细胞能量代谢与炎症反应在端粒-线粒体稳态维持和器官衰老中的作用及机制

Telomere shortening represents one of the common mechanisms for organ aging. In high-turnover tissues such as the hematopoietic system, telomere shortening triggers cellular senescence or apoptosis by activating DNA damage response, while in low-turnover tissues such as the heart, it perturbs cellular energy metabolism thereby promoting aging. PGC1a functions as a central regulator for mitochondrial biogenesis and homeostasis, in this study, we have constructed a third generation of telomere-dysfunctional mouse model (G3Terc-/-) with cardiomyocyte specific PGC1a knock-in, aiming to delineate the interaction between telomere and mitochondria and its role in the organ aging. We found PGC1a knock-in elevated cellular NAD+ level, ameliorated cardiac dysfunction and prolonged median lifespan of G3Terc-/- mice. In addition, NAD+ repletion improved mitochondrial homeostasis via attenuating inflammatory response, partially contributed by inhibiting mtDNA release-induced cGAS activation. To tackle the scientific questions regarding the relationships among DNA damage, cellular energy metabolism and inflammatory response during aging process, as well as their regulation and function in organ aging, current proposal aims to investigate the common molecular mechanisms of the interactions of telomere, cellular energy metabolism and inflammatory response in high-and low-turnover organs (hematopoietic system and heart, respectively), strengthened by the novel technique advantages of real-time high resolution NAD+ probes. Such endeavors would facilitate the discovery and understanding of common but also tissue-specific mechanisms of aging, and provide therapeutic targets for anti-aging and aging-related diseases.

端粒缩短是器官衰老的共性机制之一。在高增殖器官中，端粒缩短激活DNA损伤反应引起细胞凋亡和衰老；在低增殖器官中，端粒缩短可通过影响线粒体生物合成与代谢促进衰老。PGC1α是调控线粒体合成和稳态的关键分子。为研究端粒与线粒体稳态的关系及其在器官衰老中的作用，我们构建了心肌PGC1α高表达的第三代端粒酶敲除小鼠，发现PGC1α表达可增加细胞内NAD+水平，改善端粒酶敲除小鼠心脏功能并延长寿命。此外，对端粒酶敲除小鼠补充NAD+亦可改善线粒体稳态，抑制线粒体DNA释放，避免cGAS介导的炎症激活。本项目针对衰老过程中DNA损伤、线粒体能量代谢、以及炎症反应之间的关系以及该轴系在器官衰老中的作用等科学问题，拟采用新型NAD+探针和多种小鼠模型，研究端粒、线粒体能量代谢和炎症反应在高低增殖器官衰老过程中的分子调控及共性机制，为阐明生物体共性和器官特异性衰老机制提供依据，为干预器官衰老提供分子靶点。

本项目按照计划书内容完成了既定任务。针对衰老过程中端粒DNA损伤、线粒体能量代谢、炎症反应之间的关系，以及它们在高增殖器官（造血系统）和低增殖器官（心脏）衰老中的作用开展了深入研究。研究发现PGC-1α的精细调节对衰老状态下线粒体能量代谢及心脏功能稳态的维持至关重要，提示线粒体生物合成与自噬降解的平衡调控可能是防治心脏衰老的潜在靶点。另外，HuR介导的端粒酶TERC甲基化、L1-cGAS介导的炎症通路、YTHDF2介导的m6A修饰等在干细胞功能调控及衰老中起到重要作用。这些研究在细胞能量代谢、衰老炎症和表观遗传学层面揭示了器官衰老和稳态维持的分子机制，为干预器官衰老和退行性病变提供了潜在分子靶点。发表通讯或共同通讯SCI 论文14篇（标注基金支持），其中IF>20共1篇，IF>10共5篇，IF>5共7篇。课题主要参与人员1人入选中国科学技术协会青年人才托举工程，培养5名博士，其中3人已获批国家自然科学基金青年基金项目，其余学生也都顺利毕业。