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: 10490299
• 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/10490299
• 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 Circulation; Blood Vessels; Blood capillaries; Brain; Brown Fat; Capillary Permeability; Caring; Cerebrovascular Circulation; Chronic; 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 of activation protein; Mentored Research Scientist Development Award; Metabolic; Metabolic dysfunction; Metabolism; Modeling; Mus; Neurons; Nitric Oxide; Optical Coherence Tomography; Outcome; Parabiosis; Pathologic; Pathway interactions; Persons; Pharmacology; Phenotype; Play; Prevention; Process; Production; Rejuvenation; Reporting; Research; Role; Signal Transduction; Structure; Synapses; Techniques; Therapeutic; Thermogenesis; Tissues; Vascular Cognitive Impairment; Work; World Health Organization; adipokines; adiponectin; age related; aged; aging population; base; blood-brain barrier disruption; blood-brain barrier function; brain health; cerebral microvasculature; cerebrovascular; cerebrovascular health; cognitive performance; cost; density; design; endothelial dysfunction; experience; glucose metabolism; improved; inflammatory milieu; insulin sensitivity; lipid metabolism; lipidomics; negative affect; neuroinflammation; neurovascular; neurovascular coupling; novel; novel strategies; novel therapeutic intervention; preservation; prevent; programs; response; skills; social; systemic inflammatory response; translational study; two photon microscopy; vascular cognitive impairment and dementia

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.

项目概要/摘要 超过 5000 万 65 岁及以上的人患有血管性认知障碍和痴呆症 (VCID)。 预计到 2050 年，VCID 的发病率将增加近两倍，这将导致超过 2 万亿美元的损失 健康和社会护理支出。然而，没有任何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导致年龄相关性 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，缺乏一个关键过程 支持神经元活动所需的脑血流量的调节。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，导致毛细血管扩张 通透性和神经炎症。内皮功能障碍也会导致毛细血管密度降低 导致基础CBF减少。内皮表型的这些病理变化先于 老年人认知能力下降，表明维持或恢复脑血管的干预措施 健康可有效预防和治疗与年龄相关的VCID。脂肪组织起着关键作用 在新陈代谢和衰老之间的相互作用中发挥作用。新出现的证据表明，体内产热作用增加 脂肪组织的寿命更长。产热程序的激活导致白色和白色的重塑 棕色脂肪组织的特征是燃料利用率和胰岛素敏感性增加。这也导致了整体 改善全身炎症环境和有利的脂肪因子特征，这可能具有有益的作用 对老化脑微血管的影响。我们的初步研究提供了初步证据表明 脂肪组织生热作用的激活可改善脑微血管功能并产生积极影响 老年小鼠的认知能力。然而，循环介质或背后的脑微血管机制 生热介导的衰老过程中的积极认知结果尚不清楚。我们的中心假设是 生热程序的激活可纠正代谢功能障碍并改善全身症状 炎症，从而改善微血管内皮功能并保持认知完整性 在老化中。为了解决这一假设，提出以下目标： 目标 1：描述生热作用的特征- 诱导衰老过程中代谢和炎症环境的改变。产热介导的改变 脂肪组织分泌蛋白组将对整体代谢和全身炎症产生有益影响 老化。目标 2：确定生热作用对微血管内皮结构和 具有抗衰老的功能。长期激活生热作用可改善脑血管功能和结构 衰老并改善认知健康。拟议研究的成功完成将确定 对抗与年龄相关的 VCID 的新策略。