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

摘要： 众所周知，早期发育事件可能会产生深远的长期影响。 关于健康和疾病。例如，胎儿宫内发育迟缓、产妇营养 缺乏是包括心血管疾病在内的疾病发展的危险因素 疾病、2型糖尿病和代谢综合征。然而，目前还不清楚(或 这些早期生命事件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，我们假设在最初的几周里 出生后的生活是一个关键的“发育窗口”，在这个窗口中， 衰老是由多种因素共同决定的，包括激素水平和营养 信号。为了揭示导致这些早期生命事件的机制，我们将尝试 了解早期荷尔蒙信号何时以及如何对衰老产生深远影响 速度、寿命和与年龄相关的代谢变化。我们还将研究以下方面的影响 出生后早期的热量限制(CR)。此外，我们将比较早期的 LIFE CR对GH缺陷和耐药小鼠的影响。结果将开始填补 目前对发育对衰老的影响的认识存在差距 新陈代谢，为解决更广泛的重大公共卫生问题奠定了基础 意义。 为了确保这笔职业发展基金的成功，我组建了一个团队， 本提案中建议研究的领域的专家。所有的导师 在撰写和评估拨款提案方面有相当的经验，以及 研究哺乳动物衰老的不同领域。我们还开发了一个完整的 计划提高我的研究技能，推动我的事业向前发展。

Summary: 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.