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Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres

Oncogene volume 26, pages 2815–2821 (2007)Cite this article

Abstract

An adequate and appropriate response to physiological and pathophysiological stresses is critical for long-term homeostasis and viability of the aging organism. Previous work has pointed to the immune system, telomeres and DNA repair pathways as important and distinct determinants of a normal healthy lifespan. In this study, we explored the genetic interactions of telomeres and DNA-PKcs, a protein involved in non-homologous end-joining (NHEJ) and immune responses, in the context of a key aspect of aging and lifespan – the capacity to mount an acute and appropriate immune-mediated stress response. We observed that the combination of DNA-PKcs deficiency and telomere dysfunction resulted in a shortened lifespan that was reduced further following viral infection or experimental activation of the innate immune response. Analysis of the innate immune response in the DNA-PKcs-deficient mice with short dysfunctional telomeres revealed high basal serum levels of tumor necrosis factor α (TNFα) and hyper-active cytokine responses upon challenge with polyinosinic-polycytidylic acid (poly-IC). We further show that serum cytokine levels become elevated in telomere dysfunctional mice as a function of age. These results raise speculation that these genetic factors may contribute to misdirected immune responses of the aged under conditions of acute and chronic stress.

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Acknowledgements

We thank Dr Frederick W Alt for the DNA-PKcs mutant mice and for helpful discussions and comments on the manuscript and Dr N Simon for advice on statistical tests. The authors would also like to thank members of their laboratories for helpful discussions and comments on the manuscript. KKW is supported by National Institute of Health (NIH) grant K08AG 2400401 and the Sidney Kimmel Foundation for cancer research. RSM was supported by a Howard Ringold Fellowship from the Damon Runyon Cancer Research Fund. RW is supported by NIH grant CA34461. RAD is the American Cancer Society Research Professor and an Ellison Medical Foundation Senior Scholar and is supported by NIH grants R01CA84628, P01CA95616 and U01CA84313 and by the Robert A and Renee E Belfer Foundation Institute for Innovative Cancer Science.

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  1. K-K Wong and R S Maser: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    K-K Wong, R S Maser, E Sahin, H Xia, H Ji, K McNamara & R A DePinho

  2. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

    S T Bailey

  3. Department of Genetics and Medicine, Harvard Medical School, Boston, MA, USA

    M Naylor & R A DePinho

  4. Department of Pathology, Harvard Medical School, Boston, MA, USA

    R T Bronson

  5. Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA

    S Ghosh

  6. Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA

    R Welsh

  7. Center for Applied Cancer Science and Belfer Foundation Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA

    R A DePinho

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  1. K-K Wong
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  2. R S Maser
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Correspondence to R A DePinho.

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Wong, KK., Maser, R., Sahin, E. et al. Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres. Oncogene 26, 2815–2821 (2007). https://doi.org/10.1038/sj.onc.1210099

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  • DOI: https://doi.org/10.1038/sj.onc.1210099

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