Bioenergetics, metabolism and lifespan in p66Shc-/- mice
p66Shc-/- 小鼠的生物能学、代谢和寿命
基本信息
- 批准号:8982208
- 负责人:
- 金额:$ 22.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-06-01 至
- 项目状态:未结题
- 来源:
- 关键词:Adipose tissueAge-MonthsAgingAmino AcidsAnimalsAttenuatedBiochemicalBioenergeticsBiological AssayBody CompositionBrown FatCaloric RestrictionCaloriesCarbohydratesCatabolismChronicComorbidityDiabetes MellitusDietDietary InterventionEnergy IntakeEnergy MetabolismEnvironmentEnzymesEpidemicExperimental DesignsFastingFatty acid glycerol estersGluconeogenesisGlycolysisHeartHigh Fat DietHumanHydrogen PeroxideInstructionInsulinInvestigationKetone BodiesKetonesKnock-outKnockout MiceLeadLifeLipidsLiverLongevityMeasurementMeasuresMetabolicMetabolismMicroarray AnalysisMitochondriaModificationMusMutant Strains MiceMutationMyocardiumObesityOutcomePlayProductionProteinsResistanceRoleSkeletal MuscleStem cellsStressSucroseTestingTimeTissuesTranslatingWeight GainWild Type Mouseage relatedbasecombatdietary restrictionenzyme activityenzyme pathwayfatty acid oxidationfeedinghealthy agingketogenesismimeticsoxidationp66(ShcA) proteinprogramsprotein expressionresistance mechanismrespiratoryresponseself-renewalstem cell differentiation
项目摘要
In the preceding period, the program project has shown that deficiency in She proteins strongly alters metabolism, decreases adiposity and increases survival on a high-fat diet, and increases stress resistance and median longevity on a calorie-restricted (CR) diet. The metabolic shift in She-deficient mice strongly resembles that observed in CR animals, and consistently. She expression is decreased in fasting animals. Thus, She-deficiency appears to be a CR-mimetic. In both Shc-deflcient and CR mice there is increased capacity for fatty acid oxidation, ketogenesis, ketone body catabolism, gluconeogenesis, and amino acid catabolism, while capacity for glycolysis is decreased. She mutant mice have decreased She levels as a consequence of mutation, and CR also causes decreased levels of She proteins. She proteins may play an important role in transitioning from the fed to fasted state. In particular, the program will pursue the hypothesis that decreases in She proteins in tissues, such as skeletal muscle and liver, are needed for animals to properly adapt to dietary conditions which require a sustained increase in fatty acid oxidation (CR, low-carbohydrate diets, high-fat/high-carbohydrate diets, etc.), and it is under these conditions that the influence of Shc on lifespan is most noticeable. Thus, the aims of this project are focused on determining the influence of She proteins on the metabolic response to high-fat/high-carbohydrate diets, the role She based modifications play in the metabolic response to CR, and whether or not a diet (low-carbohydrate) that induces chronic increases in capacity for P-oxidation, ketone body metabolism and gluconeogenesis can mirror the effects of CR and decreased She levels. The three Specific Aims of this subproject are to (1) determine the mechanism for resistance to weight gain in p66Shc-/- mice on a high-fat/high-carbohydrate diet; (2) determine if low-carbohydrate the metabolic response to sustained CR is altered in p66Shc-/- mice; and (3) determine diets can mimic the metabolic changes observed in the p66Shc-/- mice and increase life span. The proposed studies will provide new information about the influence of She proteins on energy metabolism and life oxidation. span in animals consuming diets which require sustained increases in fatty acid oxidation.
在之前的一段时间里,该项目已经表明,缺乏SHE蛋白会强烈改变新陈代谢,减少肥胖,增加高脂肪饮食的存活率,并提高卡路里限制(CR)饮食的抗应激能力和平均寿命。缺乏SHE的小鼠的代谢变化与CR动物的代谢变化非常相似,而且是一致的。在禁食动物中,SHE的表达减少。因此,SHE缺乏症似乎是一种CR拟态。缺糖小鼠和完全缓解小鼠的脂肪酸氧化、酮体生成、酮体分解代谢、糖异生和氨基酸分解代谢能力均增强,而糖酵解能力降低。由于突变,SHE突变小鼠的SHE水平降低,而CR也导致SHE蛋白水平下降。SHE蛋白可能在从进食状态向禁食状态的转变过程中发挥重要作用。特别是,该计划将追求这样的假设,即动物需要适当地适应要求脂肪酸氧化持续增加的饮食条件(CR、低碳水化合物饮食、高脂肪/高碳水化合物饮食等),而在这些条件下,Shc对寿命的影响最明显。因此,本项目的目标集中在确定SHE蛋白对高脂肪/高碳水化合物饮食的代谢反应的影响,基于SHE的修饰在对CR的代谢反应中所起的作用,以及诱导P-氧化能力、酮体代谢和糖异生能力的慢性增加的饮食(低碳水化合物)是否能反映CR的效果和降低的SHE水平。这个子项目的三个具体目标是:(1)确定高脂肪/高碳水化合物饮食的p66Shc-/-小鼠抵抗体重增加的机制;(2)确定低碳水化合物饮食是否会改变p66Shc-/-小鼠对持续CR的代谢反应;以及(3)确定饮食是否可以模拟p66Shc-/-小鼠观察到的代谢变化,并延长寿命。拟议的研究将提供关于SHE蛋白对能量代谢和生命氧化的影响的新信息。在食用需要持续增加脂肪酸氧化的饮食的动物中。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JON J. RAMSEY其他文献
JON J. RAMSEY的其他文献
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{{ truncateString('JON J. RAMSEY', 18)}}的其他基金
Ketone ester diet to ameliorate age-related decline in memory and muscle mass
酮酯饮食可改善与年龄相关的记忆力和肌肉质量下降
- 批准号:
10360505 - 财政年份:2021
- 资助金额:
$ 22.19万 - 项目类别:
Optimizing ketogenic diet strategies to increase health span and longevity
优化生酮饮食策略以延长健康寿命和寿命
- 批准号:
10398865 - 财政年份:2019
- 资助金额:
$ 22.19万 - 项目类别:
Optimizing ketogenic diet strategies to increase health span and longevity
优化生酮饮食策略以延长健康寿命和寿命
- 批准号:
10153627 - 财政年份:2019
- 资助金额:
$ 22.19万 - 项目类别:
Optimizing ketogenic diet strategies to increase health span and longevity
优化生酮饮食策略以延长健康寿命和寿命
- 批准号:
10685465 - 财政年份:2019
- 资助金额:
$ 22.19万 - 项目类别:
Bioenergetics, metabolism and lifespan in p66Shc-/- mice
p66Shc-/- 小鼠的生物能学、代谢和寿命
- 批准号:
8589542 - 财政年份:2007
- 资助金额:
$ 22.19万 - 项目类别:
Alterations in membrane composition and function eith calorie restriction
热量限制导致膜成分和功能发生变化
- 批准号:
7669199 - 财政年份:2007
- 资助金额:
$ 22.19万 - 项目类别:
Alterations in membrane composition and function eith calorie restriction
热量限制导致膜成分和功能发生变化
- 批准号:
7257544 - 财政年份:2007
- 资助金额:
$ 22.19万 - 项目类别:
Bioenergetics, metabolism and lifespan in p66Shc-/- mice
p66Shc-/- 小鼠的生物能学、代谢和寿命
- 批准号:
8461016 - 财政年份:2007
- 资助金额:
$ 22.19万 - 项目类别:
Alterations in membrane composition and function eith calorie restriction
热量限制导致膜成分和功能发生变化
- 批准号:
7496044 - 财政年份:2007
- 资助金额:
$ 22.19万 - 项目类别:
Alterations in membrane composition and function eith calorie restriction
热量限制导致膜成分和功能发生变化
- 批准号:
8127789 - 财政年份:2007
- 资助金额:
$ 22.19万 - 项目类别: