Aging at Thermoneutral Temperature

热中性温度下的老化

• 批准号: 9267894
• 负责人: Andrzej Bartke
• 金额: $ 18.62万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267894
• 关键词: Acclimatization; Address; Adipose tissue; Adult; Aging; Aging-Related Process; Animals; Attenuated; Brown Fat; Characteristics; Chronic; Developing Countries; Disease; Energy Metabolism; Environment; Exhibits; Exposure to; FRAP1 gene; Fatty Acids; Food Energy; Gene Expression; Genes; Glucose; Growth Hormone Receptor; Health; Heat Losses; Hepatic; Hour; Hypopituitarism; Incidence; Indirect Calorimetry; Inflammation; Inherited; Insulin; Interleukin-6; Lead; Lipids; Liver; Longevity; Measurement; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modernization; Mus; Oxygen Consumption; Phenotype; Physical activity; Prolactin; Resistance; Role; Signal Transduction; Somatotropin; Temperature; Testing; Thermogenesis; Thyrotropin; Wild Type Mouse; adipokines; adiponectin; blood glucose regulation; fatty acid oxidation; healthy aging; improved; lean body mass; longevity gene; metabolic rate; mutant; novel; oxidation; oxidative damage; public health relevance; respiratory; trend

 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).

 描述（由申请人提供）：尽管代谢率对寿命的影响已被研究和争论了数十年，但不同能量代谢参数与衰老过程之间的因果关系却知之甚少且存在争议。垂体垂体艾姆斯侏儒 (Prop1df) 小鼠和生长激素受体缺失 (GHRKO) 小鼠的寿命非常长，并且表现出延迟、缓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体重或去脂体重的耗氧量 (VO2) 增加和呼吸商 (RQ = 呼吸交换比，RER) 减少，表明对脂质作为代谢燃料的依赖增加。有趣的是，Ames 侏儒小鼠和 GHRKO 小鼠的摄氧量增加和 RQ 减少在适应热中性温度 24 小时后消失或严重减弱。从这些新发现中，我们怀疑这些小型突变体中热量损失的增加以及产热所需能量的增加会导致能量代谢的改变（VO2 和脂肪酸 β 氧化增加；RQ ​​减少），从而促进延迟、健康的衰老和延长寿命。我们假设艾姆斯侏儒小鼠和 GHRKO 小鼠长期暴露于热中性温度会加速衰老并减少或消除它们的长寿优势。我们进一步假设，遗传正常（“野生型”）动物通过暴露于降低的环境温度而长期激活生热作用，将诱导与 GH 相关突变体中所见的延迟衰老和延长寿命相关的代谢特征，从而导致衰老速度减慢。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可以通过将长寿突变动物长期（数周至数月）暴露在热中性环境中而正常化，以及是否可以通过将正常动物长期暴露在降低的环境温度中来诱导。提出了两个具体目标。具体目标 1. 确定成年艾姆斯矮人和 GHRKO 小鼠长期暴露于热中性环境温度 (30°C) 是否会恢复（正常化）能量代谢（通过测量 V02、RQ 进行评估）、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线粒体解偶联相关的基因表达 脂肪组织、代谢、炎症、胰岛素和 mTOR 信号传导。具体目标 2. 确定同一品系的成年正常（“野生型”）小鼠长期暴露于降低的环境温度（17°C）是否会引起生热作用、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，类似于暴露于标准动物室温（23°C）的长寿命 GH 相关突变体中观察到的变化。