Regulation of Energy Metabolism and Life Span in Mammals through Indy and its

能量平衡与预期寿命之间存在密切的相关性。减少Indy（=我还没死）基因的表达，该基因编码三羧酸和二羧酸的细胞表面转运蛋白，以类似于D中热量限制的方式延长寿命并增加线粒体生物合成。melanogaster和C.优雅最初建议的基础是我们的观察结果，即在小鼠中缺失哺乳动物Indy同源物（Slc 13 A5，mIndy）也在功能和转录水平上诱导了热量限制样状态，并且mINDY-KO小鼠的特征在于线粒体生物合成增加，肝脏脂质氧化和从头脂肪生成减少。这些代谢变化保护mINDY-KO小鼠免受营养诱导的肥胖和胰岛素抵抗。在该提案的第一个资助期内，我们在先前D.黑腹菌我们首次观察到，与同窝对照小鼠相比，mINDY-KO小鼠似乎具有显著延长的寿命和健康寿命，并且mINDY-KO小鼠的寿命和健康寿命与热量限制小鼠相似，尽管mINDY-KO小鼠没有减少食物摄入。同样，我们观察到人类和非人灵长类动物中较低的mIndy表达与消瘦和代谢健康沿着，而在患有脂肪肝的肥胖胰岛素抵抗患者中发现较高的mIndy表达，这是一种通过白细胞介素-6介导的效应。我们继续表明，提高HepG 2和HEK 293细胞中的mIndy水平可以增强柠檬酸盐的脂肪生成，并诱导特定的表观遗传蛋白修饰，这在代谢调节和衰老中很重要。随着这一提议的扩展，我们现在将研究有助于改善mINDY-KO小鼠健康寿命和衰老的分子和细胞机制，重点是表观遗传机制。此外，我们将使用我们在第一个资助期产生的功能模型的损失和增益，更详细地研究mIndy在肝脏中的功能。这些模型将在脂质和葡萄糖代谢和衰老方面进行测试。总之，我们的研究将对衰老和寿命调节的病理生理学及其与代谢疾病的关系产生新的见解，并进一步验证mIndy作为治疗饮食和衰老相关代谢疾病的靶点，如非酒精性脂肪肝和胰岛素抵抗。

A close correlation exists between energy balance and life expectancy. Reduced expression of the Indy (= I am not dead yet) gene, which encodes a cell surface transporter for tri- and dicarboxylic acids, prolongs life span and augments mitochondrial biogenesis in a manner akin to caloric restriction in D. melanogaster and C. elegans. The basis of the initial proposal was our observation that deletion of the mammalian Indy homolog (Slc13A5, mIndy) in mice also induced a caloric restriction-like state, on the functional and on the transcriptional level and that mINDY-KO mice were characterized by increased mitochondrial biogenesis, hepatic lipid oxidation, and reduced de novo lipogenesis. These metabolic changes protected mINDY-KO mice from nutritionally induced adiposity and insulin resistance. Within the first funding period of this proposal, we started longevity and ageing studies in mINDY-KO mice on the basis of previous work in D. melanogaster. We observed for the first time that mINDY-KO mice seem to have markedly extended life- and health spans compared to littermate control mice, and that life- and health span in mINDY-KO mice is similar to those of calorically restricted mice, although mINDY-KO mice did not reduce food intake. In the same vein, we observed that lower mIndy expression in humans and non-human primates goes along with leanness and metabolic health, while higher mIndy expression is found in obese insulin resistant patients with fatty liver, an effect mediated via interleukin-6. We went on to show that raising mIndy levels in HepG2 and HEK293 cells enhances lipogenesis from citrate, and induces specific epigenetic protein modifications, which are important in metabolic regulation and ageing. With the extension of this proposal, we will now study the molecular and cellular mechanisms contributing to the improvement in health span and ageing in mINDY-KO mice with a focus on epigenetic mechanisms. Moreover, we will study the function of mIndy in more detail in the liver, using loss and gain of function models that we generated during the first funding period. These models will be tested in regard to lipid and glucose metabolism and ageing. Together, our studies will generate new insight into the pathophysiology of ageing and life span regulation, its relation to metabolic disease and to validate mIndy further as a target for the treatment of diet and aging related metabolic diseases, such as non-alcoholic fatty liver disease and insulin resistance.