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Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres
- Source :
- Oncogene. 26:2815-2821
- Publication Year :
- 2006
- Publisher :
- Springer Science and Business Media LLC, 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 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.
- Subjects :
- Cancer Research
Telomerase
medicine.medical_treatment
Interleukin-1beta
Longevity
Mice, Transgenic
DNA-Activated Protein Kinase
Hepatitis, Animal
Mice
Immune system
Stress, Physiological
Genetics
medicine
Animals
Chronic stress
Interleukin 6
Molecular Biology
Crosses, Genetic
Murine hepatitis virus
Innate immune system
biology
Interleukin-6
Tumor Necrosis Factor-alpha
Nuclear Proteins
Telomere
DNA-Binding Proteins
Cytokine
Liver
Immunology
biology.protein
RNA
Tumor necrosis factor alpha
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....f2a4a6500364dfc753bf57e3128b156f
- Full Text :
- https://doi.org/10.1038/sj.onc.1210099