Aging at Thermoneutral Temperature

 描述（由申请人提供）：尽管代谢率对寿命的影响已经研究和争论了几十年，但能量代谢的不同参数与衰老过程之间的因果关系知之甚少，存在争议。低血压艾姆斯侏儒（Prop 1df）小鼠和生长激素受体缺失（GHRKO）小鼠寿命显著延长，并表现出延迟、缓慢和健康衰老的许多特征。这些突变体所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体重或瘦体重的耗氧量（VO 2）增加和呼吸商（RQ =呼吸交换率，RER）降低，表明对脂质作为代谢燃料的依赖性增加。有趣的是，在适应热中性温度24小时后，艾姆斯侏儒和GHRKO小鼠的VO 2增加和RQ减少消失或严重减弱。从这些新的发现中，我们怀疑这些小型突变体中热量损失的增加以及随之而来的产热能量需求的增加会诱导能量代谢的改变（VO 2和脂肪酸β氧化增加; RQ降低），从而促进延迟，健康衰老和延长寿命。我们假设，长期暴露于热中性温度的艾姆斯侏儒和GHRKO小鼠将加速老化，减少或消除其寿命优势。我们进一步假设，通过暴露于降低的环境温度，在遗传正常（“野生型”）动物中的生热作用的慢性激活将诱导与GH相关突变体中观察到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率。作为检验这些假设的第一步，我们将确定与延迟衰老相关的特征是否通过长寿突变动物长期（数周至数月）暴露于热中性环境而正常化，以及它们是否可以通过正常动物长期暴露于降低的环境温度而诱导。提出了两个具体目标。具体目标1。为了确定成年艾姆斯侏儒和GHRKO小鼠长期暴露于热中性环境温度（30°C）是否将拯救（正常化）能量代谢（如通过测量V02、RQ所评估的）、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中的线粒体解偶联、代谢、炎症、胰岛素和mTOR信号传导相关的基因的表达。具体目标2。确定来自相同品系的成年正常（“野生型”）小鼠长期暴露于降低的环境温度（17°C）是否会诱导产热、能量代谢、葡萄糖稳态、脂肪因子水平和选定基因表达的改变，这些改变与暴露于标准动物室温（23°C）的长寿GH相关突变体中观察到的改变相似。

 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).