Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice

W. P. Vermeij, M. E T Dollé, E. Reiling, D. Jaarsma, C. Payan-Gomez, C. R. Bombardieri, H. Wu, A. J M Roks, S. M. Botter, B. C. van der Eerden, S. A. Youssef, R. V. Kuiper, B. Nagarajah, C. T. van Oostrom, R. M C Brandt, S. Barnhoorn, S. Imholz, J. L A Pennings, A. de Bruin, Gyenis & 4 others J. Pothof, Jan Vijg, H. van Steeg, J. H J Hoeijmakers

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish (US)
JournalNature
DOIs
StateAccepted/In press - Aug 24 2016

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DNA Repair-Deficiency Disorders
Diet
DNA Damage
DNA Repair
Cockayne Syndrome
Caloric Restriction
Wild Animals
Genomic Instability
Human Genome
Genes
Maintenance
Genome
Gene Expression
Neurons

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Vermeij, W. P., Dollé, M. E. T., Reiling, E., Jaarsma, D., Payan-Gomez, C., Bombardieri, C. R., ... Hoeijmakers, J. H. J. (Accepted/In press). Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature. https://doi.org/10.1038/nature19329

Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. / Vermeij, W. P.; Dollé, M. E T; Reiling, E.; Jaarsma, D.; Payan-Gomez, C.; Bombardieri, C. R.; Wu, H.; Roks, A. J M; Botter, S. M.; van der Eerden, B. C.; Youssef, S. A.; Kuiper, R. V.; Nagarajah, B.; van Oostrom, C. T.; Brandt, R. M C; Barnhoorn, S.; Imholz, S.; Pennings, J. L A; de Bruin, A.; Gyenis; Pothof, J.; Vijg, Jan; van Steeg, H.; Hoeijmakers, J. H J.

In: Nature, 24.08.2016.

Research output: Contribution to journalArticle

Vermeij, WP, Dollé, MET, Reiling, E, Jaarsma, D, Payan-Gomez, C, Bombardieri, CR, Wu, H, Roks, AJM, Botter, SM, van der Eerden, BC, Youssef, SA, Kuiper, RV, Nagarajah, B, van Oostrom, CT, Brandt, RMC, Barnhoorn, S, Imholz, S, Pennings, JLA, de Bruin, A, Gyenis, Pothof, J, Vijg, J, van Steeg, H & Hoeijmakers, JHJ 2016, 'Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice', Nature. https://doi.org/10.1038/nature19329
Vermeij WP, Dollé MET, Reiling E, Jaarsma D, Payan-Gomez C, Bombardieri CR et al. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature. 2016 Aug 24. https://doi.org/10.1038/nature19329
Vermeij, W. P. ; Dollé, M. E T ; Reiling, E. ; Jaarsma, D. ; Payan-Gomez, C. ; Bombardieri, C. R. ; Wu, H. ; Roks, A. J M ; Botter, S. M. ; van der Eerden, B. C. ; Youssef, S. A. ; Kuiper, R. V. ; Nagarajah, B. ; van Oostrom, C. T. ; Brandt, R. M C ; Barnhoorn, S. ; Imholz, S. ; Pennings, J. L A ; de Bruin, A. ; Gyenis ; Pothof, J. ; Vijg, Jan ; van Steeg, H. ; Hoeijmakers, J. H J. / Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. In: Nature. 2016.
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AU - Payan-Gomez, C.

AU - Bombardieri, C. R.

AU - Wu, H.

AU - Roks, A. J M

AU - Botter, S. M.

AU - van der Eerden, B. C.

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AU - Pennings, J. L A

AU - de Bruin, A.

AU - Gyenis,

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