延缓衰老新靶标：血管内皮lncRNA LINC00551

Senescence remains the major cause of cardiovascular diseases, but the mechanism has not been elucidated yet. Endothelial cells are the biggest endocrine tissues in our organism, always accompanied by several changes of secretion functions during senescence. In our present results, we firstly found that senescent endothelial cells secreted excessive lncRNA LINC00551, which was also positively associated with age in human plasma. Although our parabiosis experiment has certified that elevated LINC00551 can reduce mitochondrial autophagy by suppressing Parkin protein and prompt the senescence of heart, however, whether regulating LINC00551 can reverse the senescence-associated cardiovascular diseases? Whether analyzing a large number of clinical samples is possible to evaluate the role of LINC00551 in senescence synthetically and accurately, and establish the precision medicine decision system of senescence-associated diseases? The above mentioned are all key issues urgently to be solved in this project. Taken together, molecular biology, bioinformatics technology combining transgenic animals and parabiosis models are adopted in the project to validate and define the new theory we proposed, that is “Senescent Endothelium Promote Aging”. The establishment of LINC00551-senescent decision system and delaying senescence by control of mitochondrial autophagy may provide effective preventive and therapeutic approach for aging.

衰老是心血管系统疾病的主要诱因，其中的机制仍不明确。血管内皮是机体最大的内分泌组织，在衰老过程中伴随多种分泌功能的改变。我们前期研究首次发现衰老动脉内皮分泌过量的lncRNA LINC00551，并且在人血浆中的含量与年龄呈正相关，异种共生实验证明升高的LINC00551能够进入心脏中抑制Parkin蛋白减少线粒体自噬，促进心脏衰老，而操控LINC00551能否逆转衰老相关的心血管病？通过大量临床样本分析，能否对LINC00551在衰老中的角色进行综合的评估，建立衰老相关疾病精准医疗的决策系统？这些都是本项目亟待解决的重点问题。本项目采用分子生物学、生物信息学技术结合转基因、异种共生模型对以上问题进行验证和探讨，明确 “衰老内皮促衰老”新理论，通过对LINC00551的功能干预操控线粒体自噬延缓衰老，为防治衰老心血管病提供新靶点，以期对其他衰老相关疾病的治疗开辟新思路。

心脏衰老的发生和发展是老年人患心血管疾病的主要原因，严重危害健康。大量证据表明线粒体自噬水平的下降在心脏老化的发生发展过程中发挥关键作用。线粒体自噬特异性诱导因子Parkin在衰老中高表达，其功能改变将对老化产生广泛影响。长链非编码RNA（Long non-coding RNAs，lncRNAs）作为体内含量最高的转录本之一，大量研究揭示其在机体生长、疾病发生及发展过程中的关键作用，同时。在心脏衰老过程中，线粒体自噬水平显著降低，但调控线粒体自噬的上游诱因尚不明确。本研究旨在探究心脏特异性lncRNA LOC105378097（Senescence-Mitophagy Associated LncRNA，SMAL）对心脏衰老的调控作用及机制，为心脏老化病理条件下保持线粒体自噬和心血管功能提供候选方案。收集临床上不同年龄人群血清样本，实验结果显示随着年龄增长，血清中SMAL表达随着年龄的增加而上调，并在60岁时达到峰值。尾静脉注射AAV9-SMAL能够诱发小鼠心脏衰老，即心脏肥大、心脏舒张功能障碍，心肌组织Parkin表达下调，线粒体自噬受到抑制。外源性过表达Parkin则能够显著促进自然衰老小鼠心脏线粒体自噬，抑制衰老相关蛋白表达，改善衰老心脏的舒张功能，延缓心脏衰老；给予AAV9-SMAL则会逆转Parkin介导的有益作用。Pulldown及RIP结果显示，SMAL能与Parkin靶向结合。在AC16细胞中，敲减lncRNA-SMAL显著改善线粒体自噬，促进自噬溶酶体的产生，从而清除ROS的累积，抑制D-gal诱导的细胞衰老。本研究首次提出以SMAL表达含量为指标评估心脏老化程度，明确SMAL靶向Parkin对线粒体自噬过程的调控作用，可为老年心血管病的治疗提供新的策略，也为预防心脏衰老提供有效的治疗靶点。

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