长寿人群特异低表达基因LEF1延缓干细胞衰老的作用与机制研究

With the increase of aging population, China suffers huge pension and medical burden. This raises new requirements for the (anti-) aging study of our country. Longevity people (e.g. centenarians) are living healthier in most of their lifetime. Study about their molecular mechanisms of healthy aging will provide new perspective and opportunity for exploring the measures of delaying aging and improving elderly health. Our prior transcriptomes study of 171 individuals from centenarian families found that the gene LEF1 (Lymphoid enhancer-binding factor 1, one key transcription factor on Wnt signal pathway) is significantly down-regulated in both centenarians and their F1 offspring compared to the controls (spouses of F1 offspring). Numerous studies have shown that enhanced Wnt signal can accelerate aging of stem cell, suggesting that lower LEF1 expression has potential to delay stem cell aging and further promote organismal longevity. To verify this issue, we attempt to explore the role of down-regulated LEF1 expression in delaying stem cell aging and extending lifespan using in vivo and vitro functional experiments; In addition, transcriptome sequencing (RNA-Seq) will be performed to investigate its underlying regulatory mechanism of action. This project helps to in-depth understand the molecular mechanism of human healthy aging and provides new guiding basis for the study of delaying (stem cell) aging.

中国老龄化程度日趋严峻，养老和医疗负担加重，对国人衰老及抗衰老研究提出了新要求。而作为健康衰老典范的百岁老人，研究并揭示其健康衰老的分子机理，可为探索延缓衰老、改善老年人健康提供新的视角和机遇。我们前期获得171例百岁老人家系转录组数据，分析发现Wnt信号通路上淋巴样增强因子LEF1（Lymphoid enhancer-binding factor 1）在百岁老人及其F1代较对照人群（F1代配偶）都呈现显著低表达。鉴于Wnt信号增强往往加速干细胞衰老，我们推测：LEF1低表达很可能会通过延缓干细胞衰老进而促进长寿。本项目拟基于体外（干细胞）和体内（秀丽线虫）研究LEF1低表达对延缓干细胞衰老及延长寿命的作用，同时利用转录组测序技术研究其发挥作用的调控机制，旨在探究LEF1对干细胞衰老的功能作用。项目的开展有助于深入理解人类健康衰老的分子机制，并为抗（干细胞）衰老研究提供新的指导依据。

中国老龄化程度日趋严峻，养老和医疗负担加重，对国人衰老及抗衰老研究提出了新要求。而作为健康衰老典范的百岁老人，研究并揭示其健康衰老的分子机理，可为探索延缓衰老、改善老年人健康提供新的视角和机遇。我们收集分析了中国海南省多个长寿地区长寿老人和长寿F1后代配偶（作为一般对照样本）的转录组数据，发现Wnt信号通路上淋巴样增强因子LEF1（lymphoid enhancer-binding factor 1）低表达是长寿老人普遍存在的。进而，我在复制衰老细胞模型（HDF，人皮肤成纤维细胞）进行了LEF1敲降实验，结果显示细胞p16和p21蛋白表达升高、β-半乳糖苷酶染色率升高，表明LEF1低表达显著促进了细胞复制衰老。此外，我们在秀丽线虫模型中对pop-1基因（LEF1在秀丽线虫中的同源基因）进行了RNA干扰实验，结果显示降低pop-1基因表达对线虫寿命无明显改变。因此，本研究证明LEF1确实与衰老存在关系密切，即LEF1低表达可促进细胞复制衰老；LEF1可作为抗衰老、老年性疾病防治的干预靶标。