Role of Telomere In Human Lymphocyte Function and Aging

端粒在人类淋巴细胞功能和衰老中的作用

基本信息

批准号：
7732315
负责人：
Nan ping Peter Weng
金额：
$ 28.35万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Telomere and telomerase are key factors that regulate cell replicative lifespan. Telomere shortening has been observed in many types of cells in vitro and in cross-sectional analyses, and significantly shortened telomeres induce cell senescence and apoptosis. However, it remains to be determined how telomere length change in vivo and whether dysfunctional shortened telomeres contribute to age-associated decline of function. To address these questions, we conducted a longitudinal analysis of lymphocyte subset composition, telomere length and telomerase expression in peripheral blood lymphocytes and monocytes over 100 old individuals (mean starting age 82, over 5 years time). As expected, we observed some known age-associated changes, such as increase of 1) CD8+CD28-CD45RA+ cells, 2) Treg cells (CD4+CD25+Foxp3+), and 3) monocytes and NK cells in the older donors but not young donors. Interestingly, changes of telomere length are dynamic in vivo: over half of donors showed a various degree of telomere loss while less than one-third of donors had no detectable loss of telomere in PBMC, lymphocytes and monocytes. Furthermore, despite of a great degree of difference of induced telomerase activity among donors, levels of induced telomerase activity appeared to quite stable in both T and B cells for an given individual over 5 year time. Together, these findings demonstrated for the first time that the rates of telomere attrition and the levels of induced telomerase activity in blood lymphocytes in vivo differ significantly among old individuals. The physiological significance of the rates of telomere attrition, the absolute length of telomeres, and the levels of telomerase activity in lymphocytes in the overall immune function as well as factors that influence the rates of telomere attrition and telomerase expression are under current investigation.

端粒和端粒酶是调节细胞复制寿命的关键因素。在体外和横截面分析中，在许多类型的细胞中都观察到了端粒缩短，并且明显缩短了端粒诱导细胞衰老和凋亡。但是，端粒长度在体内的变化以及功能失调的缩短端粒是否有助于与年龄相关的功能下降有待确定。为了解决这些问题，我们对外周血淋巴细胞和单核细胞中的淋巴细胞组成，端粒长度和端粒酶表达进行了纵向分析，超过100个个体（平均年龄为82岁，在5年内开始）。正如预期的那样，我们观察到一些已知的年龄相关变化，例如增加1）CD8+CD28-CD45RA+细胞，2）Treg细胞（CD4+CD25+FOXP3+），以及3）年长的供体中的单核细胞和NK细胞，但不是年轻的捐助者。有趣的是，端粒长度的变化在体内是动态的：超过一半的捐助者显示出不同程度的端粒损失，而不到三分之一的供体在PBMC，淋巴细胞和单核细胞中未检测到端粒的损失。此外，尽管供体之间诱导的端粒酶活性的差异很大，但在给定的5年内，在给定的个体中，诱导的端粒酶活性水平在T和B细胞中似乎相当稳定。总之，这些发现首次证明了端粒损耗的速率和体内血液淋巴细胞中诱导的端粒酶活性的水平在旧个体中有很大差异。端粒损耗率，端粒的绝对长度以及总体免疫功能中淋巴细胞中端粒酶活性的水平以及影响端粒损耗和端粒酶表达速率的因素。