Developmental Origins of Phenotypic Characteristics that Predict Longevity

预测长寿的表型特征的发育起源

• 批准号: 8245693
• 负责人: Andrzej Bartke
• 金额: $ 14.91万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245693
• 关键词: Address; Adult; Affect; Aftercare; Age; Age-Months; Aging; Body Temperature; Characteristics; Data; Development; Diet Modification; Disease; Early treatment; Endocrine; Event; Gene Expression; Growth; Growth and Development function; Hormonal; Hormones; Insulin; Intervention; Life; Life Expectancy; Life Style; Longevity; Malnutrition; Metabolic; Metabolic syndrome; Mus; Mutant Strains Mice; Overnutrition; Oxygen Consumption; Prolactin; Puberty; Public Health; Replacement Therapy; Risk Factors; Signal Transduction; Somatotropin; Staging; Testing; Thyroxine; Time; Weaning; base; carbohydrate metabolism; glucose tolerance; hormone therapy; improved; insulin signaling; insulin tolerance; lipid metabolism; mutant; novel; nutrition; offspring; postnatal; public health relevance; respiratory; young adult

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.

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，母亲营养不良以及营养过剩是后代发展代谢综合征各种成分的风险因素。然而，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还不清楚。在长寿突变体激素替代疗法的初步数据的基础上，我们提出，快速断奶前和断奶后的增长期可能代表了一个关键的“时间窗口”的早期激素环境的影响healthspan和寿命。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个确定的（6周）时期的激素治疗是否可以影响与长寿相关的表型特征，以及在治疗停止后，这些特征中的激素诱导的改变是否会持续。为了检验这一假设，即出生后快速生长的时期代表了影响（并可能预测）衰老的代谢特征发展的关键时间窗口，提出了以下具体目标：1。确定从1周龄、2周龄或2月龄开始使用生长激素（GH）或激素组合治疗长寿低血压Prop 1 df（艾姆斯侏儒）小鼠对耗氧量（VO 2）、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的基因表达的影响。2.确定在治疗停止后，胰岛素诱导的VO 2、RQ、体温、胰岛素信号传导和基因表达的变化是否持续。3.确定早期联合使用GH、催乳素和甲状腺素与单独使用GH相比对艾姆斯侏儒小鼠脂肪因子水平、胰岛素和葡萄糖耐量以及与长寿相关的其他特征的影响。 研究结果将开始填补目前对发展对老龄化影响的理解方面的差距，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：在不同的发育阶段，营养和营养相关的内分泌信号是如何影响生长并最终影响健康和寿命的？年轻人的关键代谢参数与衰老和长寿之间的关系是什么？什么样的早期生活方式和/或药物干预可以有效地增加健康寿命和预期寿命？ 公共卫生相关性：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重要地参与了衰老和长寿的控制。我们最近的研究结果表明，生长激素在生命早期的作用（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，我们将使用正常以及长寿的突变小鼠，和治疗与生长激素或激素的组合，以阐明这种新颖的和有点意想不到的效果。我们将确定在出生后生命早期的哪个阶段激素水平影响正常和长寿小鼠不同的代谢特征，从而可以预测寿命。我们还将确定哪些激素诱导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修改饮食来推迟衰老和提高预期寿命非常重要。