Targeting Mechanisms of Organelle Remodeling to Promote Healthy Aging

项目摘要 过氧化物酶体是普遍存在的动态细胞器，在脂质代谢中具有几乎唯一的作用，但它们在脂质代谢中的作用， 调节生物体代谢和衰老的机制知之甚少。此外，人们对 调节适当的过氧化物酶体重塑和代谢的特定机制。我最近发现 在脂质氧化增加的状态下，特别是禁食，过氧化物酶体急剧重塑其形状， 改变它们的功能以适应急性代谢。值得注意的是，这种重塑过氧化物酶体形式和过氧化物酶体形式的能力， 和功能与间歇性禁食（IF）和饮食限制（DR）期间的寿命有关，这两种情况都需要 改变脂质代谢总之，这些数据表明，过氧化物酶体发挥关键但研究不足的作用， 长寿相关的代谢适应。因此，我的中心假设是， 响应于禁食的过氧化物酶体动力学和功能是代谢灵活性的关键决定因素， 中心blog因此，使用禁食作为诱导脂质氧化增加的中心机制，我专注于 过氧化物酶体在禁食适应和长寿中发挥的作用。在目标1中，我将机械地研究为什么 过氧化物酶体在禁食期间动态重塑，以及这种能力是否会增加细胞脂质氧化 效率在目的2中，我将定义过氧化物酶体蛋白输入在调节过氧化物酶体脂肪酸中的功能作用， 在禁食期间使用酸氧化（FAO），以增加代谢灵活性。最后，在R00阶段，我的目标是开发 一个独立的研究计划，调查过氧化物酶体代谢和信号的调节，他们的 在DR寿命中的作用，特别强调识别恢复年龄相关失调的新靶点 通过恢复过氧化物酶体功能来抑制脂质氧化。因此，从这一提议中产生的知识可能会 提供有关过氧化物酶体作为中心细胞器的基本信息， 代谢和衰老，并可能重新构建我们对脂质代谢中与年龄相关的变化如何 通过调节过氧化物酶体动力学和代谢来治疗靶向。

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.