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

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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.