Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment

项目摘要/摘要 超过5000万65岁及以上的人患有血管认知障碍和痴呆症(VCID)。 预计到2050年，VCID的发病率将增加近两倍，这将花费超过2万亿美元 医疗和社会保健支出。然而，目前还没有治疗或预防认知功能减退的干预措施。 老年人。微血管内皮细胞功能障碍是年龄相关性VCID的重要因素。功能改变 在微血管内皮细胞导致神经血管解偶联反应时，缺乏一个关键过程 支持神经元活动所需的脑血流量调节。此外，中国的结构性变化 内皮细胞对血脑屏障(BBB)的完整性产生负面影响，从而导致毛细血管增多 渗透性和神经炎症。内皮功能障碍也是导致毛细血管密度下降的原因之一 导致基础脑血流量下降。这些内皮细胞表型的病理变化先于 老年人认知功能衰退的发病，提示维持或恢复脑血管的干预措施 健康将是预防和治疗年龄相关性VCID的有效手段。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的作用。新出现的证据表明， 延长寿命的脂肪组织。产热程序的激活导致两个白色的重塑 棕色脂肪组织，以燃料利用率和胰岛素敏感性增加为标志。它还导致了一个整体 全身炎症环境的改善和有利的脂肪因子谱，这可能是有益的 对衰老的脑微血管系统的影响。我们的初步研究提供了初步证据 激活脂肪组织生热改善脑微血管功能并产生积极影响 衰老小鼠的认知功能。然而，循环介质或背后的脑微血管机制 生热作用介导的积极认知结果在衰老中尚不清楚。我们的中心假设是 激活生热程序纠正代谢功能障碍并改善全身 炎症，从而改善微血管内皮功能并保持认知完整性 在衰老过程中。为了解决这一假设，提出了以下目标：目标1：表征生热作用-- 在衰老过程中引起代谢和炎症环境的改变。生热作用引起的变化 在脂肪组织中，分泌体将对整体代谢和全身炎症产生有益的影响 衰老。目的2：确定生热对微血管内皮细胞结构的影响。 在衰老中起作用。长时间生热可改善脑血管功能和结构 在衰老和导致认知健康的改善。成功完成拟议的研究将确定 对抗与年龄相关的VCID的新策略。

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.