Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment

针对年龄相关血管认知障碍的脂肪组织生热作用

• 批准号: 10674854
• 负责人: Priya Balasubramanian
• 金额: $ 11.93万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674854
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Agonists; Affect; Aging; Alzheimer' s disease related dementia; Angiography; Attenuated; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Brown Fat; Capillary Permeability; Caring; Cerebrovascular Circulation; Chronic; Circulation; Cognition; Cognitive; Custom; Data; Data Science; Disease; Elderly; Endothelial Cells; Endothelium; Expenditure; FGF21 gene; Functional disorder; Future; Health; Human; Impaired cognition; Impairment; Incidence; Inflammation; Interdisciplinary Study; Intervention; Laser Speckle Imaging; Lead; Link; Lipids; Longevity; Mediating; Mediator; Mentored Research Scientist Development Award; Metabolic; Metabolic dysfunction; Metabolism; Modeling; Mus; Neurons; Nitric Oxide; Optical Coherence Tomography; Outcome; Parabiosis; Pathologic; Pathway interactions; Persons; Phenotype; Play; Prevention; Process; Production; Rejuvenation; Reporting; Research; Role; Signal Transduction; Structure; Synapses; Techniques; Therapeutic; Thermogenesis; Tissues; Vascular Cognitive Impairment; Vascular Endothelial Cell; Vascular Endothelium; Work; World Health Organization; adipokines; adiponectin; age related; aged; aging population; blood-brain barrier disruption; blood-brain barrier function; brain health; cerebral microvasculature; cerebrovascular; cerebrovascular health; cognitive performance; cost; density; design; endothelial dysfunction; experience; fibroblast growth factor 21; glucose metabolism; improved; inflammatory milieu; insulin sensitivity; lipid metabolism; lipidomics; negative affect; neuroinflammation; neurovascular; neurovascular coupling; novel; novel strategies; novel therapeutic intervention; pharmacologic; preservation; prevent; programs; response; skills; social; systemic inflammatory response; translational study; two photon microscopy; vascular cognitive impairment and dementia; vascular endothelial dysfunction

Project Summary/ Abstract More than 50 million people aged 65 and above suffer in vascular cognitive impairment and dementia (VCID). The incidence of VCID is projected to nearly triple by 2050, which will cost more than 2 trillion US dollars in health and social care expenditures. Yet, there are no interventions to treat or prevent cognitive decline in the elderly. Microvascular endothelial dysfunction is a critical contributor to age-related VCID. Functional alterations in the microvascular endothelial cells lead to neurovascular uncoupling responses, the lack of a critical process of adjustment of cerebral blood flow required to support neuronal activity. Further, structural alterations in endothelial cells negatively affect the integrity of blood-brain barrier (BBB), which leads to increased capillary permeability and neuroinflammation. Endothelial dysfunction also contributes to decreased capillary density leading to a reduction in basal CBF. These pathological changes in the endothelial phenotype precedes the onset of cognitive decline in aged humans, suggesting that interventions that maintain or restore cerebrovascular health would be effective for the prevention and treatment of age-related VCID. Adipose tissue plays a pivotal role in the interplay between metabolism and aging. Emerging evidence links increased thermogenesis in the adipose tissue with extended longevity. Activation of the thermogenic program results in remodeling of both white and brown adipose tissue marked by increased fuel utilization and insulin sensitivity. It also results in an overall improvement in systemic inflammatory milieu and a favorable adipokine profile, which could have beneficial effects on the aging cerebral microvasculature. Our preliminary studies provide prima facie evidence that activation of adipose tissue thermogenesis improves cerebromicrovascular function and positively impacts cognition in aged mice. However, the circulating mediators or the cerebromicrovascular mechanisms behind thermogenesis-mediated positive cognitive outcome in aging are not known. Our central hypothesis is that activation of thermogenic program corrects metabolic dysfunction and ameliorates systemic inflammation, thereby improving microvascular endothelial function and preserving cognitive integrity in aging. To address this hypothesis the following aims are proposed: Aim 1: Characterize thermogenesis- induced alterations in metabolic and inflammatory milieu in aging. The thermogenesis mediated alterations in adipose tissue secretome will have beneficial effects on overall metabolism and systemic inflammation in aging. Aim 2: Determine the impact of thermogenesis on microvascular endothelial structure and function in aging. Prolonged activation of thermogenesis can improve cerebrovascular function and structure in aging and lead to improved cognitive health. The successful completion of the proposed studies will identify novel strategies to counteract age-related VCID.

项目摘要/摘要 超过5000万65岁及以上的人在血管认知障碍和痴呆症（VCID）中遭受痛苦。 VCID的发病率预计到2050年将几乎三倍，这将花费超过200万亿美元 健康和社会护理支出。然而，没有干预措施可以治疗或预防认知能力下降 老年。微血管内皮功能障碍是与年龄相关的VCID的关键因素。功能改变 在微血管内皮细胞中导致神经血管解偶联反应，缺乏关键过程 支持神经元活性所需的脑血流。此外，结构性改变 内皮细胞对血脑屏障（BBB）的完整性产生负面影响，这导致毛细管增加 渗透性和神经炎症。内皮功能障碍也有助于毛细管密度降低 导致基础CBF减少。内皮表型中的这些病理变化先于 年龄人类认知能力下降的发作，表明维持或恢复脑血管的干预措施 健康将有效预防和治疗与年龄相关的VCID。脂肪组织起关键 在代谢和衰老之间的相互作用中的作用。新兴证据联系了增加的生物发生 脂肪组织具有延长的寿命。热程序的激活导致两种白色的重塑 和棕色脂肪组织以增加的燃料利用和胰岛素敏感性为标志。这也导致总体 改善系统性炎症环境和有利的脂肪因子概况，这可能具有有益的 对衰老脑微脉管系统的影响。我们的初步研究提供了表面证据 脂肪组织热发生的激活可改善脑血管功能，并积极影响 老年小鼠的认知。但是，循环介体或脑血管机制背后 热发生介导的衰老中的阳性认知结果尚不清楚。我们的中心假设是 热计划的激活纠正代谢功能障碍并改善全身性 炎症，从而改善微血管内皮功能并保持认知完整性 在衰老中。为了解决这一假设，提出了以下目的：目标1：表征热生成 - 诱导的衰老中代谢和炎症环境的改变。热发生介导的改变 在脂肪组织中，分泌组将对整体代谢和全身炎症产生有益的影响 老化。 AIM 2：确定热发生对微血管内皮结构的影响 衰老的功能。流量的长时间激活可以改善脑血管功能和结构 在衰老中，导致认知健康的改善。拟议研究的成功完成将确定 抵消与年龄有关的VCID的新型策略。