Back to Search Start Over

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

Authors :
Richard S. Maser
R. Welsh
Kwok-Kin Wong
Kate McNamara
Ronald A. DePinho
Shannon T. Bailey
Sankar Ghosh
Hongbin Ji
Ergiin Sahin
Maria L. Naylor
Roderick T. Bronson
Huili Xia
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.

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