title: Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres.
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.
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: K-K
authors.initials: KK
authors.lastname: Wong
authors.forename: R S
authors.initials: RS
authors.lastname: Maser
authors.forename: E
authors.initials: E
authors.lastname: Sahin
authors.forename: S T
authors.initials: ST
authors.lastname: Bailey
authors.forename: H
authors.initials: H
authors.lastname: Xia
authors.forename: H
authors.initials: H
authors.lastname: Ji
authors.forename: K
authors.initials: K
authors.lastname: McNamara
authors.forename: M
authors.initials: M
authors.lastname: Naylor
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: S
authors.initials: S
authors.lastname: Ghosh
authors.forename: R
authors.initials: R
authors.lastname: Welsh
authors.forename: R A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: 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
chemical_list: 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