Systemic Factors that Maintain a Young Liver Phenotype

维持年轻肝脏表型的全身因素

• 批准号: 7619156
• 负责人: ROY G SMITH
• 金额: $ 39.13万
• 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/7619156
• 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; Immune; 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; 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)：这项建议的长期目标是开发在衰老过程中保持生活质量和独立性的治疗方法。卡路里限制(CR)在衰老过程中保持健康并延长寿命；然而，分子介体(S)尚不清楚。在CR和禁食期间，激素Ghrelin的产生增加，下丘脑表达的Ghrelin受体(GHS-R1a)上调8倍。Ghrelin调控通路的特征导致了一种假说，即衰老表型与内源性Ghrelin信号受损有关，Ghrelin是CR益处的中介。在CR期间，动物必须通过改变周围组织的新陈代谢来补偿能量摄入的减少。推测Ghrelin对调节能量平衡的下丘脑弓状神经元(ARC)表达的GHS-R1a具有中枢调节作用。通过比较CR对Ghrelin-/-和GHSR-/-小鼠ARC神经肽Y(NPY)、刺鼠相关肽(AGRP)和阿片黑素皮质素原(POMC)神经元的分子效应，可以识别Ghrelin介导的信号。通过在野生型和ghrelin-/-和ghsr-/-小鼠中进行类似的比较，可以定义CR诱导的老年肝脏中ghrelin依赖的代谢变化。这一点很重要，因为肝脏是调节新陈代谢的关键，受到大脑、胰腺、脂肪和肌肉输入的调节。除了确定Ghrelin依赖的代谢效应外，还将比较CR野生型、Ghrelin-/-和GHSR-/-小鼠的寿命。推测CR不会延长突变小鼠的寿命。随机喂养的野生型小鼠将每天接受稳定的Ghrelin模拟物治疗，以检验这样的假设：在衰老过程中进行干预以挽救受损的Ghrelin信号将延长寿命并保持年轻的肝脏表型。总之，这项研究将确定CR对调节胰岛素敏感性、葡萄糖代谢、脂肪生成和肝脏脂肪堆积(脂肪变性)的选定基因、蛋白质和蛋白质修饰的变化，这些基因、蛋白质和蛋白质依赖于Ghrelin。具体目的1：验证野生型(而不是ghrelin-/-和ghsr-/-)小鼠，CR通过FoxO1介导的途径增加弓状核(ARC)神经元NPY和AgRP的表达，抑制POMC的表达，并阐明其分子机制。具体目标2：确定野生型、ghrelin-/-和ghsr-/-小鼠对长期热量限制的反应在肝脏代谢、葡萄糖耐量、胰岛素敏感性、脂肪变性和寿命方面的差异，并确定其分子机制；检验年轻表型可以在即刻维持的假设。在衰老过程中，用稳定的Ghrelin模拟物处理野生型小鼠。确定由Ghrelin介导的CR对衰老的有益影响是至关重要的，因为到目前为止还没有发现临床适用的口服活性、耐受性良好的长效Ghrelin模拟物。公共卫生相关性：显著减少实验动物的食物摄入量可预防糖尿病、降低癌症发病率并延长寿命。这些好处与血液中一种名为Ghrelin的荷尔蒙水平的增加有关。Ghrelin水平随着年龄的增长而下降。我们的研究旨在测试用更稳定的形式取代这种激素是否会在衰老过程中提供健康和生活质量方面的好处。