AgRP neurons promote the effects of calorie restriction on lifespan

卡路里限制被证明可以延长寿命。卡路里限制的一个关键方面是系统性的转变 从碳水化合物代谢到脂肪代谢。下丘脑是全身神经系统的重要调节器 并直接与小鼠的衰老过程有关。我们发现了这种细胞选择性 下丘脑Agti相关肽(AgRP)表达神经元回路的损害，部分 在随意喂养的小鼠中，下丘脑黑素皮质素系统导致许多加速衰老的表型 组织，包括免疫系统和骨骼。我们还发现，AgRP受损的雄性小鼠品系 随意喂养时，神经元回路的平均寿命较短。综合起来，这些结果给出了 推动了这一提议的中心假设，即AgRP系统是 卡路里限制导致寿命延长。我们将通过以下具体实例来验证我们的假设 目标：具体目标1.检验限制卡路里可防止人体机能衰退的假说 下丘脑AgRP神经元的时序老化。在我们的初步研究中，我们发现AgRP神经元 在随意喂养的小鼠中，表现出与衰老相关的线粒体完整性下降。我们还观察到， 卡路里限制促进AgRP基因表达，抑制POMC基因表达水平。我们向大家展示了 黑素皮质素系统的输入组织通过热量限制转移到一个星座，该星座 增强AgRP神经元活性，抑制POMC细胞。我们假设卡路里限制 抑制AgRP神经元在时序老化过程中的恶化，这种作用是通过 调节线粒体动力学和ROS生成的细胞内途径。我们将通过以下方式验证这一假设 热量限制对AgRP神经元活性、线粒体动力学和ROS的影响分析 在对照和转基因小鼠中产生线粒体分裂、融合或ROS的特定过程 控制是细胞选择性下调或上调的。具体目标2.揭示下丘脑AgRP神经元是否 对于通过限制卡路里来延长寿命至关重要。我们将利用多个转基因动物品系 AgRP神经元功能被选择性地上调或下调。动物群体将被维持终身 在每一例死亡时都将进行评估和全身尸检。在其他控件和 实验队列，我们将分析卡路里限制对系统代谢和行为的影响 老鼠。我们还将评估胰腺β细胞、脂肪、肝脏、肌肉和免疫系统参数 对照和实验动物。这些研究的实施将为综合生理学带来新的曙光 以及卡路里限制导致健康和寿命改变的分子原理。

Calorie restriction has been show to extend lifespan. A key aspect of calorie restriction is a shift in systemic metabolism from carbohydrate to lipid metabolism. The hypothalamus is a crucial regulator of systemic metabolism and has been directly implicated in the aging process of mice. We uncovered that cell-selective impairment of hypothalamic Agouti-related peptide (AgRP)-expressing neuronal circuitry, part of the hypothalamic melanocortin system, in ad libitum fed mice, results in accelerated aging phenotype of many tissues, including the immune system and bone. We also found that males of mice strains with impaired AgRP neuronal circuitry have shorter mean lifespan when ad libitum fed. Taken together these results gave impetus to the central hypothesis of this proposal, which is that the AgRP system is key mediator in calorie restriction-induced extension of lifespan. We will test our hypothesis through the following specific aims: Specific Aim 1. To test the hypothesis that calorie restriction prevents declining functioning of hypothalamic AgRP neurons in chronological aging. In our preliminary studies we found that AgRP neurons manifest aging associated decline in mitochondrial integrity in ad libitum fed mice. We also observed that calorie restriction promotes AgRP mRNA expression and suppression of POMC mRNA levels. We showed that the input organization of the melanocortin system is shifted by calorie restriction to a constellation that enhances AgRP neuronal activity and suppresses POMC cells. We hypothesize that calorie restriction suppresses deterioration of AgRP neurons during chronological aging, and that this effect is mediated by intracellular pathways regulating mitochondrial dynamics and ROS generation. We will test this hypothesis by analyzing the effect of calorie restriction on AgRP neuronal activity, mitochondrial dynamics and ROS production in control and transgenic mice, in which specific processes of mitochondrial fission, fusion or ROS control is cell-selectively down or up-regulated. Specific Aim 2. To unmask if hypothalamic AgRP neurons are critical for lifespan promotion by calorie restriction. We will utilize multiple lines of transgenic animals in which AgRP neuronal function is selectively up- or down-regulated. Groups of animals will be maintained for lifespan assessment and whole body necropsy will be carried out at the time of death in each. In other control and experimental cohorts, we will analyze the effect of calorie restriction on systemic metabolism and behavior of mice. We will also assess pancreatic beta cell-, adipose-, liver, muscle and immune system parameters of control and experimental animals. The execution of these studies will shad new light on integrative physiology and molecular principles of calorie restriction-induced alterations in heath- and lifespan.