Impact of FGF21 on healthspan and lifespan

项目总结： 这项计划项目赠款(PPG)的提案试图了解新型PRO-R的作用机制。 耶鲁大学通过召集多样化和互补性的研究小组来研究长寿激素FGF21 大学和德克萨斯大学西南分校。成纤维细胞生长因子21(FGF21)是内分泌成纤维细胞生长因子的一员 通过细胞表面受体起作用的亚家族，该受体由成纤维细胞生长因子受体与专性辅酶-2组成的复合体组成。 受体βKlotho。FGF21是一种独特的代谢激素，因为它是从肝脏分泌到血液中的 饥饿和营养匮乏，以刺激脂肪酸氧化和维持能量平衡。近期 我们PPG团队的研究表明，在小鼠体内过表达FGF21可以延长寿命， 改善胰岛素敏感性，并可能促进免疫功能。根据这些数据，核心假设是 该计划项目是FGF21是中枢神经系统-脂肪组织-免疫系统相互作用的关键驱动因素 协同推进长寿分子计划。这个项目的总体目标是阐明 FGF21‘S抗衰老作用的分子机制及其对抑制衰老的作用 与衰老相关的慢性病。考虑到研究团队的不同背景和技能，我们可以使用 用于评估FGF21对多器官系统影响的最新小鼠模型和方法学 从分子到行为的不同水平。我们提出了四个项目，以实现以下目标 本PPG：项目1在Steven Kliewer博士和David Mangelsdorf博士的领导下将调查 FGF21对生长激素作用、健康和寿命的影响。项目2由Dr. Vishwa Deep Dixit将研究FGF21介导的免疫-代谢相互作用对免疫- 衰老。项目3将由Philipp Scherer博士领导，以调查FGF21的影响- 在Tamas Horvath博士的领导下，脂联素-神经酰胺轴对衰老和项目4将进行研究 FGF21对中枢神经系统和下丘脑衰老控制的影响。核心A将促进沟通 并为数据分析提供支持，而核心B将提供集中的分析设施 对小鼠的衰老和健康寿命的影响。PPG团队将探索FGF21通过 多种组织，延长健康寿命和寿命。

PROJECT SUMMARY: This proposal for a program project grant (PPG) seeks to understand the mechanism of action of the novel pro- longevity hormone FGF21 by assembling a diverse and complementary group of investigators at Yale University and UT Southwestern. Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF subfamily that acts through a cell surface receptor composed of FGF receptors in complex with the obligate co- receptor βKlotho. FGF21 is a unique metabolic hormone as it is secreted in blood from liver in response to starvation and nutrient deprivation to stimulate fatty acid oxidation and to maintain energy balance. Recent studies from our PPG team have demonstrated that overexpression of FGF21 in mice extends lifespan, improves insulin-sensitivity and may promote immune function. Based on these data, the central hypothesis of this program project is that FGF21 is a key driver of CNS-adipose tissue-immune system interactions that coordinately promote a prolongevity molecular program. Overall objective of this project is to elucidate the molecular mechanisms underlying FGF21's anti-aging effects and to leverage these insights towards inhibiting aging-related chronic diseases. Given the diverse backgrounds and skills of the research team, we can use state-of-the-art mouse models and methodology to assess the effects of FGF21 on multiple organ systems at different levels ranging from the molecular to the behavioral. We propose four projects to pursue the aims of this PPG: Project 1 under the leadership of Drs. Steven Kliewer and David Mangelsdorf will investigate the impact of FGF21 on growth hormone action, healthspan and lifespan. Project 2 under the leadership of Dr. Vishwa Deep Dixit will study the impact of FGF21-mediated immune-metabolic interactions on immune- senescence. The project 3 will be headed by Dr. Philipp Scherer to investigate the Impact of FGF21- adiponectin-ceramide axis on aging and Project 4 under the leadership of Dr. Tamas Horvath will study the impact of FGF21 on CNS and hypothalamic control of aging. The Core A will facilitate communications between projects and provide support for data analyses and Core B will provide centralized facility for analysis of aging and healthspan in mice. The PPG team will explore the novel hypothesis that FGF21 acts through multiple tissues to increase healthspan and lifespan.