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，成人疾病的风险可以通过发育过程中起作用的因素来改变，包括 产前和产后。我们实验室最近的研究表明，激素干预仅限于六种 出生后早期的几周可以改变成年代谢特征并决定动物的寿命 会活下去。然而，早期生命干预有可能减缓衰老速度并降低老年风险 相关的慢性疾病尚未得到充分探讨。拟议的假设是干预措施 在青春期前和青春期前后的快速生长过程中，碳水化合物、脂质、 和能量代谢，从而促进健康老龄化。该假设将使用两个测试 药物和一种环境干预措施已被证明可以改善血糖 成人体内稳态良好，青少年具有良好的耐受性。在三个具体目标中，幼年小鼠将 使用二甲双胍（一种对成人 2 型糖尿病患者具有多种有益作用的药物）或 MSI-1436（一种 新的实验性抗肥胖和抗糖尿病药物，或暴露于适度减少的环境 温度，一种安全、免费且易于转化的干预措施。这三项干预措施的效果将 测试葡萄糖稳态、能量代谢、身体成分、身体耐力、对 营养压力（高脂肪饮食）和基因表达。使用 RT-PCR，对多个组织进行分析 与健康寿命和寿命机械相关的基因表达，包括与胰岛素、GH、 IGF-1、mTORC1 和 mTORC2 信号传导、葡萄糖和脂质代谢以及炎症。无偏RNA测序 还将进行脂肪组织研究，以寻找与早期生命干预联系起来的新机制 以及成人表型和衰老。每个治疗组的单独动物群将用于研究 24 岁时的葡萄糖稳态、能量代谢、身体成分和身体耐力 30个月并确定寿命。 结果将确定儿童时期和儿童时期简单而安全的生活方式干预是否有效 青春期可以促进健康寿命和寿命的延长，并开始确定健康和寿命的机制 哺乳动物衰老的发育规划和药物干预的潜在目标。 提出了三个具体目标： 具体目标 1：确定生命早期使用二甲双胍治疗对成人代谢的影响 与衰老有因果关系的特征。 具体目标 2：确定 MSI-1436（一种实验性抗- 肥胖药物）对与衰老相关的成人代谢特征的影响。 具体目标 3：确定早期环境温度轻微降低的影响 生活对成人代谢特征的影响与衰老有因果关系。