Longevity genes and calorie restriction: early post-natal effects

描述(由申请人提供)：产前发育事件会影响成人的表型和成人疾病的风险。然而，激素和营养物质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、成年健康和长寿，目前尚不清楚。我们最近已经证明：(I)从2周大开始注射生长激素(GH)的六周疗程可以完全逆转垂体功能低下的Ames侏儒小鼠寿命的显著延长；以及(Ii)通过增加一窝小鼠的仔数来限制出生后前三周的营养供应，可以延长遗传正常小鼠的中值和最长寿命。基于这些新奇且出人意料的发现，我们假设，出生后的快速生长期是终生代谢和其他表型特征发展的关键时间窗口，这些特征影响-并可能预测-在老年期间的寿命和功能。为了检验这一假设的有效性，我们将研究适度减少正常小鼠哺乳期间(或哺乳期和断奶后即刻)可用营养素的影响，以及早期(从一周到两周开始)与晚期(从八周开始)生长激素替代疗法在Ames侏儒和GHRH-/-小鼠中的效果。终点将包括长寿和一系列与健康跨度相关的年龄敏感特征，包括免疫功能、运动、抗压和白内障发展指数。我们将特别关注与燃料代谢相关的终点，测试促生长激素和胰岛素信号、胰腺β细胞功能、代谢率和呼吸商，以及肝脏、骨骼肌、皮下和腹内(内脏)脂肪中生长激素和胰岛素相关基因的表达。最后，我们将进行平行研究，看看早期生命营养限制，在断奶之前或之前和之后，是否会使GHRKO(Laron侏儒)小鼠受益，而不像Ames侏儒小鼠，当2个月大时开始热量限制(CR)时，GHRKO(Laron Dwarf)小鼠无法从热量限制(CR)中受益。建议的研究结果将被用来接受或拒绝关于早期荷尔蒙或营养干预可以影响衰老和寿命的机制的特定假设。综上所述，我们将以新的方向研究长寿基因和CR的相互作用，以解决出生后早期营养和激素信号的瞬时变化对哺乳动物衰老、健康和长寿的影响。这些研究的结果将解决目前对发育对衰老的影响的认识上的严重差距，并为解决早期营养、生长和成人健康之间的关系奠定基础，这些关系具有重大的公共卫生意义。

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.