Developmental Origins of Phenotypic Characteristics that Predict Longevity

描述(由申请人提供)：众所周知，发育事件可以作为成人疾病的决定因素。例如，母亲营养不良以及营养过剩是后代患新陈代谢综合征各种组成部分的危险因素。然而，尚不清楚早期生长和发育是否(或在多大程度上)影响哺乳动物的衰老。根据对长寿突变体进行激素替代治疗的初步数据，我们认为，断奶前后的快速生长时期可能代表着早期激素环境对健康和寿命影响的关键时间窗。为了测试这一新概念的有效性，并开始确定潜在的机制，我们将确定在出生后发育的不同阶段开始的一段明确的(六周)激素治疗是否可以影响与长寿相关的表型特征，以及激素诱导的这些特征的变化在治疗停止后是否会持续。为了验证这样一种假设，即出生后的快速生长期代表着影响(并可能预测)衰老的代谢特征发展的关键时间窗口这一假设，提出了以下具体目标：1.确定使用生长激素(GH)或从一周、两周或两个月龄开始使用激素组合治疗长寿甲状腺功能低下(Ames Dwarf)小鼠对耗氧量(VO2)、呼吸商(RQ)、体温以及与胰岛素作用、脂肪和碳水化合物代谢相关基因表达的影响。2.确定激素引起的VO2、RQ、体温、胰岛素信号和基因表达的变化在治疗停止后是否持续。3.确定早期应用生长激素、催乳素和甲状腺激素与单独使用生长激素相比，对Ames侏儒小鼠的脂肪因子水平、胰岛素和葡萄糖耐量以及其他与延长寿命有关的特征的影响。这些结果将开始填补目前对发育对衰老的影响的理解的空白，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，例如：营养和营养相关的内分泌信号在不同发育阶段如何影响生长并最终影响健康和寿命？年轻人的关键代谢参数与衰老和长寿有什么关系？什么样的早期生活方式和/或药物干预可以有效地延长健康寿命和预期寿命？ 与公共健康相关：有相当多的证据表明，生长激素(GH)和其他刺激生长的激素也在控制衰老和长寿方面发挥着重要作用。我们最近的发现表明，生长激素在生命早期的行为(从断奶前开始，一直持续到青春期)影响预期寿命。在拟议的研究中，我们将使用正常和长寿的突变小鼠，并用生长激素或激素组合治疗来阐明这一新颖的、有些意想不到的效果。我们将确定在出生后早期生命的哪些阶段，荷尔蒙水平会影响正常和长寿小鼠不同的代谢特征，从而可能预测长寿。我们还将确定这些激素诱导的变化中哪些在激素治疗停止后持续存在。由于营养对各种激素水平有重大影响，因此了解早期荷尔蒙作用与衰老之间的关系，对于发现如何通过在青春期前快速生长期间明智地改变饮食来延缓衰老和提高预期寿命至关重要。

DESCRIPTION (provided by applicant): It is well established that developmental events can act as determinants of adult disease. For example, maternal undernutrition, as well as overnutrition, represent risk factors for development of various components of metabolic syndrome in the offspring. Yet it is unknown whether (or to what extent) early growth and development influence mammalian aging. On the basis of preliminary data derived from hormonal replacement therapy in long-lived mutants, we propose that the period of rapid pre- and post-weaning growth may represent a critical "time window" for the effects of early hormonal milieu on healthspan and lifespan. To test the validity of this novel concept and to begin identifying the underlying mechanisms, we will determine whether a defined (six week) period of hormonal therapy, started at different stages of postnatal development, can influence phenotypic characteristics associated with longevity and whether the hormone-induced alterations in these characteristics will persist after the treatment is stopped. To test the hypothesis that the period of rapid postnatal growth represents a critical time window for development of metabolic characteristics that influence (and likely predict) aging, the following specific aims are proposed: 1. To determine the effects of treating long-lived hypopituitary Prop1df (Ames dwarf) mice with growth hormone (GH) or with a combination of hormones starting at one week, two weeks or two months of age on oxygen consumption (VO2), respiratory quotient (RQ), body temperature and expression of genes related to insulin action, fat and carbohydrate metabolism. 2. To determine whether hormone-induced changes in VO2, RQ, body temperature, insulin signaling and gene expression persist after the treatment is stopped. 3. To determine the effects of early treatment with a combination of GH, prolactin and thyroxine as compared to treatment with GH alone on adipokine levels, insulin and glucose tolerance and other characteristics associated with extended longevity of Ames dwarf mice. The results will begin to fill the gap in the present understanding of the developmental influences on aging and set the stage for addressing broader questions of major public health significance, e.g.: How does nutrition and nutrition-related endocrine signaling during different stages of development affect growth and ultimately healthspan and lifespan? What is the relationship of key metabolic parameters in young adults to aging and longevity? And what early lifestyle and/or pharmacological interventions could effectively increase healthspan and life expectancy? PUBLIC HEALTH RELEVANCE: There is considerable evidence that growth hormone (GH) and other hormones that stimulate growth are also importantly involved in the control of aging and longevity. Our recent findings indicate that the actions of GH early in life (starting before weaning and continuing to the age of puberty) influence life expectancy. In the proposed studies we will use normal as well as long- lived mutant mice, and therapy with GH or with a combination of hormones to elucidate this novel and somewhat unexpected effect. We will determine at which stages of early postnatal life hormone levels influence metabolic characteristics that differ in normal and long-lived mice and thus may predict longevity. We will also determine which of these hormone-induced changes persist after hormone treatment is stopped. Because nutrition has major effects on the level of various hormones, understanding the relationships between early hormone action and aging is important for discovering how aging can be postponed and life expectancy improved by judicious modifications of the diet during rapid pre-pubertal growth.