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，母亲营养不良和营养过剩是后代出现代谢综合征各种症状的危险因素。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。根据来自长寿突变体激素替代疗法的初步数据，我们提出，断奶前后的快速生长时期可能代表早期激素环境对健康寿命和寿命影响的关键“时间窗口”。为了测试这一新概念的有效性并开始确定潜在机制，我们将确定在出生后发育的不同阶段开始的规定（六周）时期的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改变在治疗停止后是否会持续存在。为了验证出生后快速生长期是影响（并可能预测）衰老的代谢特征发展的关键时间窗口的假设，提出了以下具体目标： 1. 确定从出生一周、两周或两个月开始用生长激素（GH）或激素组合治疗长寿垂体下垂体 Prop1df（Ames 侏儒）小鼠对耗氧量（VO2）、呼吸商（RQ）、体温和基因表达的影响与胰岛素作用、脂肪和碳水化合物代谢有关。 2. 确定激素引起的摄氧量、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存在。 3. 确定早期联合使用 GH、催乳素和甲状腺素治疗与单独使用 GH 治疗相比对脂肪因子水平、胰岛素和葡萄糖耐量以及与艾姆斯侏儒小鼠延长寿命相关的其他特征的影响。 研究结果将开始填补目前对发育对衰老影响的理解的空白，并为解决具有重大公共卫生意义的更广泛问题奠定基础，例如：不同发育阶段的营养和营养相关的内分泌信号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何关系？哪些早期生活方式和/或药物干预可以有效延长健康寿命和预期寿命？ 公共卫生相关性：有大量证据表明，生长激素 (GH) 和其他刺激生长的激素在控制衰老和长寿方面也发挥着重要作用。我们最近的研究结果表明，生命早期的 GH 作用（从断奶前开始一直持续到青春期）会影响预期寿命。在拟议的研究中，我们将使用正常和长寿的突变小鼠，并使用 GH 或激素组合进行治疗，以阐明这种新颖且有些出乎意料的效果。我们将确定出生后早期生命的哪些阶段激素水平会影响正常小鼠和长寿小鼠的不同代谢特征，从而可以预测寿命。我们还将确定哪些激素引起的变化在激素治疗停止后仍然存在。由于营养对各种激素的水平有重大影响，因此了解早期激素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推迟衰老和提高预期寿命非常重要。

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.