Mechanisms of Lifespan Modulation by Diet

点击翻译按钮获取中文摘要

Dietary restriction is a potent non-genetic dietary manipulation that have been shown to extend lifespan in a number of evolutionarily divergent species, ranging from yeast, to worms, flies, rodents and possibly primates. Our understanding of molecular mechanisms of DR comes primarily from studies of genetically amenable systems including yeast, worms, and flies, where DR has been imposed by either diluting the food source or by using genetic mutations that reduce feeding efficiency. However, a major drawback of these approaches is that it remains substantial uncertainty in determining the exact caloric intake of individuals under these DR paradigms, unlike this ability in studies of higher organisms. We have previously described an alternative dietary paradigm, dietary deprivation (DD), which can extend lifespan in C. elegans. Since this regimen involves complete removal of the food source, the problem of controlling food intake, which has hampered interpretation of past studies, is alleviated. Using this unambiguous method, we have investigated the genetic pathways necessary for lifespan extension by diet. We have conducted a genetic screen and have found that the heat shock response pathway is critical for DD response. In the coming year, we will investigate how DD extends lifespan through this pathway by biochemical, genetic and genomic approaches. The heat shock response pathway is evolutionarily conserved from the nematode to humans. Uncovering the conserved mechanisms will advance our knowledge on the effects of diet on aging and longevity in mammals, including humans. Drosophila melanogaster is also a powerful genetic system that has been utilized extensively to address many basic biological questions including aging and dietary restriction (DR). To further investigate the effects of macronutritions in the diet on lifespan, we have measured lifespan of flies fed diets of various ratios of macronutritions, including protein and carbohydrates. In addition, to address the association of reproduction with lifespan, we have also measured the reproduction of flies in these conditions. We have found that dietary composition has profound effects on lifespan and reproduction but not in a coordinated manner. The results have provided us a foundation to investigate mechanisms of dietary regulation in D. melanogaster. In the coming year, we will take advantage of availability of a large number of mutants in public stock centers, and conduct genetic screens to identify which genes are required for lifespan extension by DR. Identification of genetic pathways involved in DR will provide insight on lifespan regulation. In summary, we have started addressing issues related to dietary regulation of lifespan in this new initiative. By utilizing a unique and robust dietary regimen in C. elegans, we are dissecting molecular mechanisms of dietary regulation of lifespan. With D. melanogaster, we are studying mechanisms by which genes and which tissues are critical for lifespan extension by dietary restriction. This project will allow us identify the conserved pathways required for lifespan extension by dietary restriction, which will be valuable for understanding human aging and more importantly for developing efficient aging intervention strategies for humans.