Role of Telomere In Human Lymphocyte Function and Aging

端粒是染色体的末端结构，在维持染色体完整性和控制细胞复制方面起着至关重要的作用。外周血单核细胞(PBMCs)端粒长度随年龄增长的情况从横断面研究中得到了很好的证明。但端粒长度在体内的实际变化及其与个体内随年龄增长的影响因素的关系尚未完全解决。在这里，我们报告了一项对216名年龄在20到90岁之间的受试者的外周血单核细胞、淋巴细胞和单核细胞端粒长度的纵向分析，这些受试者在零、五年和十二年的随访中被评估。在5年和12年的随访中，PBMC的端粒长度分别减少了34%和46%，无明显变化的分别为56%和47%，增加的分别为10%和7%。在任何特定的受试者中，T细胞、B细胞和单核细胞的端粒变化率是不同的。静息T细胞、B细胞和活化T细胞端粒酶活性随增龄而降低。最后，端粒酶活性下降，幼稚细胞减少，以及血糖和IL-6水平升高等生理条件的改变解释了T细胞端粒随年龄增长的很大一部分磨损。这些发现表明，体内PBMCs端粒长度随年龄的变化在不同的个体和细胞类型中以不同的速率发生，并揭示了T细胞端粒长度随年龄的变化受端粒酶活性、初始T细胞百分比和健康状况变化的影响。 端粒是保护染色体完整性的关键机制，在淋巴细胞中，端粒在细胞分裂后和衰老过程中的磨损是显而易见的。然而，端粒缩短在年龄相关性免疫功能下降中的意义尚不清楚。了解端粒长度在体内增龄性免疫功能下降中的作用。我们比较了22名健康的老年人对流感的免疫反应，他们的外周血单核细胞(PBMC)端粒长度相对较短或较长。来自对流感疫苗抗体反应强烈的个体的B细胞的端粒明显长于抗体反应差的个体。短端粒组和长端粒组的单核细胞来源的抗原提呈细胞诱导了类似的流感M1特异性CD8+T细胞的扩张。接种疫苗并没有增加血液中M1特异的CD8+T细胞，然而，来自长端粒组的M1特异性CD8+T细胞在体外表现出明显好于短端粒组的扩增。最后，与分裂较少的细胞相比，M1特异性CD8+T细胞经历了更多的扩张，其端粒明显更长。端粒长度与强大的淋巴细胞反应呈正相关，端粒磨损可能是与年龄相关的适应性免疫下降的原因。 电离辐射(IR)是细胞损伤的主要来源。尽管最近在了解细胞即时反应的机制方面取得了进展，但IR对细胞功能的长期影响及其与衰老的关系还没有得到很好的研究。本文报告了第二次世界大战期间广岛原子弹爆炸对415名幸存者的长期影响及其随年龄的变化。我们用Southern印迹法以观察者盲法测量了白细胞的端粒长度，发现端粒长度与IR剂量呈负相关(p=0.008)，这种影响在较年轻的幸存者中更为明显，尤其是12岁的幸存者(p=0.0004)。尽管在横断面数据中观察到了与剂量相关的端粒缩短随年龄的延迟，但我们11年的纵向随访没有显示出与IR暴露相关的端粒缩短速率随年龄的变化。此外，IR降低了在未服用药物的幸存者中观察到的端粒长度和所选生物标记物之间的相关性。这些生物标志物包括尿酸代谢、细胞因子(IL-1、IL-10、IL-6和肿瘤坏死因子)和血液中的T细胞计数。综上所述，这些发现表明，IR对白细胞端粒长度的长期有害影响具有剂量和年龄依赖性，并包括与白细胞端粒长度相关的生物标志物的改变。

Telomeres are end structure of chromosome and essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within individuals with age have not been fully addressed. Here, we report a longitudinal analysis of telomere length in PBMCs, lymphocytes and monocytes of two hundred and sixteen human subjects aged from 20s to 90s assessed at zero, five- and twelve- year follow-up. For the 5- and 12-year follow-up, telomere length in PBMCs decreased in 34% and 46%, exhibited no detectable change in 56% and 47%, and increased in 10% and 7% of the subjects, respectively. The rate of telomere change was distinct for T-, B-cells and monocytes for any given subject. Telomerase activity declined with age in resting T- and B cells and activated T cells. Finally, a significant portion of telomere attrition in T cells with age was explained by a decline in telomerase activity, decreased naive cells and the change in physiological conditions such as elevated blood glucose and IL-6 levels. These findings show that changes in telomere length of PBMCs with age in vivo occur at different rates in different individuals and cell types, and reveal that changes in telomere length in T cells with age is influenced by telomerase activity, nave T cell percentage and changes in health conditions. Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age-associated decline of immune function is unknown. To understand the role of telomere length in the age-associated decline of immune function in vivo. We compared immune responses against influenza in 22 healthy older adults who had relatively short or long telomere lengths in peripheral blood mononuclear cells (PBMCs). B cells from individuals with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Monocyte-derived antigen-presenting cells of both short and long telomere groups induced similar expansions of influenza M1-specific CD8+ T cells. Vaccination did not increase M1-specific CD8+ T cells in blood, however, M1-specific CD8+ T cells from the long telomere group exhibited significantly better expansion in vitro compared to those from the short telomere group. Finally, M1-specific CD8+ T cells that underwent more expansions had significantly longer telomeres compared to cells with fewer divisions. Telomere length is positively associated with a robust lymphocyte response and telomere attrition may contribute to the age-associated decline of adaptive immunity. Ionizing radiation (IR) is a major source of cellular damage. Despite recent progress in understanding the mechanisms of the immediate cellular response, the long term impact of IR on cell function and its relationship with aging are not well studied. Here, we report a study of the long term effects of IR exposure resulting from the atomic bombing at Hiroshima during WWII on telomere length in leukocytes and its change with age in 415 survivors with two time points (50-58 years after exposure as first sample and 60-68 years as second sample). We measured telomere lengths of leukocytes in an observer-blind manner by the Southern blot method and found that telomere length was inversely correlated with the dose of IR (p=0.008), and this effect was more profound in survivors who were exposed at younger ages, specifically <12 years old (p=0.0004). Even though a dose-related retardation of telomere shortening with age was observed in the cross-sectional data, our longitudinal follow-up of 11-years did not show IR exposure-related alteration of the rate of telomere shortening with age. In addition, IR diminished the associations between telomere length and selected biomarkers that were observed in survivors with no dose. Such biomarkers included uric acid metabolism, cytokines (IL-1&#61538;, IL-10, IL-6 and TNF-&#61537;), and T cell counts in blood. Together, these findings showed that the long lasting detrimental effects of IR on telomere length in leukocytes were both dose- and age-dependent, and included alteration of biomarkers that are associated with telomere length in leukocytes.