叶绿素代谢物pyropheophorbide-a延长秀丽线虫寿命的机制研究

Aging is the fundamental mystery of life. It is well acknowledged that mitochondria is closely related to aging, but the mechanism is still poorly understood. It has been an important topic to study how genes and environmental factors affect lifespan through mitochondria, and to search effective ways to slow aging and lengthen life in the field of aging. This project focuses on the mechanism of how chlorophyll metabolite absorbing light extend lifespan, based on the photochemical reduction hypothesis. We will study its effect on ATP decline in C. elegans models, mitochondrial homeostasis, mitochondrial coenzyme Q pool, dissect its relationship between the components of mitochondrial respiratory chain and the existing aging signaling pathways, gene interactions, the role of the metabolic pathways or associated proteins of the key molecules in the signal pathway in C. elegans model. It will help to elucidate its molecular mechanism of prolonging life, and it is likely to find a new signaling pathway linking mitochondria, mitochondrial respiratory chain and aging, and might lead to the discovery of an internal anti-aging mechanism that is accessible to intervention. All of these would provide a new evidence for the mitochondrial theory of aging. The dietary chlorophyll metabolites absorbing light could be a new environmental factors of aging and provide a new mechanisms to explain aging. Meanwhile, the chlorophyll and related metabollites, as a new chemical anti-aging intervention, could be consumed as nutrients or therapeutic agents for prevention of aging and aging-related diseases.

衰老是生命的根本奥秘，衰老与线粒体之间的联系极为公认，但仍知之甚少，争论不断。基因和环境因素如何通过线粒体影响寿命，及发现有效的干预方法延缓衰老，是衰老研究领域的一项重要课题。本项目以叶绿素代谢物/光照为切入点，以光化学还原反应为理论假说，以秀丽线虫为主要模型，研究其对不同线虫模型ATP降低、线粒体稳态、辅酶Q储库的作用，通过研究与线粒体呼吸链各组成和与现有衰老信号通路的关系、相互作用基因、关键物质生物代谢途径或关联蛋白在信号通路中的作用，从生化、细胞、分子、整体水平，阐明其延长寿命机制，极有可能发现连接线粒体、呼吸链、衰老的新信号通路、揭示可能存在的机体内在“青春泉”，为线粒体衰老学说提供新证据。首次发现来自食物的叶绿素代谢物吸收光延长线虫寿命，为衰老提供了一种新的环境影响因素和新机制。叶绿素及其相关代谢物，可作为一种新的延缓衰老化学干预法，以营养素或治疗剂应用于衰老、衰老相关疾病防治。

衰老是生命的根本奥秘，衰老与线粒体之间的联系极为公认，但仍知之甚少，争论不断。基因和环境因素如何通过线粒体影响寿命，及发现有效的干预方法延缓衰老，是衰老研究领域的一项重要课题。“叶绿素代谢物pyropheophorbide-a延长秀丽线虫寿命的机制研究”项目获准实施后，通过项目组全体成员团结协作，课题进展顺利，已发表论文10篇，申请发明专利1项，参加学术会议交流4次，培养研究生6名，达到了预期目标。. 本项目建立了一种ATP缺陷线虫模型——ATP合酶亚基RNAi线虫模型，发现其可延长线虫寿命及ATP水平受多种因素调节规律；确定了叶绿素代谢物/光照可延长线虫寿命，与叶绿素代谢物剂量、线虫处理的不同时期有关；确定了叶绿素代谢物/光照作用于线粒体呼吸链，其延长寿命主要依赖于线粒体电子传递链；确定了叶绿素代谢物/光照显著提高线粒体功能；揭示了叶绿素代谢物/光照延长线虫寿命作用主要依赖于缺氧诱导因子HIF-1通路。此外本项目引入有序微结构光学调控这一交叉领域，研究了在荧光或光子带隙调控下，光环境对线虫寿命的影响；制备了一种选择性荧光探针，可灵敏定量线虫体内衰老信号分子H2S；制备了一种可有效对抗Aβ蛋白毒性的吡啶甲胺化合物，可作为治疗衰老相关疾病AD的潜在药物。. 本项目揭示了连接线粒体、呼吸链、衰老的新信号通路，为线粒体衰老学说提供新证据，为揭示可能存在的机体内在“青春泉”提供了重要实验线索。本项目的发现为衰老提供了一种新的环境影响因素和新机制，也可作为一种新的延缓衰老化学干预法，以营养素或治疗剂应用于衰老、衰老相关疾病防治。