Nicotinamide riboside supplementation for treating elevated systolic blood pressure and arterial stiffness in middle-aged and older adults
补充烟酰胺核苷治疗中老年人收缩压升高和动脉僵硬度
基本信息
- 批准号:10159516
- 负责人:
- 金额:$ 57.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAcetylcholineAddressAdministrative SupplementAdultAffectAgeAge-YearsAgingAnti-Inflammatory AgentsApoptosisAutomobile DrivingBiological AvailabilityBloodBlood PressureCOVID-19COVID-19 pandemicCell Culture TechniquesCellsCellular StructuresChronicClinicalClinical TrialsDNADNA DamageDNA RepairDietDiseaseElderlyEndotheliumEvaluationExposure toFunctional disorderFundingGeriatricsGerontologyHealthHumanHypertensionImpairmentIndividualInfectionInflammationInflammatoryInterventionLeukocytesLipopolysaccharidesLungMediatingMononuclearMorbidity - disease rateMusNicotinamide adenine dinucleotideNitric OxideOxidantsOxidative StressParentsPathogenesisPathogenicityPathway interactionsPeptidyl-Dipeptidase APeripheral Blood Mononuclear CellPharmacologyPhasePilot ProjectsPlacebosPredispositionPrevention strategyProcessProductionRandomized Clinical TrialsReactive Oxygen SpeciesRecoveryResearchRespiratory BurstRiskRisk FactorsSIRT1 geneSamplingSerumSeveritiesSignal PathwaySupplementationTissuesTranslatingVascular EndotheliumVascular PermeabilitiesViralage relatedarterial stiffnessbrachial arterycohortcomorbiditycytokinecytokine release syndromedietary supplementsendothelial dysfunctionevidence baseimprovedin vivoinfection rateinfection riskmiddle agemortalitynicotinamide riboside supplementationnicotinamide-beta-ribosidenoveloral supplementationpreventpulmonary artery endothelial cellreceptor
项目摘要
PROJECT SUMMARY/ABSTRACT
The severe acute respiratory syndrome coronavirus (SARS-CoV)-2 that causes Coronavirus Disease 2019
(COVID-19) disproportionately affects older adults such that individuals 60 years and older have markedly
increased risk of infection, severity of morbidity, and mortality. This increased vulnerability with aging is due in
part to greater systemic inflammation and oxidative stress, impaired nitric oxide (NO)-mediated endothelial
dysfunction, and nicotinamide adenine dinucleotide (NAD+) deficiency both at baseline and post-infection. As
such, novel “geroprotective strategies” that: 1) improve baseline risk factor profile for COVID-19; and 2)
restore NAD+ levels, inhibit inflammation and oxidative stress, and improve NO bioavailability/endothelial
dysfunction induced during infection, are essential for reducing severity/lethality of COVID-19 in older adults.
We recently showed that chronic supplementation (6 weeks) with nicotinamide riboside, a natural dietary
compound, boosts NAD+ bioavailability in older adults. We then translated the results of this pilot study into
an NIA-funded (R01 AG061514) phase IIa randomized clinical trial assessing the efficacy of 3 months of
nicotinamide riboside treatment for lowering systolic blood pressure (SBP) and aortic stiffness in older adults
with baseline SBP in the elevated to stage 1 hypertension range. This 5-year clinical trial is currently in year 2.
The pathogenesis of COVID-19 includes NAD+ deficiency, hyper-inflammation, excessive reactive oxygen
species (ROS) bioactivity, and pulmonary and systemic NO-mediated endothelial dysfunction. Our preliminary
results in older adults suggest that nicotinamide riboside reduces pro-inflammatory cytokine production in
peripheral blood mononuclear cells (PBMC), decreases endothelial ROS bioactivity, increases endothelial NO
production, and improves in vivo systemic vascular endothelial function. However, these promising initial
findings must be confirmed in a larger cohort to establish the potential efficacy of nicotinamide riboside
supplementation as a geroprotective strategy for prevention and treatment of COVID-19 in older adults.
The purpose of this administrative supplement is to address a major research objective for the NIA
Division of Geriatrics and Clinical Gerontology in NOT-AG-20-022: The evaluation of pharmacological
interventions that may prevent or mitigate morbidity and/or improve post-infection health in older adults
exposed to SARS-CoV-2. This will be accomplished by: 1) assessing PBMC inflammatory cytokine production
before/after nicotinamide riboside treatment and incubation with specific NAD+-pathway metabolites; 2)
evaluating ex vivo endothelial function in human pulmonary artery endothelial cells bathed in subject serum
with/without COVID-19-like inflammatory and oxidative stress ± protective NAD+ metabolites; and 3) assessing
in vivo systemic endothelial function with nicotinamide riboside treatment. The expected results will establish
nicotinamide riboside as a promising geroprotective strategy for: a) reducing risk of SARS-CoV-2 infection; b)
inhibiting multiple pathways driving COVID-19 morbidity; and c) aiding post-infection recovery in older adults.
项目概要/摘要
导致 2019 年冠状病毒病的严重急性呼吸综合征冠状病毒 (SARS-CoV)-2
(COVID-19) 对老年人的影响尤为严重,60 岁及以上的人明显
感染风险、发病严重程度和死亡率增加是由于老龄化导致的脆弱性增加。
部分导致更大的全身炎症和氧化应激,一氧化氮(NO)介导的内皮细胞受损
基线和感染后均存在功能障碍和烟酰胺腺嘌呤二核苷酸 (NAD+) 缺乏。
这样,新颖的“老年保护策略”可以:1) 改善 COVID-19 的基线风险因素概况;2)
恢复 NAD+ 水平,抑制炎症和氧化应激,并提高 NO 生物利用度/内皮细胞
感染期间引起的功能障碍对于降低老年人中 COVID-19 的严重程度/致死率至关重要。
我们最近证明,长期补充(6 周)烟酰胺核苷(一种天然膳食)
化合物,可提高老年人的 NAD+ 生物利用度,然后我们将这项试点研究的结果转化为结果。
NIA 资助的 (R01 AG061514) IIa 期随机临床试验评估了 3 个月的疗效
烟酰胺核苷治疗可降低老年人的收缩压 (SBP) 和主动脉僵硬度
基线 SBP 处于升高至 1 期高血压范围的情况 这项为期 5 年的临床试验目前处于第二年。
COVID-19的发病机制包括NAD+缺乏、过度炎症、活性氧过多
物种(ROS)生物活性,以及肺和全身NO介导的内皮功能障碍。
老年人的结果表明,烟酰胺核苷可减少促炎细胞因子的产生
外周血单核细胞 (PBMC),降低内皮 ROS 生物活性,增加内皮 NO
产生,并改善体内全身血管内皮功能但是,这些初步有希望。
研究结果必须在更大的队列中得到证实,以确定烟酰胺核苷的潜在功效
补充剂作为预防和治疗老年人 COVID-19 的老年保护策略。
本行政补充文件的目的是解决 NIA 的主要研究目标
NOT-AG-20-022 中老年病学和临床老年学分部:药理学评价
可以预防或减轻发病率和/或改善老年人感染后健康的干预措施
暴露于 SARS-CoV-2 这将通过以下方式完成:1) 评估 PBMC 炎症细胞因子的产生。
烟酰胺核苷处理和与特定 NAD+ 途径代谢物孵育之前/之后;
评估沐浴在受试者血清中的人肺动脉内皮细胞的离体内皮功能
有/无 COVID-19 样炎症和氧化应激 ± 保护性 NAD+ 代谢物;以及 3) 评估
用烟酰胺核苷治疗的体内全身内皮功能将建立预期的结果。
烟酰胺核苷作为一种有前途的老年保护策略,可用于:a) 降低 SARS-CoV-2 感染的风险;b)
抑制导致 COVID-19 发病的多种途径;c) 帮助老年人感染后恢复。
项目成果
期刊论文数量(0)
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DOUGLAS R SEALS其他文献
DOUGLAS R SEALS的其他文献
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{{ truncateString('DOUGLAS R SEALS', 18)}}的其他基金
Targeting cellular senescence to prevent accelerated vascular aging induced by the common chemotherapeutic agent doxorubicin
靶向细胞衰老以防止常见化疗药物阿霉素引起的加速血管老化
- 批准号:
10505896 - 财政年份:2022
- 资助金额:
$ 57.2万 - 项目类别:
Passive heat therapy for lowering systolic blood pressure and improving vascular function in mid-life and older adults
被动热疗可降低中年和老年人的收缩压并改善血管功能
- 批准号:
10712162 - 财政年份:2022
- 资助金额:
$ 57.2万 - 项目类别:
Passive heat therapy for lowering systolic blood pressure and improving vascular function in mid-life and older adults
被动热疗可降低中年和老年人的收缩压并改善血管功能
- 批准号:
10596067 - 财政年份:2022
- 资助金额:
$ 57.2万 - 项目类别:
Passive heat therapy for lowering systolic blood pressure and improving vascular function in mid-life and older adults
被动热疗可降低中年和老年人的收缩压并改善血管功能
- 批准号:
10375083 - 财政年份:2022
- 资助金额:
$ 57.2万 - 项目类别:
Targeting cellular senescence to prevent accelerated vascular aging induced by the common chemotherapeutic agent doxorubicin
靶向细胞衰老以防止常见化疗药物阿霉素引起的加速血管老化
- 批准号:
10684719 - 财政年份:2022
- 资助金额:
$ 57.2万 - 项目类别:
Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans
线粒体靶向抗氧化剂补充剂可改善人类与年龄相关的血管功能障碍
- 批准号:
10538571 - 财政年份:2021
- 资助金额:
$ 57.2万 - 项目类别:
Inspiratory muscle strength training for lowering blood pressure and improving endothelial function in postmenopausal women: comparison with "standard of care" aerobic exercise
用于降低绝经后妇女血压和改善内皮功能的吸气肌力量训练:与“标准护理”有氧运动的比较
- 批准号:
10414050 - 财政年份:2021
- 资助金额:
$ 57.2万 - 项目类别:
Inspiratory muscle strength training for lowering blood pressure and improving endothelial function in postmenopausal women: comparison with "standard of care" aerobic exercise
用于降低绝经后妇女血压和改善内皮功能的吸气肌力量训练:与“标准护理”有氧运动的比较
- 批准号:
10178631 - 财政年份:2021
- 资助金额:
$ 57.2万 - 项目类别:
Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans
线粒体靶向抗氧化剂补充剂可改善人类与年龄相关的血管功能障碍
- 批准号:
10319609 - 财政年份:2021
- 资助金额:
$ 57.2万 - 项目类别:
Inspiratory muscle strength training for lowering blood pressure and improving endothelial function in postmenopausal women: comparison with "standard of care" aerobic exercise
用于降低绝经后妇女血压和改善内皮功能的吸气肌力量训练:与“标准护理”有氧运动的比较
- 批准号:
10576933 - 财政年份:2021
- 资助金额:
$ 57.2万 - 项目类别:
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