Time restricted eating for prevention of age-related vascular cognitive decline in older adults

限制饮食时间以预防老年人与年龄相关的血管认知能力下降

• 批准号: 10739956
• 负责人: Stefano Tarantini
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739956
• 关键词: Address; Adherence; Affect; Age; Age Years; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animal Model; Attenuated; Biological Availability; Blood; Blood Vessels; Brain; Brain region; Caloric Restriction; Calories; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Communities; Consumption; Data; Deacetylation; Dementia; Development; Diet Habits; Dietary Intervention; Eating; Elderly; Endothelial Cells; Endothelium; Energy Intake; Fasting; Functional disorder; Goals; Health; Hour; Human; Hyperemia; Impaired cognition; Impairment; Individual; Inflammation; Intake; Intermittent fasting; Laser Speckle Imaging; Link; Literature; Longevity; Mediating; Mus; Neurons; Nutrient; Oxidative Stress; Oxygen; Participant; Pathogenesis; Pathway interactions; Performance; Peripheral; Play; Prevention; Prevention approach; Public Health; Publishing; Research; Role; SIRT1 gene; Series; Serum; Stimulus; Testing; Therapeutic Intervention; Time; Time-restricted feeding; Vascular Cognitive Impairment; Vascular Endothelium; Vascular blood supply; Vasodilation; age related; aged; anti aging; brain endothelial cell; cerebrovascular; cerebrovascular health; circulating biomarkers; clinically relevant; cognitive function; cognitive performance; cognitive testing; design; functional near infrared spectroscopy; high risk; human subject; improved; improved outcome; innovative technologies; lifestyle factors; lifestyle intervention; neurovascular; neurovascular coupling; novel therapeutic intervention; nutrition; pre-clinical; preservation; prevent; response; retina blood vessel structure; translational barrier

PROJECT SUMMARY/ABSTRACT Cognitive impairment associated with Alzheimer’s disease and Related Dementias (ADRD) and aging has emerged as one of the major public health challenges of our time. Recent clinical studies, as well as those in animal models, support that preservation of cognitive health depends on an adequate cerebral blood flow (CBF) supply to the active brain regions. Importantly, in the healthy, young brain cerebral blood supply is readily adjusted to meet the increased oxygen and nutrient demand of activated neurons. This homeostatic mechanism, termed "neurovascular coupling" (NVC) or "functional hyperemia", is required for normal brain function. Preclinical and clinical evidence shows that aging per se significantly impairs endothelium mediated NVC responses, which play a causal role in age- related vascular cognitive impairment (VCI) and the development of ADRD. Lifestyle factors, including nutrition and dietary habits, significantly affect cerebrovascular health and, thereby, influence the pathogenesis of age-related cognitive impairment and ADRD. Caloric restriction (CR), which exerts multifaceted anti-aging and lifespan-extending effects, has been demonstrated to be an effective nutritional intervention that can improve vascular health and cognitive function. CR activates SIRT1-dependent pathways in the vasculature, which attenuates cellular oxidative stress and rescues endothelial vasodilation. However, adherence to CR remains a challenge and a translational barrier as most humans may not be able, or willing, to reduce their caloric intake by 30% over extended periods of time. Intermittent fasting can recapitulate the benefits of CR without limiting calorie intake in older adults. Time restricted eating (TRE) is considered the best approach to intermittent fasting for elderly individuals as it allows consumption of required calories within a condensed daily eating window (4-10 hours), resulting in the greatest fasting stimulus without a net reduction in calorie intake. Yet, the impact of TRE on cerebrovascular function and, potentially the delay of ADRD and age-related VCI, to preserve cognition is currently unknown. Our central hypothesis is that closer adherence to TRE will improve NVC responses and micro- and macrovascular endothelial function, potentially through activation of SIRT1-dependent vasoprotective pathways, resulting in the improvement of cognitive performance. This hypothesis will be tested by assessing the effects of TRE (10 hours eating window) in community dwelling older adults (55-80 years of age) in a 6-month study. Aim 1 will determine the impact of TRE on NVC responses using innovative technologies such as functional near-infrared spectroscopy (fNIRS) and dynamic retinal vessel analysis (DVA), and on microvascular endothelial function using laser speckle contrast imaging and flow-mediated dilation approaches in community dwelling older adults. Aim 2 will determine the impact of TRE on circulating biomarkers and cerebromicrovascular endothelial cell SIRT1 activity.

项目概要/摘要 与阿尔茨海默氏病和相关痴呆症 (ADRD) 以及衰老相关的认知障碍 已成为我们这个时代的主要公共卫生挑战之一。最近的临床研究以及动物研究 模型，支持认知健康的保持取决于充足的脑血流量（CBF）供应 活跃的大脑区域。重要的是，在健康、年轻的大脑中，脑供血很容易调整以满足 激活神经元的氧气和营养需求增加。这种稳态机制被称为“神经血管 耦合”（NVC）或“功能性充血”是正常脑功能所必需的。临床前和临床证据 研究表明，衰老本身会显着损害内皮介导的 NVC 反应，而这在年龄增长中起着因果作用。 相关的血管性认知障碍（VCI）和 ADRD 的发展。 生活方式因素，包括营养和饮食习惯，显着影响脑血管健康，从而 影响年龄相关认知障碍和 ADRD 的发病机制。热量限制 (CR) 多方面的抗衰老和延长寿命的功效，已被证明是一种有效的营养品 可以改善血管健康和认知功能的干预措施。 CR 激活 SIRT1 依赖性通路 血管系统，减轻细胞氧化应激并挽救内皮血管舒张。然而，坚持 CR 仍然是一个挑战和转化障碍，因为大多数人可能无法或不愿意减少热量 长期摄入量减少 30%。间歇性禁食可以概括 CR 的好处而不限制 老年人的卡路里摄入量。限时饮食（TRE）被认为是间歇性禁食的最佳方法 老年人，因为它允许在浓缩的每日饮食窗口（4-10小时）内消耗所需的卡路里， 产生最大的禁食刺激，而不会净减少卡路里摄入量。然而，TRE 对 脑血管功能，并可能延迟 ADRD 和与年龄相关的 VCI，以保持认知，目前是 未知。 我们的中心假设是，更严格地遵守 TRE 将改善 NVC 反应以及微观和 大血管内皮功能，可能通过激活 SIRT1 依赖性血管保护途径， 从而提高认知能力。该假设将通过评估以下因素的影响来检验： 在一项为期 6 个月的研究中，针对社区居住的老年人（55-80 岁）进行了 TRE（10 小时进食窗口）。目标1将 使用功能性近红外等创新技术确定 TRE 对 NVC 反应的影响 光谱（fNIRS）和动态视网膜血管分析（DVA），以及使用微血管内皮功能 社区居住老年人的激光散斑对比成像和血流介导的扩张方法。目标2将 确定 TRE 对循环生物标志物和脑微血管内皮细胞 SIRT1 活性的影响。