MOLECULAR BASIS OF SNELL DWARF AND LITTLE LONGEVITY

酵母、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是由基因控制的。线虫秀丽线虫提供了遗传和生化证据，确定了控制长寿的候选基因。这涉及到DAF-2、AGE-1和DAF-16基因的减弱，这些基因与哺乳动物胰岛素受体(INR)家族和信号通路的同源性表明，该途径(S)可能调节有利于脊椎动物长寿的代谢特征。小鼠矮小突变体Snell(dw/dw)、Ames(df/df)和Little(Lit/Lit)比它们的正常兄弟姐妹活得更长。矮生突变的性质，即生长激素(GH)、促甲状腺激素(TSH)和催乳素(PRL)缺乏，可能导致与长寿线虫突变体相似的生理特征。由于这些小鼠是唯一的脊椎动物长寿遗传模型，而且线虫和长寿矮小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。在这个研究项目中，我们将确定Snell和Lit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。特定的AIMS 1将确定Snell和LIT小鼠是否表现出延迟衰老的特征，如由于生长激素、胰岛素和IGF-I缺乏而导致的功能减退表型；免疫功能；以及应激反应基因的调节。在特定目标2中，我们计划使用内分泌补充来确定TH和PR1缺乏作为长寿决定因素的特定作用；在特定目标3中，我们将使用条件转基因Snell侏儒和LIT小鼠来确定GH缺乏在长寿中的作用，在这些小鼠中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决定寿命的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与长寿有关的途径，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.