SCHS, mitochondria, healthy aging and longevity

描述(申请人提供)：肥胖和糖尿病在美国很流行。肥胖和糖尿病的后果和并存对老年人有巨大的负面影响，因此抗击肥胖和糖尿病的战略可能会对美国老龄化人口的一个主要问题产生重大影响。二十年来对多种物种衰老和长寿的基础遗传学研究也表明，通过胰岛素/IGF-1途径控制胰岛素，并减少肥胖是健康衰老的关键特征。因此，公共健康研究和基础衰老研究汇聚在一起，表明对抗肥胖和糖尿病的机制可能会对老年人的健康产生重大影响。在上一个奖项中，该计划项目组建了一个经验丰富的团队，在分子、细胞器、组织和整个有机体水平上理解和整合Shc缺乏的后果。研究表明，Shc基因敲除(KO)小鼠通过增加胰岛素/IGF-1信号和“低胰岛素生活方式”来抵抗肥胖和糖尿病，具有抗应激能力，代谢有较大程度的改变，热量限制的中位寿命延长，干细胞功能增强。在目前的提案中，该计划项目将确定基于Shc的机制：1)减少突变小鼠的肥胖和增加高脂饮食下的存活率，2)延长限制热量的中位寿命，以及3)改善干细胞功能。此外，该计划将确定模拟Shc缺乏症的药物和饮食，作为促进人类健康衰老的先导。因此，这项工作的最终成果将不仅是详细了解SHCS的抗肥胖机制、抗糖尿病和抗应激功能，还将包括支持健康老龄化的先导化合物和营养干预。

DESCRIPTION (provided by applicant): Obesity and diabetes are epidemic in the U.S. The consequences and comorbidities of obesity and diabetes have a massive negative impact on the aged, and thus strategies to combat obesity and diabetes could have a major impact on a major problem for the aging U.S. population. Twenty years of basic genetic research into aging and longevity across multiple species has also implicated insulin control, via the insulin/igf-1 pathway, and reduced adiposity as critical features of healthy aging. Thus, public health studies and basic aging studies converge and suggest that mechanisms to combat obesity and diabetes could have a major impact on the health of seniors. In the previous award, the program project assembled an experienced team to understand and integrate the consequences of Shc-deficiency at the molecular, organellar, tissue and whole-organismal levels. The research conducted demonstrated that Shc knockout (KO) mice resist obesity and diabetes, through increased insulin/igf-1 signaling and a 'low-insulin lifestyle,' are stress resistant, and have majr modifications of metabolism, extended median lifespan on caloric restriction, and increased stem cell function. In the current proposal, the program project will identify the Shc-based mechanism of: 1) decreased adiposity and increased survival on high-fat diet in mutant mice, 2) extended median lifespan on caloric restriction, and 3) improved stem cell function. In addition, the program will 4) identify drugs and diets that simulate Shc-deficiency, to be used as leads to promote healthy human aging. Thus, the ultimate product of the work will be not only a detailed understanding of the anti-obesity mechanism, anti-diabetic and anti-stress functions of Shcs, but also lead compounds and nutritional interventions that support healthy aging.