Effects of NAD restoration on neurovascular coupling in community dwelling older adults

NAD 恢复对社区老年人神经血管耦合的影响

基本信息

批准号：
10681463
负责人：
Aikaterini Thanou
金额：
$ 60.92万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681463
关键词：
Address Age Age Years Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Animal Model Animals Attenuated Blood Cells Blood Vessels Brain Brain region Cerebrovascular Circulation Circulation Clinical Clinical Research Clinical Trials Communities Data Dementia Development Double-Blind Method Elderly Endothelium Enzymes Etiology Functional disorder Human Hyperemia Impaired cognition Impairment Individual Intervention Laboratories Laser Speckle Imaging Link Literature Measures Mediating Metabolic Mus NADH Neurocognitive Neurons Nicotinamide adenine dinucleotide Nutrient Oral Oxygen Participant Pathology Pattern Peripheral Pharmacological Treatment Placebo Control Placebos Process Production Public Health Publishing Randomized Reactive Oxygen Species Reporting Research Research Design Retina Role Sampling Self Administration Series Serum Supplementation Testing Time United States National Institutes of Health Vascular Cognitive Impairment Vascular Diseases Vascular Endothelium Vascular blood supply Whole Blood Withdrawal age related aged arteriole brain endothelial cell cell age cerebral microvasculature clinically relevant cognitive function cognitive performance design effective therapy endothelial dysfunction extracellular functional near infrared spectroscopy improved juvenile animal metabolomics middle age neurovascular neurovascular coupling nicotinamide riboside supplementation nicotinamide-beta-riboside normal aging pre-clinical preclinical study preservation prevent response restoration retina blood vessel structure tool treatment effect

项目摘要

Age-related cognitive decline has emerged as one of the major public health challenges of our time. It is well known that normal cognitive function requires an adequate blood supply to support neuronal activity. In the healthy young brain, cerebral blood flow is rapidly adjusted to meet the increased oxygen and nutrient demands of active brain regions via a homeostatic mechanism known as neurovascular coupling (NVC, or functional hyperemia). Preclinical and clinical studies demonstrate that NVC is impaired in normal aging, and experimentally induced impairment of NVC responses in young animals results in cognitive impairment. Restoration of NVC in these animals by targeted pharmacological treatments improves cognitive function. Testing specific interventions in humans that have demonstrated efficacy in animal models is a reasonable and prudent approach that may improve impaired NVC and may be the key to developing effective therapies to reverse or prevent age-related cognitive decline and Alzheimer’s Disease/ Alzheimer’s Disease related dementias (AD/ADRD) in older adults. Endothelial dysfunction and impairment of NVC responses have been associated with increases in the production of reactive oxygen species (ROS) that are one of the well-defined ‘Hallmarks of Aging’. Nicotinamide Adenine Dinucleotide (NAD) is one of the major regulators of ROS and has been shown to attenuate ROS production. Our preliminary studies indicate that NAD levels are profoundly reduced in brain vascular endothelial cells of aged mice and that restoration of NAD levels in normal aged mice (equivalent of ≥60 years of age in humans) using an NAD precursor rescues age-related endothelial dysfunction, restores NVC responses and attenuates cognitive decline. Age-related NAD depletion, endothelial dysfunction, and impaired NVC responses are observed in older adults even in the absence of predisposing vascular pathology. Although supplementation with the NAD precursor, nicotinamide riboside (NR), has been reported to increase blood cell NAD levels in humans, effects on endothelial function and NVC responses have not been investigated. Addressing this scientific gap is essential to further develop our understanding of the etiology of NVC impairment and establish its role in the genesis of cognitive decline in aging and AD/ADRD. Our central hypothesis is that restoration of NAD levels with NR in older adults will improve NVC responses and micro- and macrovascular endothelial function. This hypothesis will be tested by assessing the effects of treatment with oral NR (1g/day per os for 8 weeks) or placebo (8 weeks) in community dwelling older adults (60-85 years of age) in a randomized, double-blinded, placebo-controlled, parallel study design. These studies will determine whether NR supplementation alleviates endothelial and neurovascular dysfunction and, potentially, cognitive decline. We anticipate that identifying NAD dysregulation during aging as a driver of vascular dysfunction will not only result in development of new and urgently needed tools to treat vascular dysfunction in aging, but also advance research related to the etiology of AD/ADRD.

与年龄相关的认知下降已经成为我们时代的主要公共场所之一。一种称为神经血管耦合的稳态机制。与年龄相关的认知下降的治疗阿尔茨海默氏病/阿尔茨海默氏病与痴呆症（AD/ ADRD）ULTS有关。衰老的标志。与年龄相关的NAD耗竭障碍和NVC反应受损，在没有易感性的血管病理学的情况下，正在努力。 OFC OFC OFC。在社区居住的老年人（60-85岁）中，每OS持续8周）或安慰剂（8周），在随机，双盲，安慰剂对照的，平行研究中，Wille确定NR Suppppatelial and Ppppatial and Pppatelial and Heurovasselial and Neurowescular and NAD和NAD和NAD功能障碍的功能障碍不会开发新的且急需的工具来治疗衰老中的LAR功能障碍，而是进步与AD/ADRD病因相关的研究。