Cited by 138Genetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and SenescenceGrowth Hormone and Insulin-like Growth Factors

Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity

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Garinis, George A., Uittenboogaard, Lieneke M., Stachelscheid, Heike, Fousteri, Maria, van Ijcken, Wilfred, Breit, Timo M., van Steeg, Harry, Mullenders, Leon H. F. +5 more·2009·Nature Cell Biology

Abstract

The accumulation of stochastic DNA damage throughout an organism's lifespan is thought to contribute to ageing. Conversely, ageing seems to be phenotypically reproducible and regulated through genetic pathways such as the insulin-like growth factor-1 (IGF-1) and growth hormone (GH) receptors, which are central mediators of the somatic growth axis. Here we report that persistent DNA damage in primary cells from mice elicits changes in global gene expression similar to those occurring in various organs of naturally aged animals. We show that, as in ageing animals, the expression of IGF-1 receptor and GH receptor is attenuated, resulting in cellular resistance to IGF-1. This cell-autonomous attenuation is specifically induced by persistent lesions leading to stalling of RNA polymerase II in proliferating, quiescent and terminally differentiated cells; it is exacerbated and prolonged in cells from progeroid mice and confers resistance to oxidative stress. Our findings suggest that the accumulation of DNA damage in transcribed genes in most if not all tissues contributes to the ageing-associated shift from growth to somatic maintenance that triggers stress resistance and is thought to promote longevity.

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  • Unrepaired transcription-blocking lesions suppress IGF-1 signaling in mouse and human cells, resulting in elevated stress resistance.

    “Unrepaired transcription-blocking lesions suppress IGF-1 signaling in mouse and human cells resulting in elevated stress resistance94.”

    From The central role of DNA damage in the ageing process (2021) · cites this paper as [94]

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  1. [68]Kirkwood T Repair and its evolution: survival versus reproduction 1981 Oxford Blackwell 165 189

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Authors
Garinis, G. A., Uittenboogaard, L. M., Stachelscheid, H., Fousteri, M., van Ijcken, W., Breit, T. M., van Steeg, H., Mullenders, L. H. F., van der Horst, G. T. J., Brüning, J. C., Niessen, C. M., Hoeijmakers, J. H. J., & Schumacher, B.
Affiliations
  • Erasmus MC (NL)
  • University of Cologne (DE)
  • Leiden University Medical Center (NL)
  • University of Amsterdam (NL)
Corresponding author
Schumacher, Björn
Venue
Nature Cell Biology
Published
2009-04-12
Volume
11
Issue
5
Pages
604-615
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
OpenAlex
W2048614750
Cited by
138
References
72
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 11 · 2019: 5 · 2018: 5 · 2017: 9 · 2016: 13 · 2015: 6 · 2014: 16 · 2013: 14 · 2012: 9
FWCI
3.38
Type
journal article
Language
en
Open access
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • UvA-DARE (University of Amsterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
  • Rivm (National Institute for Public Health and the Environment) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • National Institute on Aging (1P01 AG-17242, P01AG017242)
  • National Institute of Environmental Health Sciences (1UO1 ES011044, U01ES011044)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
DNA damage, aging, longevity, IGF-1 receptor, growth hormone receptor, RNA polymerase II stalling, transcriptional silencing, progeroid mice, oxidative stress resistance, gene expression changes, cellular senescence, growth hormone
MeSH terms
Aging, Animals, Animal Structures, DNA, DNA Damage, DNA Repair, Growth, Humans, Longevity, Mice, Inbred C57BL, Models, Biological, Neoplasms, Progeria, Receptors, Somatotropin, RNA Polymerase II, Stress, Physiological, Transcription, Genetic, Ultraviolet Rays, Receptor, IGF Type 1, Mice, Knockout, Oxidative Stress, Gene Expression Profiling, Mice, Rats

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