广西长寿人群中脂代谢平衡调节基因与环境交互作用的抗衰老机制研究

Our previous studies had found that lipid metabolism regular gene mutations were associated with promoting and maintaining the balance of lipid metabolism, and were linked with anti-aging properties in the Guangxi longevity population. But there is neither report about lipid metabolism regulator genes-environment interaction nor it about the effect of how to promote the balance of lipid metabolism and how to slow the aging process of human being by the GxE. For further analyzing the mechanism of anti-aging effect with genes-environment interaction, we hypothesize that the interaction (G×E) between lipid metabolism gene mutations(G) and environment (E) is one important cause of longevity in the Guangxi population. To test our hypothesis, we will use methods of next-generation sequencing technology, phylogeny tree，bio-informational analysis and validation in many populations to identify lipid metabolism gene mutations associated with longevity. In order to obtain physiological and biochemical evidences of lipid metabolism gene mutations associated with longevity, we will test and compare lipid metabolism gene mutations between longevity population and their local natural aging individuals, as well as their corresponding serum metabolism index levels, phenotype traits of longevity and environmental factors. Then, we will calculate the effect of GxE interaction to determine its impact on human life extension and lipid metabolism. After, we test its mechanism of promoting and maintaining the balance of lipid metabolism and anti-aging properties from crowd, individual and in vitro cell and molecular level. Our study is expected to provide new ideas on how to keep healthy in old people and on prevention and control of age-related diseases.

本组前期在广西长寿人群中发现:脂代谢平衡调节基因变异可促进和维护脂代谢平衡,具抗衰老作用。而这些基因变异(G)与环境因素(E)交互作用,G×E交互作用经促进脂代谢平衡延缓人体衰老的效应仍未知;为进一步探究脂代谢与环境交互作用抗衰老机理,本课题假设,脂代谢调节基因(CETP、FOXO、APOE等)变异及其与环境因素交互作用可能与广西长寿人群抗衰老有关。为检验该假设,拟应用NGS、系统发生和生物信息学分析识别及多人群验证上述变异基因;通过检测和比较长寿与当地自然衰老个体上述基因变异、血脂代谢水平和长寿表型特征及相关环境因素差异,获得相关基因变异与长寿关联的生理生化证据,并分析G×E交互作用,从人群，个体和体外的细胞，分子水平检验其促进脂代谢平衡延缓衰老的关键作用机制。明确脂代谢相关基因变异和G×E交互作用对延长寿命贡献，及与机体代谢水平的关系。结果有望为维护老年健康及衰老疾病防治提供新思路。

随着人口老龄化，衰老相关疾病或功能紊乱明显增长，目前尚无法从根本上干预和防治衰老相关疾病，因此，老年群体健康维护意义重大。退行性变和衰老相关疾病的发生、发展与代谢尤其与脂代谢失平衡相关。长寿由遗传和环境因素共同作用所致，本课题组前期研究发现脂代谢调节基因变异可促进和维护脂代谢平衡，与广西人群的长寿相关联。这些基因变异(G)与环境因素(E)交互作用，G×E交互作用经促进脂代谢平衡延缓人体衰老的效应仍未知。我们拟应用NGS和生物信息学分析等识别及验证脂代谢调节变异基因，通过检测和比较长寿与当地自然衰老个体上述基因变异、血脂水平和长寿表型特征及相关环境因素差异，获得相关基因变异与长寿关联的证据，分析交互作用，从人群、个体和细胞水平检验其促进脂代谢平衡延缓衰老机制。本项目通过对广西和中国其他地区健康长寿队列人群31920例研究，发现并验证了ABO基因4个新的变异同时与长寿表型和代谢表型显著相关，这些变异通过糖基化反应改变vWF/ADAMTS13和sE-selectin/ICAM1两个通路共同调节脂代谢水平。同时，识别并验证了MTHFD1基因的1个新变异同时与长寿表型和代谢表型显著相关，发现了TFPI rs7586970 T位点ADAMTS7 rs3825807 A位点与脂质健康代谢和长寿相关联。基因型-表型研究发现：与健康长寿和代谢有显著关联的表型为BMI、血压和血脂；从全外显子组和转录组识别并验证的与长寿关联的320个基因中筛选出19个共有差异表达基因，蛋白质组共有的233个基因中筛选出6个与健康长寿关联的共有差异表达基因；多组学联合分析获得了53个差异表达基因；长寿家族史、多子女数和适当高的收缩压（154.631±25.983 mmHg）可能有益于广西长寿地区的人群长寿。另外，结合五个生物学年龄（长寿）关联甲基化位点、性别、民族首次成功构建生物学年龄预测模型。细胞模型研究建立了脂代谢平衡调节基因APOC1促进脂代谢稳态的细胞模型，进一步研究发现APOC1基因不影响细胞寿命及脂代谢状态，但影响程序性细胞凋亡过程中的细胞色素C、含半胱氨酸的天冬氨酸蛋白水解酶(Caspase 3 )和Caspase 8表达水平。