1. ¹Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
2. ²Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
3. ³Department of Genetics and Medicine, Harvard Medical School, Boston, MA, USA
4. ⁴Department of Pathology, Harvard Medical School, Boston, MA, USA
5. ⁵Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA
6. ⁶Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
7. ⁷Center for Applied Cancer Science and Belfer Foundation Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA

Correspondence: Dr RA DePinho, Department of Medical Oncology Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, M413, Boston, MA 02115, USA. E-mail: ron_depinho@dfci.harvard.edu

⁸These authors contributed equally to this work.

Received 28 June 2006; Revised 11 September 2006; Accepted 27 September 2006; Published online 30 October 2006.

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 (TNF) 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.