Systemic Factors that Maintain a Young Liver Phenotype

维持年轻肝脏表型的全身因素

• 批准号: 8289523
• 负责人: ROY G SMITH
• 金额: $ 38.63万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289523
• 关键词: Affect; Age; Aging; Agonist; Animals; Biological Rhythm; Blood; Brain; Brain region; Caloric Restriction; Cardiovascular Physiology; Chronic; Clinical; Diabetes Mellitus; Eating; Elderly; Endotoxic Shock; Energy Intake; Fasting; Fatty Liver; Fatty acid glycerol esters; GHS-R1a; Gene Proteins; Glucose; Half-Life; Health; Health Benefit; Hormones; Hypothalamic structure; Incidence; Insulin; Intervention; Link; Liver; Liver Regeneration; Longevity; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Metabolic; Metabolism; Molecular; Mus; Muscle; Mutant Strains Mice; Neurons; Pancreas; Pathway interactions; Peptides; Peripheral; Phenotype; Physiologic pulse; Post-Translational Protein Processing; Pro-Opiomelanocortin; Production; Quality of life; Rejuvenation; Research; Resistance; Sex Behavior; Signal Transduction; Structure of nucleus infundibularis hypothalami; Testing; Tissues; Translating; Transplantation; Wild Type Mouse; Yeasts; age related; bench to bedside; design; embryo tissue; energy balance; feeding; ghrelin; ghrelin receptor; glucose metabolism; glucose tolerance; healthy aging; immune function; impaired capacity; improved; in vivo; insulin sensitivity; lipid biosynthesis; liver metabolism; mimetics; molecular phenotype; neuropeptide Y; neuroprotection; prevent; public health relevance; receptor; response; therapy development; translational approach; young adult

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to develop therapy that will maintain quality of life and independence during aging. Caloric restriction (CR) maintains health during aging and increases longevity; however, the molecular mediator(s) is unknown. During CR and fasting, production of the hormone ghrelin increases and the ghrelin receptor (GHS-R1a) expressed in the hypothalamus is upregulated 8-fold. Characterization of ghrelin regulated pathways led to the hypothesis that the aging phenotype is associated with impaired endogenous ghrelin signaling and that ghrelin is a mediator of the benefits of CR. During CR, the animal must compensate for reduced energy intake by modifying metabolism in peripheral tissues. It is speculated that accommodation is mediated centrally by the action of ghrelin on GHS-R1a expressed on hypothalamic arcuate neurons (ARC) that regulate energy balance. By comparing the molecular effects of CR on ARC neuropeptide Y (NPY), agouti-related peptide (AGRP) and pro-opiomelanocortin (POMC) neurons of wild type mice with ghrelin-/- and Ghsr-/- mice the ghrelin mediated signals can be identified. By similar comparisons in wildtype and ghrelin-/- and Ghsr-/- mice, CR-induced ghrelin dependent metabolic changes in the aging liver can be defined. This is important because the liver is pivotal for regulating metabolism and is modulated by input from the brain, pancreas, fat and muscle. In addition to defining ghrelin dependent metabolic effects, longevity of CR wildtype, ghrelin-/- and Ghsr-/- mice will be compared. It is speculated that CR will not extend the lifespan of the mutant mice. Ad lib fed wildtype mice will be treated daily with a stable ghrelin mimetic to test the hypothesis that intervening to rescue impaired ghrelin signaling during aging will increase longevity and maintain a young liver phenotype. In summary, this research will identify changes resulting from CR on selected genes, proteins and protein modifications that regulate insulin sensitivity, glucose metabolism, lipogenesis and fat accumulation in the liver (steatosis), that are ghrelin dependent. Specific Aim 1: Test the hypothesis that in wildtype, but not in ghrelin-/- and Ghsr-/- mice, that CR increases expression of Npy and Agrp and suppresses expression of Pomc in neurons of the arcuate nucleus (ARC) via FoxO1 mediated pathway and elucidate the molecular mechanisms. Specific Aim 2: Determine the differences in responses of wildtype, ghrelin-/- and Ghsr-/- mice to long-term caloric restriction that pertain to liver metabolism, glucose tolerance, insulin sensitivity, steatosis and longevity and define the molecular mechanisms; test the hypothesis that a young phenotype can be sustained in ad lib. fed wildtype mice during aging by treatment with a stable ghrelin mimetic. Identifying the beneficial effects of CR on aging that are mediated by ghrelin is fundamentally important because of the availability of orally active well tolerated long-acting ghrelin mimetics that have so far not found a clinical niche. Public Health Relevance: Markedly reducing food intake in experimental animals prevents diabetes, lowers the incidence of cancer and prolongs lifespan. These benefits are associated with increases in blood levels of a hormone called ghrelin. Ghrelin levels decline as a function of age. Our research is designed to test whether replacing this hormone with a more stable form will provide health and quality of life benefits during aging.

描述（由申请人提供）：该提案的长期目标是开发疗法，以维持衰老期间的生活质量和独立性。热量限制（CR）在衰老期间保持健康并增加寿命；但是，分子介质尚不清楚。在CR和禁食期间，下丘脑中表达的激素生长素蛋白的产生增加了8倍。生长素释放蛋白调节途径的表征导致了以下假设：衰老表型与内源性生长素蛋白信号的受损有关，而生长素蛋白是CR益处的中介。在CR期间，动物必须通过修饰周围组织中的新陈代谢来补偿能量摄入减少。据推测，在调节能量平衡的下丘脑弧神经元（ARC）上表达的GHS-R1A对GHS-R1A的作用将适应性介导。通过比较CR对野生型小鼠的CR对野生型小鼠的弧神经肽Y（NPY）的分子作用，与GHSR - / - 和GHSR - / - / - 小鼠的野生型小鼠的神经元（POMC）神经元有关。通过在野生型和生长素蛋白 - / - 和GHSR - / - 小鼠中的类似比较中，可以定义肝脏诱导的肝诱导的肝脏代谢变化。这很重要，因为肝脏对调节新陈代谢是关键的，并且通过大脑，胰腺，脂肪和肌肉的输入来调节。除了定义依赖性的代谢作用外，还将比较Cr WildType，Ghrelin - / - 和GHSR - / - 小鼠的寿命。据推测，CR不会延长突变小鼠的寿命。 Ad Lib喂养的野生型小鼠每天将使用稳定的生长素蛋白模拟物进行治疗，以检验以下假设：介入衰老期间挽救损害的生长素蛋白信号的介入将增加寿命并维持幼年的肝表型。总而言之，这项研究将确定CR在选定基因，蛋白质和蛋白质修饰上产生的变化，这些变化是调节胰岛素依赖性胰岛素（steatosis）的胰岛素敏感性，葡萄糖代谢，脂肪生成和脂肪积累的变化。具体目的1：检验以下假设：在野生型中，但在生长素蛋白 - / - 和ghsr - / - 小鼠中，CR会增加NPY和AGRP的表达，并抑制通过FOXO1介导途径的神经核（ARC）中POMC的表达，并抑制了通过FOXO介导途径的途径，并抑制了分子​​机制。具体目的2：确定野生型，生长素蛋白 - / - 和ghsr - / - 小鼠对长期热量限制的反应差异，与肝脏代谢，葡萄糖耐受性，胰岛素敏感性，脂肪变性，脂肪变性和寿命有关，并定义分子机制；检验以下假设：年轻表型可以在AD LIB中维持。通过稳定的生长素蛋白模拟物治疗在衰老过程中喂养野生型小鼠。由于迄今为止还没有发现临床生态位，因此确定CR对由生长素蛋白介导的衰老的有益作用在根本上至关重要。 公共卫生相关性：显着降低实验动物的食物摄入可防止糖尿病，降低癌症的发生并延长寿命。这些好处与称为生长素蛋白的激素的血液水平升高有关。生长素素水平随着年龄的变化而下降。我们的研究旨在测试以更稳定的形式代替这种激素是否会在衰老期间提供健康和生活质量益处。