Targeting Mechanisms of Organelle Remodeling to Promote Healthy Aging

点击翻译按钮获取中文摘要

Project Summary Peroxisomes are ubiquitous, dynamic organelles with almost exclusive roles in lipid metabolism, yet their role in regulating organismal metabolism and aging is poorly understood. Furthermore, even little is known about the specific mechanisms regulating appropriate peroxisomal remodeling and metabolism. I have recently identified that during states of increased lipid oxidation, specifically fasting, peroxisomes acutely remodel their shape and alter their function to allow for acute-metabolic adaptation. Notably, this ability to remodel both peroxisomal form and function is linked to longevity during intermittent fasting (IF) and dietary restriction (DR), both of which require altered lipid metabolism. Together these data suggest that peroxisomes play a critical yet understudied role in longevity-associated metabolic adaptation. Therefore, my central hypothesis is that the ability to remodel peroxisomal dynamics and function in response to fasting is a key determinant of metabolic flexibility and longevity. Thus, using fasting as a central mechanism inducing increased lipid oxidation, I have focused on the role peroxisomes play in fasting adaptation and longevity. In Aim 1, I will investigate mechanistically why peroxisomes dynamically remodel during fasting and whether this ability increases cellular lipid oxidation efficiency. In Aim 2, I will define the functional role of peroxisomal protein import in regulating peroxisomal fatty acid oxidation (FAO) during fasting to increase metabolic flexibility. Finally, in the R00 phase, I aim to develop an independent research program investigating the regulation of peroxisome metabolism and signaling, their role in DR-longevity, with a specific emphasis on identifying novel targets that restore age-related dysregulation of lipid oxidation via restoring peroxisomal function. Thus, knowledge generated from this proposal will likely provide fundamental information on peroxisomes as central organelles with increasing relevance to organismal metabolism and aging and likely reframe our understanding of how age-related changes in lipid metabolism can be therapeutically targeted via modulation peroxisomal dynamics and metabolism.