The effects of early life nutritional and hormonal signals on mammalian aging

描述(由申请人提供)：公认的是，早期发育事件可以对健康和疾病产生深远的长期影响。例如，胎儿宫内发育迟缓、产妇营养不足是心血管疾病、2型糖尿病和代谢综合征等疾病发展的危险因素。然而，尚不清楚这些早期生命事件是否(或在多大程度上)也影响哺乳动物的衰老和寿命。根据最新的发现，我们假设出生后的头几周是一个关键的“发育窗口”，在这个窗口中，衰老的速度是由包括激素水平和营养信号在内的多种因素共同决定的。为了揭示这些早期生命事件的机制，我们将试图了解早期荷尔蒙信号何时以及如何对衰老速度、寿命和与年龄相关的代谢变化产生深刻影响。我们还将研究出生后早期卡路里限制(CR)的影响。此外，我们还将比较早期生命CR对GH缺陷和耐药小鼠的影响。这些结果将开始填补目前对发育对衰老和新陈代谢的影响的了解的空白，并为解决具有重大公共卫生意义的更广泛的问题奠定基础。为了确保这项职业发展补助金的成功，我已经在这项提案中建议研究的领域组建了一个专家小组。所有的导师在撰写和评估拨款提案以及研究哺乳动物衰老的不同领域方面都有相当丰富的经验。我们还制定了一个完整的计划，以提高我的研究技能，推动我的事业向前发展。

DESCRIPTION (provided by applicant): It is well accepted that early developmental events can have profound long-term effects on health and diseases. For example, Intrauterine growth retardation, maternal nutrition deficiency represent risk factors for development of diseases including cardiovascular diseases, type 2 diabetes and metabolic syndrome. However, it is unknown whether (or to what extent) these early life events also influence mammalian aging and longevity. On the basis of most recent findings, we hypothesize that the first few weeks of postnatal life represents a critical "developmental window" in which the rate of aging is set by a combination of factors including hormonal levels and nutritional signals. To uncover mechanisms responsible for these early life events, we will try to understand when and how early hormonal signaling can have a profound effect on aging rate, lifespan and age-associated metabolic changes. We will also examine the effects of calorie restriction (CR) during early postnatal life. Moreover, we will compared the early life CR effects on the GH-deficient and resistant mice. The results will begin to fill the gap in the present understanding of the developmental influences on aging and metabolism and set the stage for addressing broader questions of major public health significance. To ensure the success of this career development grant, I have assembled a team of experts in the areas that are proposed to be studied in this proposal. All of the mentors have considerable experience in writing and evaluating grant proposals, as well as in researching diverse areas of mammalian aging. We have also developed a complete plan for enhancing my research skills and pushing my career forward.