MOLECULAR BASIS OF SNELL DWARF AND LITTLE LONGEVITY

酵母菌、线虫、果蝇和啮齿动物的实验模型表明，衰老和长寿在一定程度上受到遗传控制。 线虫C. elegans提供了遗传和生化证据，确定了控制长寿的候选基因。 这涉及daf-2、age-1和daf-16基因的衰减，这些基因与胰岛素受体（InR）家族和信号传导途径的同源性表明该途径可以调节有利于脊椎动物长寿的代谢特征。侏儒突变小鼠斯内尔（dw/dw）、艾姆斯（df/df）和利特尔（lit/lit）的寿命明显长于它们的正常同胞。侏儒突变的性质，即，生长激素（GH）、促甲状腺激素（TSH）和催乳素（Prl）缺乏可能导致与长寿的C.秀丽线虫突变体 由于这些小鼠是唯一的脊椎动物长寿遗传模型，并且由于线虫和长寿侏儒突变体的“抗衰老”过程的生理特征惊人地相似，这些小鼠为研究决定脊椎动物长寿的分子和遗传过程提供了极好的资源。在这项研究计划中，我们将确定斯内尔和利特侏儒小鼠的生理特征是否是脊椎动物衰老的长寿决定因素。 具体目标1将确定Snell和lit小鼠是否表现出延迟衰老的特征，如由于GH、胰岛素和IGF-I缺乏引起的功能降低表型;免疫功能;以及应激反应基因的调节。 在具体目标2中，我们计划使用内分泌补充剂来确定TH和Pr 1缺乏作为长寿决定因素的具体作用;在具体目标3中，我们将使用条件性转基因Snell侏儒和lit小鼠来确定GH缺乏在长寿中的作用，其中GH表达是可调节的，即， 随意打开或关闭。 我们的长期目标是通过识别长寿决定因素来阐明脊椎动物寿命的分子和遗传基础。 实现这些目标将确定涉及长寿的途径，并为理解这些途径的作用机制奠定基础。

Experimental models of yeast, nematodes, fruit flies, and rodents indicate that aging and longevity are, in part, under genetic control. The nematode C. elegans, has provided genetic and biochemical evidence that identifies candidate genes that govern longevity. This involves attenuation of the daf-2, age-1 and daf-16 genes whose homologies to the mammalian-insulin receptor (InR) family and signaling pathway suggest that this pathway(s) may regulate metabolic characteristics that favor vertebrate longevity. The mouse dwarf mutants Snell (dw/dw), Ames (df/df) and little (lit/lit), live significantly longer than their normal siblings. The nature of the dwarf mutations, i.e., growth hormone (GH), thyroid stimulating hormone (TSH) and prolactin (Prl) deficiencies may result in physiological characteristics similar to those of the long-lived C. elegans mutants. Since these mice are the only vertebrate genetic models of longevity, and since the physiological characteristics of the "anti-aging" processes of the nematode and the long-lived dwarf mutants are strikingly similar, these mice provide an excellent resource to study the molecular and genetic processes that determine longevity in vertebrates. In this research program we will determine whether the physiological characteristics of the Snell and lit dwarf mice are longevity-determining factors of vertebrate aging. Specific Aims 1 will determine whether the Snell and lit mice exhibit such characteristics of delayed senescence as a reduction-of-function phenotype due to GH, insulin and IGF-I deficiency; immunological function; and regulation of stress response genes. In Specific Aim 2 we plan to use endocrine supplementation to determine the specific role of TH and Pr1 deficiencies as longevity-determining factors; In Specific Aim 3 we will determine the role GH deficiency in longevity using conditional transgenic Snell dwarf and lit mice in which GH expression is regulatable i.e., turned on or off at will. Our long-range goal is to elucidate the molecular and genetic basis of vertebrate life span by identifying the longevity-determining factors. Achieving these aims will identify pathways involving longevity and lay down foundations for understanding the mechanism by which these pathways act.