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
First Page
2815
Last Page
2821
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.
Recommended Citation
Wong KK,
Maser RS,
Sahin E,
Bailey ST,
Xia H,
Ji H,
McNamara K,
Naylor M,
Bronson RT,
Ghosh S,
Welsh R,
DePinho RA.
Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres. Oncogene 2007 May; 26(20):2815-21.