Developmental Programming of Mammalian Aging

摘要 众所周知，成人疾病的风险可以通过发育过程中的因素来改变，两者都是 出生前和出生后。我们实验室最近的研究表明，荷尔蒙干预仅限于6次 出生后早期的几周会改变成年动物的代谢特征，并决定动物 都会活下来。然而，早期生活干预减缓老龄化速度和降低衰老风险的潜力-- 相关的慢性病还没有得到充分的探索。提出的假设是，干预措施 在青春期前和青春期周围的快速生长过程中，碳水化合物、脂肪、 和能量代谢，从而促进健康衰老。这一假说将使用两种方法进行检验 已经证明可以改善血糖的药物和一种环境干预 成年人体内的动态平衡，以及青少年的耐受性。在三个特定的目标中，幼年老鼠将被 二甲双胍是一种对成人2型糖尿病有多种益处的药物，或者用MSI-1436治疗，a 新型实验性减肥和抗糖尿病药物，或暴露于适度减少的环境中 温度，一种安全、免费且易于翻译的干预措施。这三种干预措施的效果将是 接受葡萄糖稳态、能量代谢、身体成分、身体耐力、对 营养应激(高脂肪饮食)和基因表达。利用RT-PCR，多个组织将被分析 机制上与健康和长寿有关的基因的表达，包括与胰岛素、生长激素、 IGF-1、mTORC1和mTORC2信号、糖脂代谢和炎症。无偏的RNA-Seq 还将对脂肪组织进行研究，以寻找将早期生活干预联系起来的新机制 成体表型和衰老。来自每个治疗组的单独的动物队列将用于研究 血糖稳态、能量代谢、身体成分和身体耐力 30个月，并确定长寿。 这一结果将决定在儿童和儿童时期进行简单而安全的生活方式干预 青春期可促进健康和寿命的延长，并开始识别 哺乳动物衰老的发育规划和药物干预的潜在靶点。 提出了三个具体目标： 具体目标1：确定早期应用二甲双胍对成人代谢的影响 与衰老有因果关系的特征。 具体目标2：确定MSI-1436(一种实验性抗艾滋病药物)对早期生命治疗的影响 减肥药)对与衰老有因果关系的成人代谢特征的影响。 具体目标3：确定早期温和降低环境温度的影响 生活对成年人的代谢特征与衰老有因果关系。

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.