Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity
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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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Self-citation
- 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
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2009-04-12
- Volume
- 11
- Issue
- 5
- Pages
- 604-615
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2782455
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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