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

与年龄相关的认知能力下降已经成为我们这个时代的主要公共卫生挑战之一。众所周知，正常的认知功能需要足够的血液供应来支持神经元活动。在健康的年轻大脑中，脑血流通过一种称为神经血管耦合（NVC，或功能性充血）的稳态机制迅速调整，以满足活跃脑区域增加的氧气和营养需求。临床前和临床研究表明，NVC在正常衰老过程中受损，实验诱导的幼龄动物NVC反应受损可导致认知障碍。通过靶向药物治疗恢复这些动物的NVC可改善认知功能。在动物模型中测试已证明有效的人类特定干预措施是一种合理和谨慎的方法，可以改善受损的NVC，并且可能是开发有效疗法的关键，以逆转或预防老年人与年龄相关的认知能力下降和阿尔茨海默病/阿尔茨海默病相关痴呆（AD/ADRD）。内皮功能障碍和NVC反应的损害与活性氧（ROS）的产生增加有关，活性氧是“衰老的标志”之一。烟酰胺腺嘌呤二核苷酸（Nicotinamide Adenine Dinucleotide， NAD）是ROS的主要调节因子之一，已被证明可以减弱ROS的产生。我们的初步研究表明，老年小鼠的脑血管内皮细胞中的NAD水平显著降低，使用NAD前体恢复正常老年小鼠（相当于≥60岁的人类）的NAD水平可以挽救与年龄相关的内皮功能障碍，恢复NVC反应并减轻认知能力下降。即使在没有易感血管病理的老年人中，也可以观察到与年龄相关的NAD消耗、内皮功能障碍和NVC反应受损。虽然有报道称补充NAD前体烟酰胺核苷（NR）可增加人血细胞NAD水平，但尚未研究其对内皮功能和NVC反应的影响。解决这一科学差距对于进一步发展我们对NVC损伤病因的理解以及确定其在衰老和AD/ADRD认知能力下降中的作用至关重要。我们的中心假设是，老年人用NR恢复NAD水平将改善NVC反应和微血管和大血管内皮功能。该假设将在随机、双盲、安慰剂对照、平行研究设计中，通过评估社区居住老年人（60-85岁）口服NR（每天1克，持续8周）或安慰剂（8周）治疗的效果来验证。这些研究将确定NR补充剂是否减轻内皮和神经血管功能障碍，并可能减轻认知能力下降。我们预计，确定衰老过程中NAD失调作为血管功能障碍的驱动因素，不仅将导致开发新的和迫切需要的治疗衰老血管功能障碍的工具，而且还将推进与AD/ADRD病因相关的研究。

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.