Developmental Origins of Phenotypic Characteristics that Predict Longevity

描述（由申请人提供）：发育事件可以作为成人疾病的决定因素，这是公认的。例如，母亲营养不良和营养过剩是后代代谢综合征各种组成部分发展的危险因素。然而，早期生长发育是否（或在多大程度上）影响哺乳动物的衰老尚不清楚。基于长寿命突变体激素替代治疗的初步数据，我们提出断奶前和断奶后的快速生长时期可能是早期激素环境对健康寿命和寿命影响的关键“时间窗口”。为了检验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确定的（6周）激素治疗是否可以影响与寿命相关的表型特征，以及激素诱导的这些特征的改变是否会在治疗停止后持续存在。为了验证这一假设，即出生后的快速生长时期是影响（并可能预测）衰老的代谢特征发育的关键时间窗口，提出了以下具体目标：目的：确定在1周、2周或2个月大时使用生长激素（GH）或联合使用激素治疗长寿垂体功能低下的Prop1df （Ames dwarf）小鼠对耗氧量（VO2）、呼吸商（RQ）、体温和胰岛素作用、脂肪和碳水化合物代谢相关基因表达的影响。2. 确定停止治疗后，激素诱导的VO2、RQ、体温、胰岛素信号和基因表达的变化是否持续。3. 确定生长激素、催乳素和甲状腺素联合早期治疗与单独使用生长激素治疗相比对脂肪因子水平、胰岛素和葡萄糖耐量以及与延长Ames侏儒小鼠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内分泌信号如何影响生长并最终影响健康寿命和寿命？青壮年关键代谢参数与衰老和长寿的关系是什么？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？

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.