Manipulating evolutionarily conserved mechanisms of nutrient signaling and energy metabolism promotes healthy aging in many species. While the most robust and well-studied model is dietary restriction (DR), a chronic reduction in caloric intake without malnutrition, its therapeutic potential is limited by negative associated side effects and difficulty of clinical implementation. The search to generate more viable therapies from this research has uncovered alternative dietary interventions that could promote healthy aging, independent of reduced overall caloric intake. One such regimen is intermittent fasting (IF), which suggests that simply altering the timing of food intake can increase longevity and disease resistance, independent of caloric intake. These mechanisms are relatively understudied, but evidence suggests that IF modulates longevity in mechanisms that are distinct from those of chronic DR. Studying IF-longevity could therefore elucidate novel approaches to target aging, and IF as a therapy itself may be more translatable than chronic DR. The central aim of this proposal is therefore to utilize the genetically tractable and transparent model organism C. elegans to identify novel mechanisms underlying IF and longevity. Here, I show new data to suggest the transcription factor CREB and mitochondrial dynamics are indispensable for lifespan extension by IF. This project will dissect the mechanisms by which CREB mediates IF-longevity on the level of transcription, organelle biology and metabolism. I will interrogate the potential role of CREB as a cell non-autonomous modulator of IF-longevity from the central nervous system and investigate if mitochondrial dynamics lies functionally downstream of CREB to mediate IF- longevity. The spatial and functional requirement of mitochondrial remodeling for IF-longevity will be determined to elucidate whether CREB and mitochondrial dynamics are required in the same tissue. Two-photon excited fluorescence of endogenous NADH and FAD levels will then be used as a non-invasive method to measure metabolic state in vivo. I will use this technique to simultaneously extract information on mitochondrial network morphology and how it corresponds to metabolic changes during IF and manipulation of CREB activity. Overall, these studies will provide new mechanistic insight into IF biology, which can be harnessed to develop new therapeutics against aging. Pallas? position as a graduate student in Dr. William Mair?s laboratory at the Harvard T.H. Chan School of Public Health gives her access to all the resources necessary to complete this project. As part of the training plan, Pallas will develop her career plan, writing and communication skills through participation in local and national/international scientific conferences, peer reviewing journal articles, and mentoring undergraduate students. The goal is to further develop her scientific acumen in experimental design in order to move her further toward independence as she transitions into a postdoctoral position.
Intermittent fasting (IF) is a dietary intervention that promotes healthy aging independent of chronic restriction of food intake. Although the therapeutic potential of IF may be more translatable than chronic DR, the mechanisms underlying IF and longevity are understudied. This project aims to apply state-of-the-art genetic and cell biology techniques to elucidate the role of CREB as a novel regulator of IF-longevity.
