长寿人群特异低表达基因—甲状腺素转运蛋白MCT10调控衰老的作用机制研究

Rapid population aging brings a heavy burden to Chinese society and economy, and raises new requirements to the research on aging and age-related diseases. Longevity population is considered as an ideal model to study protective factors for healthy aging because of their ability of delaying or even escaping age-related diseases. We previously performed RNA-sequencing on 121 samples from longevity families. Analyzing the transcriptome data identified that the gene expression of thyroid hormone (TH) transporter MCT10 was significantly lowly expressed in both longevity subjects and their offspring. Although TH can cause cell senescence, and its levels have been inversely associated with lifespan in longevity human subjects and naturally long-lived rodent, TH does not work until it is transported into cells by TH transporters. Therefore, we hypothesize that the lowly expressed MCT10 may limit the transport of TH into cells, weaken the effect of TH on cell senescence, and delay the aging process and further extend the lifespan of individuals. Thus, we first investigate the role of MCT10 on cell senescence by MCT10 shRNA or overexpression in in-vitro experiments, and further investigate its role in regulating individuals’ aging/lifespan using MCT10 knockout or transgenic Caenorhabditis elegans or mice. Furthermore, we aim to uncover the mechanism of MCT10 in influencing aging/lifespan based on transcriptomic analysis and molecular biological techniques. The project may help to clarify the mechanism of TH in affecting aging/lifespan, and may provide new targets for the prevention and treatment of TH- and age-related diseases, also helpful for the development of anti-aging drugs.

人口快速老龄化给中国社会和经济带来沉重的负担，也对衰老及老年病研究提出新的要求。而长寿人群能延缓甚至规避衰老相关疾病的困扰，使其成为研究健康保护因子的理想模型。我们测定长寿家系121例样本的转录组后发现：甲状腺素（TH）转运蛋白基因MCT10在长寿老人及后代均显著低表达。虽然TH可促进细胞衰老，且长寿老人、动物的TH水平和寿命负相关，但TH必须通过转运蛋白从胞外运至胞内才能发挥功能，于是我们推测：MCT10表达降低可能限制TH进入细胞、减弱其促衰老作用，进而延缓个体衰老、延长寿命。因此，本项目拟利用shRNA和过表达等手段研究MCT10对细胞衰老的作用；并基于基因工程线虫和小鼠模型，研究MCT10对个体衰老/寿命的影响；最后基于转录组及分子生物学手段，诠释MCT10影响衰老/寿命的机制。研究结果将有助于深入理解TH影响衰老/寿命的机理，也可能为TH相关老年病防治及抗衰老药物开发提供新靶点。

人口快速老龄化是中国乃至全世界所面临的严峻问题，给中国社会和经济带来沉重的负担，也对衰老及老年病研究提出新的要求。而百岁老人能延缓甚至规避衰老相关疾病的困扰，使其成为研究健康保护因子的理想模型。本项目通过体外细胞实验和线虫实验研究，我们得到以下结果，（1）通过体外细胞实验发现：a. 在MCT-10正常表达的情况下，添加适当浓度（5 nmol/L）的TH（T3）能够诱导细胞衰老；b. 敲降MCT-10的表达，同时在细胞中添加TH（5 nmol/L T3），没有出现T3诱导的细胞衰老表型（P = 0.0119），这表明MCT-10可能是影响了甲状腺激素进入细胞发挥其促衰老的作用，进而达到延缓衰老，促进长寿的作用。c. 在HDF细胞系中使MCT-10高表达，细胞只有衰老的趋势，没有统计学意义。（2）通过线虫实验研究发现：a. 添加不同浓度的甲状腺激素后,结果显示甲状腺激素对线虫寿命有显著影响，在0.5 μg/ml时，线虫寿命与对照相比较较短；b. 敲低线虫MCT-10的同源基因MCT-3基因的表达，观测线虫寿命，结果显示，敲低MCT-3，对线虫寿命没有显著的影响。以上研究结果初步证明甲状腺素转运蛋白MCT-10调控由TH引起的细胞衰老。这一研究结果将有助于深入了解TH影响衰老/寿命的机理，也可能为TH相关老年病防治及抗衰老药物开发提供新靶点。该项目根据研究计划和研究内容顺利开展并完成既定目标，受该项目的资助，已经发表学术论文7篇，培养研究生3名。