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 α (TNFα) 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.
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References
Alexopoulou L, Holt AC, Medzhitov R, Flavell RA . (2001). Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413: 732–738.
Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA et al. (1997). Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25–34.
Bonizzi G, Karin M . (2004). The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25: 280–288.
Bruunsgaard H, Andersen-Ranberg K, Hjelmborg JB, Pedersen BK, Jeune B . (2003). Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 115: 278–283.
Bruunsgaard H, Pedersen BK . (2003). Age-related inflammatory cytokines and disease. Immunol Allergy Clin NAm 23: 15–39.
Chu W-M, Gong X, Li Z-W, Takabayashi K, Ouyang H-H, Chen Y et al. (2000). DNA-PKcs is required for activation of innate immuntity by immunostimulatory DNA. Cell 103: 909–918.
Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, Ryu SY . (1993). Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol 150: 5219–5230.
Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G et al. (1993). Interleukin-6 and aging: blood levels and mononuclear cell production increase with advancing age and in vitro production is modifiable by dietary restriction. Lymphokine Cytokine Res 12: 225–230.
Espejel S, Franco S, Sgura A, Gae D, Bailey SM, Taccioli GE et al. (2002). Functional interaction between DNA-PKcs and telomerase in telomere length maintenance. EMBO J 21: 6275–6287.
Espejel S, Klatt P, Menissier-de Murcia J, Martin-Caballero J, Flores JM, Taccioli G et al. (2004). Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs. J Cell Biol 167: 627–638.
Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver DT, Alt FW . (1998). A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity 9: 367–376.
Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J . (2003). Aging and genome maintenance: lessons from the mouse? Science 299: 1355–1359.
Hayden MS, Ghosh S . (2004). Signaling to NF-kappaB. Genes Dev 18: 2195–2224.
Karpova AY, Trost M, Murray JM, Cantley LC, Howley PM . (2002). Interferon regulatory factor-3 is an in vivo target of DNA-PK. Proc Natl Acad Sci USA 99: 2818–2823.
Lieber MR, Ma Y, Pannicke U, Schwarz K . (2003). Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4: 712–720.
Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J et al. (2004). Gene regulation and DNA damage in the ageing human brain. Nature 429: 883–891.
Maser RS, DePinho RA . (2004). Telomeres and the DNA damage response: why the fox is guarding the henhouse. DNA Repair (Amsterdam) 3: 979–988.
Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C et al. (1999). Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96: 701–712.
Salminen A, Helenius M, Lahtinen T, Korhonen P, Tapiola T, Soininen H et al. (1997). Down-regulation of Ku autoantigen, DNA-dependent protein kinase, and poly(ADP-ribose) polymerase during cellular senescence. Biochem Biophys Res Commun 238: 712–716.
Smogorzewska A, Karlseder J, Holtgreve-Grez H, Jauch A, de Lange T . (2002). DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr Biol 12: 1635–1644.
Um JH, Kim SJ, Kim DW, Ha MY, Jang JH, Kim DW et al. (2003). Tissue-specific changes of DNA repair protein Ku and mtHSP70 in aging rats and their retardation by caloric restriction. Mech Age Dev 124: 967–975.
Wollscheid-Lengeling E, Muller R-J, Balling R, Schughart K . (2004). Maintaining your immune system – one method for enhanced longevity. Sci Aging Knowl Environ 2004: pe2.
Wong KK, Chang S, Weiler SR, Ganesan S, Chaudhuri J, Zhu C et al. (2000). Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat Genet 26: 85–88.
Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y et al. (2003). Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421: 643–648.
Acknowledgements
We thank Dr Frederick W Alt for the DNA-PKcs mutant mice and for helpful discussions and comments on the manuscript and Dr N Simon for advice on statistical tests. The authors would also like to thank members of their laboratories for helpful discussions and comments on the manuscript. KKW is supported by National Institute of Health (NIH) grant K08AG 2400401 and the Sidney Kimmel Foundation for cancer research. RSM was supported by a Howard Ringold Fellowship from the Damon Runyon Cancer Research Fund. RW is supported by NIH grant CA34461. RAD is the American Cancer Society Research Professor and an Ellison Medical Foundation Senior Scholar and is supported by NIH grants R01CA84628, P01CA95616 and U01CA84313 and by the Robert A and Renee E Belfer Foundation Institute for Innovative Cancer Science.
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Wong, KK., Maser, R., Sahin, E. et al. Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres. Oncogene 26, 2815–2821 (2007). https://doi.org/10.1038/sj.onc.1210099
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DOI: https://doi.org/10.1038/sj.onc.1210099
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