.C.v.d.E., A.d.B., Á.G., and J.P. contributed to editing the manuscript. W.P.V., M.E.T.D., E.R., R.M.C.B., and S.B. performed and analysed the mouse lifespan cohorts. E.R., B.N., C.T.v.O., R.M.C.B., S.B., and S.I. performed genotyping and coordinated animal sectioning. S.A.Y., R.V.K., and A.d.B. assessed the ageing pathology characteristics. R.V.K. and S.I. performed FACS analysis of nuclei. S.M.B. and B.C.E. quantified bone changes. H.W. and A.J.M.R. quantified vascular function. C.R.B. performed the immunological analyses. W.P.V., D.J., R.M.C.B., and S.B. performed and analysed phenotypical scoring and behavioural analysis. W.P.V. and D.J. characterized neuropathological changes. W.P.V., E.R., C.P.-G., C.T.v.O., J.L.A.P., Á.G., and J.P. performed transcriptomic analyses and analysed the data. W.P.V., M.E.T.D., E.R., C.T.v.O. R.M.C.B., S.B., and S.I. performed the molecular studies.

Corresponding authors

Correspondence to M. E. T. Dollé or J. H. J. Hoeijmakers.

Reviewer Information Nature thanks C. Lopez-Otin, M. Mattson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Pathology scores of aging-related histopathological phenotypes in liver, kidney and sciatic nerve of AL and DR wt and Ercc1δ/− mice

  2. 2.

    Supplementary Table 2

    Gene ontology pathway and upstream regulator transcription factor analysis of DEG response by DR in wt and Ercc1δ/−

Videos

  1. 1.

    DR delays onset of neurological abnormalities in Ercc1δ/− mice

    AL-fed Ercc1δ/− mouse (shown on the right), at 16 weeks of age, shows abnormal gait, trembling and balance problems. These age-related neurological symptoms are absent in the littermate DR Ercc1δ/− mouse (left) at 16 weeks but eventually may develop after 35 weeks of age (see Figure 2a-c). Video contains audio comments. (reference to website with access to the video: http://cluster15.erasmusmc.nl/drvideos/index.html).

  2. 2.

    DR dramatically improves accelerating rotarod performance of 16 week-old Ercc1δ/− mice

    Wildtype AL and DR and Ercc1δ/− AL and DR mice, form right to left respectively, were tested for locomotor performance on an accelerating rotarod. The average time of four animals per group is shown in Figure 2d. Video contains audio comments. (reference to website with access to the video: http://cluster15.erasmusmc.nl/drvideos/index.html).

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DOI

https://doi.org/10.1038/nature19329

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