Vasoprotection by Caloric Restriction Mimetics in Aging

衰老过程中热量限制模拟物的血管保护作用

• 批准号: 8146105
• 负责人: Anna Csiszar
• 金额: $ 17.28万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146105
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Animal Feed; Animals; Antioxidants; Aorta; Apoptosis; Apoptotic; Arteries; Attention; Attenuated; Behavioral; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Caloric Restriction; Carbon Dioxide; Cells; Cerebrovascular Circulation; Cerebrum; Characteristics; Cognitive; Complex; Data; Dementia; Diet; Disease; Drug Metabolic Detoxication; Elderly; Endothelial Cells; Exhibits; Free Radicals; Functional disorder; Genes; Genetic; Goals; Healthcare Systems; Hippocampus (Brain); Homeostasis; Hypoxia; Impaired cognition; Impairment; Inflammation; Injury; Intervention; K-Series Research Career Programs; Learning; Liver; Longevity; Mammals; Mediating; Mediation; Medical; Memory; Metabolic; Modeling; Molecular Target; Mus; NF-E2-related factor 2; Names; Neurocognitive; Neurons; Oklahoma; Organ; Oxidation-Reduction; Oxidative Stress; Pathologic Processes; Pathway interactions; Performance; Phenotype; Physiology; Play; Production; Proteins; Publishing; Quality of life; Regimen; Regional Blood Flow; Regulation; Resistance; Resveratrol; Risk; Role; Role Concepts; Seminal; Serum; Societies; Stroke; Structure; Sulforaphane; System; Testing; Training; Tube; Up-Regulation; Vascular System; Vascular blood supply; Wild Type Mouse; age related; aged; aging brain; angiogenesis; capillary; cerebrovascular; cognitive function; density; design; dietary restriction; feeding; improved; middle age; migration; mimetics; novel; novel strategies; older patient; prevent; protective effect; public health relevance; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): This is Beeson Career Development Award application designed to provide Dr. Anna Csiszar with additional training related to neurocognitive function at the Reynolds Oklahoma Center on Aging. Dr. Csiszar is an outstanding, well published candidate and the additional training will provide expertise in behavioral analyses, neurostereology, and cerebrovascular analyses necessary for her to achieve independence. Cognitive function decreases with age even in the absence of overt pathological processes. This decline in cognitive function clearly diminishes quality of life, is a major factor in loss of independence, and imparts a costly burden to society as a whole and to the medical health care system in particular. Previous studies demonstrated that age-related cerebrovascular rarefaction and microvascular dysfunction impair hippocampal blood flow, which has an etiologic role in cognitive decline during aging. The goal of this proposal is to identify key cellular mechanisms that can be targeted therapeutically to prevent/reverse age-related cerebral microvascular alterations maintaining normal hippocampal blood flow and protecting neurocognitive function. The direction and hypotheses of this application emerge from key findings that caloric restriction (CR) and the CR mimetic resveratrol have the potential to beneficially impact vascular physiology in aged mammals. We propose to test the hypothesis that caloric restriction protects the cerebral microvasculature from the deleterious effects of oxidative stress associated with aging, via induction of the Nrf2/ARE- regulated ROS detoxification systems. We posit that pharmacological activation of this pathway in endothelial cells (with resveratrol or sulforaphane) mimics the effects of caloric restriction, which contribute significantly to an intervention strategy for protection of neurocognitive function during aging. The following aims are proposed: 1) Assess whether CR and CR mimetics can delay/prevent the age-associated decline in cerebral regional blood flow, the reduction in capillary and arteriolar density and angiogenesis, and the decline in spatial learning and memory and determine whether genetic depletion of Nrf2 abrogates the microvascular protective effects of CR and resveratrol treatment. 2) Determine whether CR and CR mimetics can delay/prevent age-associated microvascular oxidative stress and impairment of local vasoregulatory mechanisms via induction of Nrf2/ARE-dependent antioxidant systems. 3) Determine whether systemic factors induced by CR in aged animals confer anti-oxidative, anti-apoptotic and pro-angiogenic effects on cerebral microvascular endothelial cells. Cultured endothelial cells will be treated with sera from ad libitum or CR fed animals and cellular ROS production, angiogenic potential and resistance to oxidative stress-induced apoptosis will be assessed. The role of Nrf2 activation in the protective effects of CR sera treatment will be elucidated. The proposed studies will provide the first comprehensive analysis of the role of the Nrf2/ARE pathway in maintaining a youthful cerebral microvascular phenotype during CR and will provide novel and definitive information on novel approaches to prevent/reverse cerebrovascular dysfunction and functional changes in the brain with age that are precursors to age-related disease, loss of cognitive function and the increased risk of dementia. PUBLIC HEALTH RELEVANCE: A decline in cognitive function clearly diminishes quality of life, is a major factor in loss of independence, and imparts a costly burden to society as a whole and to the medical health care system in particular. The age-related impairment of cerebral blood supply significantly contributes to cognitive decline in the elderly. The goal of this project is to identify novel molecular targets that can be activated pharmacologically to protect the cerebral blood vessels from free radical mediated injury and thus to improve cerebral blood flow and cognitive function in elderly patients. We will test the hypotheses that in the vascular system a protein named Nrf2 mediates multifaceted vasoprotective effects. We posit that treatment with Nrf2-activating molecules, or inducing Nrf2 by dietary restriction can exert significant cerebral vasoprotective effects protecting cognitive function in aged mice.

描述（由申请人提供）：这是 Beeson 职业发展奖申请，旨在为 Anna Csiszar 博士在俄克拉荷马州雷诺兹老龄化中心提供与神经认知功能相关的额外培训。 Csiszar 博士是一位杰出的、发表了大量论文的候选人，额外的培训将提供她实现独立所需的行为分析、神经立体学和脑血管分析方面的专业知识。即使没有明显的病理过程，认知功能也会随着年龄的增长而下降。认知功能的下降明显降低了生活质量，是失去独立性的一个主要因素，并给整个社会，特别是医疗保健系统带来了高昂的负担。先前的研究表明，与年龄相关的脑血管稀疏和微血管功能障碍会损害海马血流，这在衰老过程中认知能力下降中起着病因作用。该提案的目标是确定可进行治疗的关键细胞机制，以预防/逆转与年龄相关的脑微血管改变，维持正常的海马血流并保护神经认知功能。该应用的方向和假设源于以下重要发现：热量限制 (CR) 和 CR 模拟白藜芦醇有可能对老年哺乳动物的血管生理学产生有益影响。我们建议测试以下假设：热量限制通过诱导 Nrf2/ARE 调节的 ROS 解毒系统，保护脑微血管免受与衰老相关的氧化应激的有害影响。我们假设内皮细胞中该通路的药理学激活（使用白藜芦醇或萝卜硫素）模拟了热量限制的效果，这对保护衰老过程中的神经认知功能的干预策略做出了重大贡献。提出以下目标：1) 评估 CR 和 CR 模拟物是否可以延迟/预防与年龄相关的脑区域血流量下降、毛细血管和小动脉密度和血管生成的减少以及空间学习和记忆的下降，并确定 Nrf2 的遗传耗竭是否会消除 CR 和白藜芦醇治疗的微血管保护作用。 2)确定CR和CR模拟物是否可以通过诱导Nrf2/ARE依赖的抗氧化系统来延迟/预防与年龄相关的微血管氧化应激和局部血管调节机制的损伤。 3)确定老年动物CR诱导的全身因素是否对脑微血管内皮细胞产生抗氧化、抗凋亡和促血管生成作用。将用来自随意或 CR 喂养的动物的血清处理培养的内皮细胞，并评估细胞 ROS 的产生、血管生成潜力和对氧化应激诱导的细胞凋亡的抵抗力。将阐明 Nrf2 激活在 CR 血清治疗的保护作用中的作用。拟议的研究将首次全面分析 Nrf2/ARE 通路在 CR 期间维持年轻脑微血管表型中的作用，并将提供有关预防/逆转脑血管功能障碍和随年龄增长而发生的脑功能变化的新方法的新颖且明确的信息，这些变化是与年龄相关的疾病、认知功能丧失和痴呆风险增加的先兆。 公共卫生相关性：认知功能下降明显会降低生活质量，是失去独立性的一个主要因素，并给整个社会，特别是医疗保健系统带来高昂的负担。与年龄相关的脑供血障碍显着导致老年人认知能力下降。该项目的目标是确定可以通过药理学激活的新分子靶点，以保护脑血管免受自由基介导的损伤，从而改善老年患者的脑血流量和认知功能。我们将测试以下假设：在血管系统中，一种名为 Nrf2 的蛋白质介导多方面的血管保护作用。我们假设用 Nrf2 激活分子治疗或通过饮食限制诱导 Nrf2 可以发挥显着的脑血管保护作用，保护老年小鼠的认知功能。