Dietary restriction is a potent non-genetic dietary manipulation that has been shown to extend lifespan in almost all the species tested so far. Our understandings of molecular mechanisms of DR come 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 substantially uncertain in determining the exact caloric intake of individuals under these DR paradigms, unlike this ability in studies of higher organisms, such as rodents. To address this issue, we previously developed an alternative dietary paradigm, dietary deprivation (DD), and found that it could extend lifespan in C. elegans compared to the control fed ad libitum (AL). 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. The heat shock response pathway is evolutionarily conserved from the nematode to humans. A manuscript is under preparation to describe our findings. We are currently investigating how this conserved pathway modulates the lifespan of worms under the DD condition. Uncovering the conserved mechanisms will advance our knowledge on the effects of diet on aging and longevity in mammals, including humans. Drosophila melanogaster is another 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 macronutrients 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. We have been taking advantage of availability of a large number of fly mutants in the public stock centers, and conducting 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. Numerous studies in rodents have indicated that DR can extend not only lifespan but also healthspan. To investigate the mechanisms of DR on healthspan, we have employed the primary cell culture system to investigate the neuroprotective function of DR. Adiponectin is a 30 KD protein primarily produced by adipose tissues prior to its release into circulation, and is thought to have multiple functions in the peripheral and central nervous systems. The adiponectin level is significantly induced by DR. We hypothesized that adiponectin plays an important role in mediating the neuroprotection by DR. Using the cultured primary hippocampal cells, we found that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Our data also suggest that the AMPK pathway is involved in adiponectin-induced neuroprotection. A manuscript describing our findings is under review by a scientific journal. In summary, we have addressed several issues related to dietary regulation of lifespan in this project. 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. Using the cellular model, we are investigating the signaling pathways involved in the beneficial effects of DR. This project will allow us identify the conserved pathways required for lifespan extension by DR, which will be valuable for understanding human aging and more importantly for developing efficient aging intervention strategies for humans.
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