Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Increased cell-to-cell variation in gene expression in ageing mouse heart


The accumulation of somatic DNA damage has been implicated as a cause of ageing in metazoa1,2. 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 mice3,4. 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Reproducibility of unbiased, global mRNA amplification of mouse cardiomyocytes.
Figure 2: Increased cell-to-cell variation in gene expression among cardiomyocytes from the heart of old as compared with young mice.
Figure 3: H 2 O 2 treatment of MEFs increases cell-to-cell variation in gene expression in parallel to the induction of genome rearrangements.


  1. Vijg, J. & Dollé, M. E. Large genome rearrangements as a primary cause of aging. Mech. Ageing Dev. 123, 907–915 (2002)

    Article  CAS  PubMed  Google Scholar 

  2. Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005)

    Article  CAS  PubMed  Google Scholar 

  3. Dollé, M. E., Snyder, W. K., Gossen, J. A., Lohman, P. H. & Vijg, J. Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. Proc. Natl Acad. Sci. USA 97, 8403–8408 (2000)

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  4. Dollé, M. E. & Vijg, J. Genome dynamics in aging mice. Genome Res. 12, 1732–1738 (2002)

    Article  PubMed  PubMed Central  Google Scholar 

  5. Levsky, J. M., Shenoy, S. M., Pezo, R. C. & Singer, R. H. Single-cell gene expression profiling. Science 297, 836–840 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Levsky, J. M. & Singer, R. H. Gene expression and the myth of the average cell. Trends Cell Biol. 13, 4–6 (2003)

    Article  CAS  PubMed  Google Scholar 

  7. Klein, C. A. et al. Combined transcriptome and genome analysis of single micrometastatic cells. Nature Biotechnol. 20, 387–392 (2002)

    Article  CAS  Google Scholar 

  8. Kang, P. M., Haunstetter, A., Aoki, H., Usheva, A. & Izumo, S. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circ. Res. 87, 118–125 (2000)

    Article  CAS  PubMed  Google Scholar 

  9. Kaern, M., Elston, T. C., Blake, W. J. & Collins, J. J. Stochasticity in gene expression: from theories to phenotypes. Nature Rev. Genet. 6, 451–464 (2005)

    Article  CAS  PubMed  Google Scholar 

  10. Becskei, A., Kaufmann, B. B. & van Oudenaarden, A. Contributions of low molecule number and chromosomal positioning to stochastic gene expression. Nature Genet. 37, 937–944 (2005)

    Article  CAS  PubMed  Google Scholar 

  11. Parrinello, S. et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nature Cell Biol. 5, 741–747 (2003)

    Article  CAS  PubMed  Google Scholar 

  12. Boerrigter, M. E., Dollé, M. E., Martus, H. J., Gossen, J. A. & Vijg, J. Plasmid-based transgenic mouse model for studying in vivo mutations. Nature 377, 657–659 (1995)

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Orgel, L. E. The maintenance of the accuracy of protein synthesis and its relevance to ageing. Proc. Natl Acad. Sci. USA 49, 517–521 (1963)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Finch, C. E. & Kirkwood, T. B. Chance, Development, and Aging (Oxford Univ. Press, New York, 2000)

    Google Scholar 

  15. Rea, S. L., Wu, D., Cypser, J. R., Vaupel, J. W. & Johnson, T. E. A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans. Nature Genet. 37, 894–898 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. Golden, T. R. & Melov, S. Microarray analysis of gene expression with age in individual nematodes. Aging Cell 3, 111–124 (2004)

    Article  CAS  PubMed  Google Scholar 

  17. Fraser, H. B., Hirsh, A. E., Giaever, G., Kumm, J. & Eisen, M. B. Noise minimization in eukaryotic gene expression. PLoS Biol. 2, e137 (2004)

    Article  PubMed  PubMed Central  Google Scholar 

  18. Busuttil, R. A., Rubio, M., Dollé, M. E., Campisi, J. & Vijg, J. Oxygen accelerates the accumulation of mutations during the senescence and immortalization of murine cells in culture. Aging Cell 2, 287–294 (2003)

    Article  CAS  PubMed  Google Scholar 

  19. Dollé, M. E., Martus, H. J., Gossen, J. A., Boerrigter, M. E. & Vijg, J. Evaluation of a plasmid-based transgenic mouse model for detecting in vivo mutations. Mutagenesis 11, 111–118 (1996)

    Article  PubMed  Google Scholar 

Download references


This work was supported by an NIH grant to J.V. and a BioFuture grant from the German Federal Ministry for Education and Science to C.A.K. We thank K. Khrapko and R. Beems for advice and useful suggestions. Author Contributions J.V. conceived, designed and supervised the study (initially with M.E.T.D.), obtained the funding and took the primary role in writing the paper. R.B. designed and performed the experiments, assisted by K.A.R., A.D.D. and R.A.B. R.B.C., G.B.C. and B.H.P. performed statistical analyses and made the figures. C.H.H. and C.A.K. provided the modified protocol for global mRNA amplification.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jan Vijg.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Methods and Supplementary Figure 1 Legend. (DOC 41 kb)

Supplementary Table 1

Selected genes for real-time PCR quantitative analysis in single cells (DOC 106 kb)

Supplementary Figure 1

Possible effects of enzymatic dissociation or age of the animal on gene expression in cardiac tissues. (PDF 16 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bahar, R., Hartmann, C., Rodriguez, K. et al. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441, 1011–1014 (2006).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing