Aging at Thermoneutral Temperature

 描述(申请人提供)：虽然代谢率对寿命的影响已经研究和辩论了几十年，但不同能量代谢参数与衰老过程之间的因果关系尚不清楚，也存在争议。下丘脑型Ames侏儒(Prop1df)和生长激素受体缺失(GHRKO)小鼠寿命显著延长，表现出延缓、减慢和健康衰老的许多特征。这些突变体共有的许多表型特征被认为代表了延长寿命的机制。这些特征包括每克总或瘦体重的氧耗(VO2)增加和呼吸商(RQ=呼吸交换比，RER)降低，这表明对作为代谢燃料的脂质的依赖增加。有趣的是，Ames侏儒和GHRKO小鼠的VO2增加和RQ减少在适应中温24小时后消失或严重减弱。从这些新的发现，我们怀疑，增加的热量损失和随之而来的热量需求的增加，在这些微小的突变导致能量代谢的变化(增加VO2和脂肪酸β氧化；降低RQ)，促进延迟，健康的衰老和延长寿命。我们假设，Ames、侏儒和GHRKO小鼠长期暴露在中温下会加速衰老，减少或消除它们的长寿优势。我们进一步假设，通过暴露在环境温度降低的环境中，遗传正常(“野生型”)动物的产热慢性激活将诱导与生长激素相关突变体中的延迟衰老和延长寿命相关的代谢特征，从而导致较慢的衰老速度。作为检验这些假说的第一步，我们将确定与延迟衰老相关的特征是否通过延长(几周到几个月)长寿命突变动物暴露在中温环境中而正常化，以及是否可以通过延长正常动物暴露在降低环境温度下来诱导它们。提出了两个具体目标。具体目的1.确定成年Ames侏儒和GHRKO小鼠长期暴露于中温环境温度(30℃)是否会挽救(正常化)能量代谢(通过测量V02、RQ)、葡萄糖稳态、循环脂联素、IL-6和脂质水平以及与棕色和白色脂肪组织线粒体解偶联、代谢、炎症、胰岛素和mTOR信号相关的基因表达。具体目的2.确定相同品系的成年正常(“野生型”)小鼠长期暴露于较低的环境温度(17℃)是否会导致产热、能量代谢、葡萄糖稳态、脂肪因子水平和选定基因的表达发生变化，这些基因与长期处于标准动物室温(23℃)下的生长激素相关突变体中观察到的基因相似。

 DESCRIPTION (provided by applicant): Although the influence of metabolic rate on longevity has been studied and debated for decades, the cause:effect relationship between different parameters of energy metabolism and the process of aging is poorly understood and controversial. Hypopituitary Ames dwarf (Prop1df) mice and growth hormone receptor deleted (GHRKO) mice are remarkably long-lived and exhibit many features of delayed, slower and healthy aging. Many phenotypic characteristics shared by these mutants are believed to represent mechanisms of extended longevity. These characteristics include increased oxygen consumption (VO2) per gram of total or lean body mass and reduced respiratory quotient (RQ = respiratory exchange ratio, RER), indicative of increased reliance on lipids as metabolic fuel. Intriguingly, the increase in VO2 and the reduction in RQ in Ames dwarf and GHRKO mice disappear or are severely attenuated after 24 hours of acclimation to thermoneutral temperature. From these novel findings, we suspect that increased heat loss and the consequent increase in energy demand for thermogenesis in these diminutive mutants induce alterations in energy metabolism (increased VO2 and fatty acids β oxidation; reduced RQ) that promote delayed, healthy aging and extended longevity. We hypothesize that chronic exposure of Ames dwarf and GHRKO mice to thermoneutral temperature will accelerate aging and reduce or eliminate their longevity advantage. We further hypothesize that chronic activation of thermogenesis in genetically normal ("wild type") animals by exposure to reduced environmental temperature will induce metabolic characteristics that are associated with the delayed aging and extended longevity seen in GH-related mutants and thus lead to a slower rate of aging. As the first step in testing these hypotheses, we will determine whether characteristics associated with delayed aging are normalized by extended (weeks to months) exposure of long-lived mutant animals to thermoneutral environment and whether they can be induced by extended exposure of normal animals to reduced environmental temperature. Two Specific Aims are proposed. Specific Aim 1. To determine whether chronic exposure of adult Ames dwarf and GHRKO mice to thermoneutral ambient temperature (30°C) will rescue (normalize) energy metabolism (as assessed by measurements of V02, RQ), glucose homeostasis, circulating adiponectin, IL-6 and lipid levels and expression of genes related to mitochondrial uncoupling in brown and white adipose tissue, metabolism, inflammation, insulin and mTOR signaling. Specific Aim 2. To determine whether chronic exposure of adult normal ("wild type") mice from the same strains to reduced environmental temperature (17°C) will induce alterations in thermogenesis, energy metabolism, glucose homeostasis, adipokine levels and expression of selected genes resembling those observed in long-lived GH-related mutants exposed to standard animal room temperature (23°C).