Targeting Mechanisms of Organelle Remodeling to Promote Healthy Aging - 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.
