广西巴马长寿家系白细胞端粒长度的变化与炎性衰老的相关性研究

Telemore shortening rate may be influcenced by genetic factors, physiological or pathological inflammatory cytokines, and oxidative stress simultaneously. Peripheral leukocytes, which replicate actively when stimulated, are not only the sources but also the targets of most inflammatory cytokines and reactive oxygen species (ROS). Thus, the dynamic trajectory of leukocytic telomere length (LTL) with increasing age may reflect comprehensively the genetic status and the maintaining capacity of the telemere and the degree of inflammation and oxidative stress of the body and thus is regarded as one of the important biomarker of aging. Recently, the concept of inflammaging was put forward because different degree of inflammation is always presented throughout one's life span. Bama, a county located in the northwest of Guangxi Province, has been well known for its longevity and has been a research base of longevity. Our previous NNSF project results showed that, the LTL of long-lived individuals and their offspring is remarkably longer than that of general population. Herein, we aim to investigate the long-lived cohort longitudinally by measuring the LTL, the yearly telomere shortening rate, the transcriptional and translational level of serum and leukocytic primary age-related inflammatory cytokines and total IgG levels, and by genotyping the common polymorphisms of telomerase gene (TERT,TERC) and inflammatory cytokines genes (TNF-α，IL-1α，IL-1β，IL-1Ra，IL-6，IFN-γ，IL-10，TGF-β1，CRP), in an attempt to further understand the telomere length dynamics and its association with inflammaging, as well as the possible roles in which polymorphisms of relevant genes play in the Bama long-lived population.

端粒缩短的速率受遗传、体内生理或病理性炎症因子及氧化应激的共同影响。血循环中的白细胞增殖活跃，是多数炎性因子和氧自由基产生的场所，也是炎性因子和氧自由基攻击的对象，故白细胞端粒长度（LTL）随年龄增大而呈现的动态变化模式综合反映了端粒的遗传状况、修复能力、机体的炎症程度及氧化应激水平，并被认为是衰老重要的生物学标记。鉴于个体一生都伴随着不同程度的炎症，最近有学者提出炎性衰老（inflammaging）的概念。广西巴马是著名的长寿之乡和长寿研究基地。我们前一项目结果显示，长寿老人及其子代LTL明显长于普通人群。本项目拟对该群体进行纵向研究，再次检测该群体的LTL，计算其每年的缩短速率，并测定重要炎性衰老相关因子的血清水平及白细胞表达水平，检测端粒酶基因hTERT和hTERC及炎性因子基因的常见多态，进一步探讨该长寿群体LTL变化规律及其与炎性衰老的关系，并探讨相关基因遗传变异在其中的作用。

端粒为染色体末端的特殊结构，对染色体及遗传物质的稳定性至关重要。然而，随着年龄的增大，端粒不断缩短，最终失去对染色体的保护而引发细胞衰老等生物学事件。端粒缩短的速率受遗传、炎症因子及氧化应激的共同影响。血循环中的白细胞增殖活跃，是多数炎性因子和氧自由基产生的场所，也是炎性因子和氧自由基攻击的对象，故白细胞端粒长度（leukocyte telomere length, LTL）随年龄增大而呈现的动态变化模式综合反映了端粒的遗传状况、修复能力、机体的炎症程度及氧化应激水平，并被认为是衰老重要的生物学标记。广西巴马及其周边县份长寿老人众多，是研究人类长寿/衰老的重要基地。本项目应用荧光定量PCR，TaqMan MGB探针及iMLDR基因分型技术以及ELISA等方法对巴马地区长寿老人、长寿老人的子女及当地无长寿家族史的普通老年人群进行LTL测定、端粒酶基因、常见炎性因子基因多态性检测及其血清水平的检测，以了解长寿老人的LTL状况、LTL的遗传模式及端粒酶和炎性因子基因多态性对LTL的影响。主要结果显示：（1）长寿老人的子代群体中，女性LTL明显长于男性；子代LTL同时呈现母系和父系遗传模式。（2）端粒酶TERC基因三个位点rs12696304、rs16847897及rs3772190的基因型及等位基因频率在长寿、子女、对照组间的分布无差异；对照组在位点rs3772190，GA基因型LTL最长，其次为GG 基因型，AA基因型LTL最短，其他位点的基因型对LTL影响不大。（3）长寿家系IL-10 rs1800896 CC/CT 基因型频率明显高于对照组，逻辑回归分析显示此基因型与长寿相关联。（4）一些代谢相关基因的有害变异如BDNF 66Met，COMT 158Met，PPARD +294C等在普通老年人群中积累并与不良代谢后果（如脂质代谢异常）相关。以上结果提示，与LTL有关的某些端粒酶基因及炎性因子基因的多态性，可能减缓广西巴马地区长寿老人体细胞端粒缩短的速度，从而延长健康寿命；另一方面，一些不利的基因多态性，尤其是与代谢综合征相关的基因变异，在普通人群中积累，可能增加代谢综合征的风险，从而加速端粒的缩短，不利于健康长寿。