Role of Telomere In Human Lymphocyte Function and Aging

端粒是染色体的末端结构，对维持染色体的完整性和控制细胞复制至关重要。从横断面研究中可以很好地证明外周血单个核细胞（PBMC）中端粒长度随年龄的增长。但端粒长度的实际体内变化及其与个体内年龄相关因素的关系尚未完全解决。在这里，我们报告了在0年、5年和12年随访时评估的216名年龄从20岁到90岁的人类受试者的PBMC、淋巴细胞和单核细胞中端粒长度的纵向分析。在5年和12年的随访中，PBMCs中的端粒长度分别减少了34%和46%，56%和47%的受试者未表现出可检测到的变化，10%和7%的受试者增加。对于任何给定的受试者，T细胞、B细胞和单核细胞的端粒变化率是不同的。在静止的T细胞和B细胞以及活化的T细胞中，端粒酶活性随年龄的增长而下降。最后，随着年龄的增长，T细胞中端粒磨损的一个重要部分被解释为端粒酶活性下降，幼稚细胞减少和生理条件的变化，如血糖和IL-6水平升高。这些发现表明，在不同的个体和细胞类型中，体内PBMC的端粒长度随年龄的变化以不同的速率发生，并且揭示了T细胞中端粒长度随年龄的变化受到端粒酶活性、原始T细胞百分比和健康状况变化的影响。 端粒为保护染色体的完整性提供了一种关键机制，在细胞分裂后和衰老期间，端粒的磨损在淋巴细胞中是明显的。然而，端粒缩短在与年龄相关的免疫功能下降中的意义尚不清楚。 了解端粒长度在年龄相关的体内免疫功能下降中的作用。我们比较了22名健康老年人对流感的免疫反应，这些老年人在外周血单核细胞（PBMC）中具有相对较短或较长的端粒长度。来自对流感疫苗有强烈抗体反应的个体的B细胞比那些抗体反应差的人具有明显更长的端粒。 短端粒组和长端粒组的单核细胞衍生的抗原呈递细胞诱导流感M1特异性CD 8 + T细胞的类似扩增。疫苗接种没有增加血液中M1特异性CD 8 + T细胞，然而，与来自短端粒组的那些相比，来自长端粒组的M1特异性CD 8 + T细胞在体外表现出显著更好的扩增。最后，与分裂较少的细胞相比，经历更多扩增的M1特异性CD 8 + T细胞具有显著更长的端粒。端粒长度与淋巴细胞反应的增强呈正相关，端粒磨损可能导致年龄相关的适应性免疫下降。 电离辐射（IR）是细胞损伤的主要来源。尽管最近在理解即时细胞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尚未得到充分研究。本文报道了415名二战期间广岛原子弹爆炸后的幸存者在两个时间点（第一个样本为暴露后50-58年，第二个样本为暴露后60-68年）的白细胞端粒长度及其随年龄变化的长期影响。我们通过Southern印迹法以双盲方式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），并且这种影响在年轻时暴露的幸存者中更为深刻，特别是<12岁（p=0.0004）。尽管在横断面数据中观察到端粒缩短随年龄的剂量相关延迟，但我们11年的纵向随访并未显示端粒缩短率随年龄的IR相关改变。 此外，IR减少了端粒长度和所选生物标志物之间的关联，这些生物标志物在未接受剂量的幸存者中观察到。这些生物标志物包括尿酸代谢、细胞因子（IL-1、IL-10、IL-6和TNF-α）和血液中的T细胞计数。总之，这些发现表明，IR对白细胞中端粒长度的持久有害影响是剂量和年龄依赖性的，并且包括与白细胞中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.