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改变， 出生前和出生后。我们实验室最近的研究表明，激素干预仅限于6个 出生后早期的几周可以改变成年人的代谢特征， 会活下去然而，生命早期干预减缓衰老速度和降低衰老风险的潜力- 相关的慢性疾病尚未得到充分探讨。提出的假设是， 在快速的青春期前和青春期周围生长期间，可以产生碳水化合物，脂质， 和能量代谢，从而促进健康衰老。这一假设将使用两个 药理学和一种环境干预已经显示出改善葡萄糖 在成年人中保持体内平衡，并被青少年很好地耐受。在三个特定目标中，将对幼年小鼠进行 二甲双胍治疗，二甲双胍是一种对2型糖尿病成人有多种有益作用的药物，或MSI-1436治疗， 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，安全，免费和易于翻译的干预。这三种干预措施的效果将 测试葡萄糖稳态，能量代谢，身体成分，身体耐力， 营养应激（高脂肪饮食）和基因表达。使用RT-PCR，将分析多个组织的 与健康寿命和寿命相关的基因的表达，包括与胰岛素，GH， IGF-1、mTORC 1和mTORC 2信号传导、葡萄糖和脂质代谢以及炎症。无偏RNA测序 还将对脂肪组织进行研究，以寻找与早期生命干预有关的新机制 以及成年表型和衰老。每个给药组的单独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在24岁时， 30个月，并确定寿命。 研究结果将决定是否在儿童时期进行简单和安全的生活方式干预， 青春期可以促进健康和寿命的延长，并开始确定 哺乳动物衰老的发育程序和药理学干预的潜在目标。 提出了三个具体目标： 具体目的1：确定生命早期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：确定使用MSI-1436（一种实验性抗肿瘤药物）进行早期生命治疗的影响。 肥胖药物）对与衰老有因果关系的成人代谢特征的影响。 具体目标3：确定环境温度轻度降低对早期 寿命对成年代谢特征的影响与衰老有因果关系。

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.