Longevity and Stress Resistance

长寿和抗压能力

• 批准号: 8682004
• 负责人: STEPHEN F VATNER
• 金额: $ 6.98万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2015-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682004
• 关键词: Acyl Coenzyme A; Adenylate Cyclase; Adipose tissue; Age; Biochemistry; Bioinformatics; Biostatistics Core; Blood; Caloric Restriction; Cause of Death; Cholesterol; Energy Intake; Fatty Acids; Fatty acid glycerol esters; Genomics; Glucagon; Glucose; Glycogen; Goals; Heart; Histology; Hormonal; Insulin; Investigation; Ketones; Knock-out; Knockout Mice; Leptin; Liver; Longevity; Mediating; Metabolic; Metabolism; Modeling; Molecular; Nonesterified Fatty Acids; Parents; Pathology; Physiology; Population; Proteomics; Public Health; Resistance; Skeletal Muscle; Stress; Study models; Testing; Time; adenylyl cyclase type V; adiponectin; adverse outcome; animal care; deep sequencing; fatty acid metabolism; fatty acid oxidation; glucose uptake; programs; response

DESCRIPTION (provided by applicant): In the parent program project we had hypothesized that AC5 disruption (knock out, KO) was a model of longevity and planned to compare it to the most widely studied model of longevity, caloric restriction (CR). We hypothesized that the combination of AC5 KO and CR might result in even greater longevity, if there were sufficiently different mechanisms involved that could act synergistically. In the first two years of the program project the testing of this hypothesis resulted in dramatically different results, i.e., the AC5 KO mice with superimposed CR all died within one month. The goal of this revised application is to investigate the mechanisms in depth mediating this lethal combination, since the shared molecular and cellular mechanisms are likely the key molecular mechanisms mediating longevity and stress resistance. Since both models demonstrate significant alterations in metabolism, first we will examine the major mechanisms involved in response to limited caloric intake or to enhanced metabolism, e.g., glucose utilization, depletion of glycogen stores, and utilization of fatty acids. Next we will examine the molecular mechanisms shared by these major models of longevity and stress resistance by genomic and proteomic investigation. To accomplish this we are proposing a fourth Project for this Program Project. The new project ('Common Longevity Mechanisms in Caloric Restriction and AC5 Knockout') will also utilize all the Cores (Core A: Administration/ Physiology, Core B: Animal Care, Core C: Proteomics/Genomics, Core D: Bioinformatics/Biostatistics and Core E: Pathology). The central hypothesis of this revised revision application is that AC5 inhibition and CR induce longevity and stress resistance through similar mechanisms, and that this project will identify the shared mechanisms, which are both common and unique, mediating longevity and stress resistance. Specific Aim 1: To examine glucose and fatty acid metabolism in blood, liver, heart, skeletal muscle and adipose tissue in AC5 KO mice and compare to WT with moderate and severe caloric restriction. A second goal will be to compare the effects of superimposition of the two levels of CR in AC5 KO. Specific Aim 2: To determine the cause of death in AC5 KO mice with superimposition of CR using pathology, histology and biochemistry. Specific Aim 3: To determine shared molecular mechanisms that regulate longevity, stress resistance and metabolism in AC5 KO and CR using genomic and proteomic approaches.

描述（由申请人提供）：在母项目中，我们假设AC 5破坏（敲除，KO）是一种长寿模型，并计划将其与最广泛研究的长寿模型热量限制（CR）进行比较。我们假设，AC 5 KO和CR的组合可能会导致更长的寿命，如果有足够不同的机制参与，可以协同作用。在项目的头两年，对这一假设的检验导致了截然不同的结果，即，具有叠加CR的AC 5 KO小鼠在一个月内全部死亡。本修订申请的目标是深入研究介导这种致命组合的机制，因为共享的分子和细胞机制可能是介导寿命和抗逆性的关键分子机制。由于这两种模型都显示出代谢的显著改变，首先我们将研究参与响应有限热量摄入或增强代谢的主要机制，例如，葡萄糖利用、糖原储存的消耗和脂肪酸的利用。接下来，我们将通过基因组学和蛋白质组学研究来研究这些主要的长寿和抗逆模型所共有的分子机制。为了实现这一目标，我们提出了这个计划项目的第四个项目。新项目（“热量限制和AC 5敲除中的常见长寿机制”）还将利用所有核心（核心A：管理/生理学，核心B：动物护理，核心C：蛋白质组学/基因组学，核心D：生物信息学/生物统计学和核心E：病理学）。该修订版申请的中心假设是AC 5抑制和CR通过类似的机制诱导长寿和抗应激，并且该项目将确定共同的机制，这些机制既常见又独特，介导长寿和抗应激。 具体目标1：检查AC 5 KO小鼠血液、肝脏、心脏、骨骼肌和脂肪组织中的葡萄糖和脂肪酸代谢，并与中度和重度热量限制的WT进行比较。第二个目标是比较AC 5 KO中两种CR水平叠加的效果。 具体目的2：使用病理学、组织学和生物化学确定CR叠加的AC 5 KO小鼠的死亡原因。 具体目标3：使用基因组和蛋白质组学方法确定AC 5 KO和CR中调节寿命、抗逆性和代谢的共同分子机制。