Increased cell-to-cell variation in gene expression in ageing mouse heart
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The accumulation of somatic DNA damage has been implicated as a cause of ageing in metazoa. One possible mechanism by which increased DNA damage could lead to cellular degeneration and death is by stochastic deregulation of gene expression. Here we directly test for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice, followed by global mRNA amplification and quantification of mRNA levels in a panel of housekeeping and heart-specific genes. Although gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. We had demonstrated previously an increased load of genome rearrangements and other mutations in the heart of aged mice. To confirm that increased stochasticity of gene expression could be a result of increased genome damage, we treated mouse embryonic fibroblasts in culture with hydrogen peroxide. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at a lacZ reporter locus. These results underscore the stochastic nature of the ageing process, and could provide a mechanism for age-related cellular degeneration and death in tissues of multicellular organisms.
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Stochastic variation in gene expression in aged tissues is thought to contribute to age-associated organ decline even when tissue-wide expression is unchanged.
“stochastic variations in gene expression in aged tissues are thought to be a contributing factor to age-associated organ decline even if gene expression across the tissue remains unaltered (59).”
From Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability (2016) · cites this paper as [59]
RNA isolated from individual cardiomyocytes of young and old mice showed broad mosaicism in gene expression among cells within individual mice and increased differences in expression between cells.
“In a groundbreaking single cell study, RNA isolated from individual cardiomyocytes of young and old mice showed broad mosaicism in gene expression among cells within individual mice and increased differences in expression between cells.45.”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [45]
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- Authors
- Bahar, R., Hartmann, C. H., Rodriguez, K. A., Denny, A. D., Busuttil, R. A., Dollé, M. E. T., Calder, R. B., Chisholm, G. B., Pollock, B. H., Klein, C. A., & Vijg, J.
- Affiliations
- Buck Institute for Research on Aging (US)
- Institut für Immunologie (DE)
- The University of Texas at San Antonio Health Science Center (US)
- National Institute for Public Health and the Environment (NL)
- Corresponding author
- Vijg, Jan
- ORCID
- Venue
- Nature
- Published
- 2006-06
- Volume
- 441
- Issue
- 7096
- Pages
- 1011-1014
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2067432938
- Cited by
- 603
- References
- 20
- Citations by year
- 2026: 22 · 2025: 20 · 2024: 26 · 2023: 38 · 2022: 25 · 2021: 29 · 2020: 35 · 2019: 42 · 2018: 29 · 2017: 40 · 2016: 28 · 2015: 35 · 2014: 28 · 2013: 22 · 2012: 29
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Rivm Repository (Netherlands National Institute for Public Health and the Environment) (submittedVersion)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion, other-oa)
- Funders
- National Institute on Aging (R36AG033401, P01AG017242)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- aging, transcriptional noise, cardiomyocytes, genome rearrangement, genotoxic stress, hydrogen peroxide, stochastic gene expression, heart
- MeSH terms
- Aging, Animals, Heart, Hydrogen Peroxide, Male, Mice, Inbred C57BL, Myocardium, RNA, Messenger, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, Mice
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