Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres.
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.
Wong
K-K
KK
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Maser
R S
RS
Sahin
E
E
Bailey
S T
ST
Xia
H
H
Ji
H
H
McNamara
K
K
Naylor
M
M
Bronson
R T
RT
Ghosh
S
S
Welsh
R
R
DePinho
R A
RA
D000818:Animals; D003433:Crosses, Genetic; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006520:Hepatitis, Animal / Q000097:blood / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000473:pathology; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D006517:Murine hepatitis virus / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D009687:Nuclear Proteins; D014409:Tumor Necrosis Factor-alpha; C422952:telomerase RNA; D012313:RNA; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D019098:Telomerase