Title

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

Document Type

Article

Publication Date

2007

Keywords

Crosses-Genetic, DNA-Activated-Protein-Kinase, DNA-Binding-Proteins, Hepatitis-Animal, Interleukin-1beta, Interleukin-6, Liver, Longevity, Mice-Transgenic, Murine-hepatitis-virus, Nuclear-Proteins, RNA, Stress, Telomerase, Telomere, Tumor-Necrosis-Factor-alpha

JAX Source

Oncogene 2007 May; 26(20):2815-21.

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 alpha (TNFalpha) 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.