Developmental Programming of Mammalian Aging

哺乳动物衰老的发育规划

• 批准号: 9896217
• 负责人: Andrzej Bartke
• 金额: $ 19.64万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896217
• 关键词: Address; Adipose tissue; Adolescence; Adolescent; Adult; Age; Age-Months; Aging; Animals; Anti-Obesity Agents; Antidiabetic Drugs; Body Composition; Body Weight; Cell Culture Techniques; Characteristics; Child; Childhood; Chronic Disease; Consumption; Development; Diabetes Mellitus; Disease; Dose; Energy Metabolism; Exposure to; Fat-Restricted Diet; Future; Gene Expression; Gene Expression Profiling; Goals; Growth; Health; High Fat Diet; Hormonal; Human; Inflammation; Insulin; Insulin-Like Growth Factor I; Intervention; Knowledge; Laboratories; Life; Life Style; Link; Longevity; Metabolic; Metabolism; Metformin; Modification; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organism; Pharmaceutical Preparations; Pharmacology; Phenotype; Physical Endurance; Public Health; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Signal Transduction; Stress; Temperature; Testing; Time; Tissues; Translations; Work; age related; blood glucose regulation; carbohydrate metabolism; cohort; cost; diabetic; environmental intervention; glucose metabolism; healthspan; healthy aging; improved; in vivo; lifestyle intervention; lipid metabolism; metabolic phenotype; novel; novel strategies; peripubertal period; postnatal; postnatal development; programs; rapid growth; response; sex; transcriptome sequencing; treatment group

Abstract It is well known that the risk of adult disease can be altered by factors acting during development, both pre- and postnatally. Recent studies in our laboratory have shown that hormonal intervention limited to six weeks during early postnatal life can alter adult metabolic characteristics and determine how long an animal will live. However, the potential of early life interventions to slow the rate of aging and reduce the risk of age- related chronic diseases has not been adequately explored. The proposed HYPOTHESIS is that interventions during rapid pre- and peri-pubertal growth can produce permanent beneficial changes in carbohydrate, lipid, and energy metabolism, thus promoting healthy aging. This hypothesis will be tested using two pharmacological and one environmental intervention which have already been shown to improve glucose homeostasis in adults and to be well tolerated by juveniles. In three SPECIFIC AIMS, juvenile mice will be treated with metformin, a drug with multiple beneficial effects in adults with type 2 diabetes or with MSI-1436, a novel experimental anti-obesity and anti-diabetic drug, or exposed to a modest reduction of environmental temperature, a safe, cost free and readily translatable intervention. The effects of these three interventions will be tested on glucose homeostasis, energy metabolism, body composition, physical endurance, responses to nutritional stress (high fat diet), and gene expression. Using RT-PCR, multiple tissues will be analyzed for expression of genes mechanistically related to healthspan and longevity, including those related to insulin, GH, IGF-1, mTORC1 and mTORC2 signaling, glucose and lipid metabolism, and inflammation. Unbiased RNA-Seq studies of adipose tissue will also be conducted to search for novel mechanisms linking early life interventions and adult phenotype and aging. Separate cohort of animals from each treatment group will be used for studies of glucose homeostasis, energy metabolism, body composition, and physical endurance at the ages of 24 and 30 months and for determination of longevity. The results will determine whether simple and safe lifestyle interventions during childhood and adolescence can promote extension of healthspan and lifespan and begin to identify mechanisms of developmental programing of mammalian aging and potential targets for pharmacological interventions. Three Specific Aims are proposed: Specific Aim 1: To determine the impact of early life treatment with metformin on adult metabolic characteristics causally related to aging. Specific Aim 2: To determine the impact of early life treatment with MSI-1436 (an experimental anti- obesity drug) on adult metabolic characteristics causally related to aging. Specific Aim 3: To determine the impact of a mild reduction of environmental temperature during early life on adult metabolic characteristics causally related to aging.

抽象的 众所周知，成人疾病的风险可能会因发育过程中起作用的因素而改变，两者都可以改变 前后。我们实验室的最新研究表明，荷尔蒙干预仅限于六个 产后早期生活期间的几周可以改变成人代谢特征并确定动物多长时间 会活的。但是，早期生命干预措施降低衰老率并降低年龄的风险的潜力 - 相关的慢性疾病尚未得到充分探讨。提出的假设是干预措施 在快速前后，伯伯伯碱生长会产生碳水化合物脂质的永久有益变化， 和能量代谢，从而促进健康的衰老。该假设将使用两个 药理和一种环境干预措施已被证明可以改善葡萄糖 成人的体内平衡，并受到少年的耐受性。在三个特定目标中，少年小鼠将是 用二甲双胍治疗，一种在2型糖尿病的成年人中具有多种有益作用的药物或MSI-1436，A 新型的实验性抗肥胖和抗糖尿病药物，或暴露于环境的适度降低 温度，安全，不含成本且易于翻译的干预措施。这三种干预措施的影响将 对葡萄糖稳态，能量代谢，身体成分，身体耐力，对反应进行测试 营养应激（高脂肪饮食）和基因表达。使用RT-PCR，将分析多个组织 与健康跨度和寿命有关的基因表达，包括与胰岛素有关的基因 IGF-1，MTORC1和MTORC2信号传导，葡萄糖和脂质代谢以及炎症。无偏的RNA-seq 还将进行脂肪组织的研究，以搜索与早期生命干预联系起来的新型机制 以及成人表型和衰老。每个治疗组的单独的动物队列将用于研究 葡萄糖稳态，能量代谢，身体成分和身体耐力，年龄在24岁时 30个月，用于确定寿命。 结果将决定儿童期间简单安全的生活方式干预措施是否 青春期可以促进HealthSpan和寿命的扩展，并开始确定 哺乳动物衰老和药理学干预措施的潜在靶标的发育编程。 提出了三个具体目标： 特定目的1：确定二甲双胍早期治疗对成人代谢的影响 特征与衰老有关。 特定目的2：确定MSI-1436早期治疗的影响（一种实验性抗 肥胖药物）关于成年代谢特征与衰老有关的因果关系。 特定目的3：确定早期环境温度轻度降低的影响 成人代谢特征的生活与衰老有关。