Longevity genes and calorie restriction: early post-natal effects

描述（由申请人提供）：产前发育事件可影响成人表型和成人疾病风险。然而，目前尚不清楚激素和营养素对出生后早期生长的作用是否（或在多大程度上）会影响哺乳动物的衰老，成年健康和寿命。我们最近的研究表明：（i）出生后2周开始注射生长激素（GH）6周可完全逆转低出生率艾姆斯侏儒小鼠寿命的显著延长;和（ii）通过增加一窝幼鼠的数量来限制出生后前3周的营养可利用性，从而增加遗传正常小鼠的中位寿命和最长寿命。基于这些新的和很大程度上出乎意料的发现，我们假设，出生后快速生长的时期代表了一个关键的时间窗口，为发展终身代谢和其他表型特征，影响和可能预测寿命和功能在老年。 为了检验这一假设的有效性，我们将研究正常小鼠在哺乳期间（或哺乳期和断奶后即刻）适度减少可用营养素的影响，以及艾姆斯侏儒和GHRH-/-小鼠孤立GH缺乏症的早期（从1或2周开始）与晚期（从8周开始）GH替代治疗的影响。终点将包括寿命和一系列与健康寿命相关的年龄敏感特征，包括免疫功能、运动、抗应激和白内障发展指数。我们将特别关注与燃料代谢相关的终点，测试促生长素和胰岛素信号传导、胰腺β细胞功能、代谢率和呼吸商，以及肝脏、骨骼肌和皮下及腹内（内脏）脂肪中GH和胰岛素相关基因的表达。最后，我们将在平行研究中观察在断奶之前或之前和之后的早期生活营养限制是否会使GHRKO（Laron侏儒）小鼠受益，GHRKO（Laron侏儒）小鼠与艾姆斯侏儒小鼠不同，当CR在2个月大时开始时，GHRKO小鼠不能从卡路里限制（CR）中受益。拟议研究的结果将用于接受或拒绝有关早期激素或营养干预可能影响衰老和寿命的机制的特定假设。 总之，我们将把我们的长寿基因和CR的相互作用的研究在一个新的方向，以解决在哺乳动物的衰老，健康寿命和长寿的出生后早期的营养和激素信号的瞬时变化的影响。这些研究的结果将解决目前对老龄化发展影响的理解中的关键差距，并为解决具有重大公共卫生意义的早期营养，生长和成人健康之间的关系奠定基础。

DESCRIPTION (provided by applicant): Prenatal developmental events can influence adult phenotype and the risk of adult disease. However, it is unknown whether (or to what extent) the actions of hormones and nutrients on early postnatal growth can influence mammalian aging, adult health and longevity. We have recently shown that: (i) the remarkable extension of longevity in hypopituitary Ames dwarf mice can be completely reversed by a six-week course of growth hormone (GH) injections started at the age of 2 weeks; and (ii) limiting nutrient availability during the first three weeks of postnatal life by increasing the numbers of pups in a litter increases both median and maximal lifespan in genetically normal mice. Based on these novel and largely unexpected findings, we hypothesize that the period of rapid postnatal growth represents a critical time window for development of lifelong metabolic and other phenotypic characteristics that influence-and likely predict-longevity and functionality during old age. To test the validity of this hypothesis, we will examine the impact of modestly reducing the amount of available nutrients during suckling (or suckling and the immediate post-weaning period) in normal mice, and the effects of early (starting at one or two weeks) as compared to late (starting at eight weeks) GH replacement therapy in Ames dwarfs and in GHRH-/- mice with isolated GH deficiency. Endpoints will include both longevity and a series of age-sensitive traits related to health span, including indices of immune function, locomotion, stress resistance, and cataract development. We will pay special attention to endpoints related to fuel metabolism, with tests of somatotropic and insulin signaling, pancreatic beta cell function, metabolic rate and respiratory quotient, and expression of GH and insulin-related genes in the liver, skeletal muscle, and both subcutaneous and intra-abdominal (visceral) fat. Lastly, we will in parallel studies see whether early life nutrient limitation, before or before and after weaning, will benefit GHRKO (Laron dwarf) mice, which unlike Ames dwarf mice fail to benefit from calorie restriction (CR) when CR is started at the age of 2 months. Results of the proposed studies will be used to accept or reject specific hypotheses concerning mechanisms by which early hormonal or nutritional interventions can influence aging and longevity. In sum, we will take our studies of the interactions of longevity genes and CR in a novel direction to address the impact of transient changes in nutritional and hormonal signals during early postnatal life on mammalian aging, health span and longevity. Results of these studies will address critical gaps in the present understanding of developmental influences on aging and set a stage for addressing the relationships between early nutrition, growth and adult health which are of major public health significance.