Wong K-K, Maser R S, Sahin E, Bailey S T, Xia H, Ji H, McNamara K, Naylor M, Bronson R T, Ghosh S, Welsh R, DePinho R A
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Oncogene. 2007 May 3;26(20):2815-21. doi: 10.1038/sj.onc.1210099. Epub 2006 Oct 30.
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.
对生理和病理生理应激做出充分且恰当的反应，对于衰老生物体的长期内稳态和生存能力至关重要。先前的研究指出，免疫系统、端粒和DNA修复途径是正常健康寿命的重要且独特的决定因素。在本研究中，我们在衰老和寿命的一个关键方面——产生急性且恰当的免疫介导应激反应的能力——的背景下，探讨了端粒与DNA-PKcs（一种参与非同源末端连接（NHEJ）和免疫反应的蛋白质）之间的遗传相互作用。我们观察到，DNA-PKcs缺陷与端粒功能障碍相结合导致寿命缩短，在病毒感染或先天免疫反应的实验性激活后，寿命进一步缩短。对具有短功能障碍端粒的DNA-PKcs缺陷小鼠的先天免疫反应分析显示，肿瘤坏死因子α（TNFα）的基础血清水平较高，在用聚肌苷酸-聚胞苷酸（poly-IC）攻击后细胞因子反应过度活跃。我们进一步表明，随着年龄的增长，端粒功能障碍小鼠的血清细胞因子水平会升高。这些结果引发了一种推测，即在急性和慢性应激条件下，这些遗传因素可能导致老年人免疫反应的错误导向。
