NAD Metabolism in Aging and Disease: Dysfunction and Intervention

衰老和疾病中的 NAD 代谢：功能障碍和干预

• 批准号: 10259770
• 负责人: ANTHONY A. SAUVE
• 金额: $ 34.75万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259770
• 关键词: Address; Adenosine Kinase; Affect; Age; Aging; Anabolism; Applications Grants; Biochemical Process; Biogenesis; Biological Assay; Bloom Syndrome; Body Composition; Cell model; Cells; Complex; DNA Repair; DNA Repair Gene; Data; Defect; Dependence; Dermal; Disease; Disease Outcome; Disease model; Drug Metabolic Detoxication; Enhancers; Fibroblasts; Functional disorder; Generations; Genetic; Glucose Clamp; Grant; Growth; Health; Hepatocyte; High Fat Diet; Homeostasis; Hormones; Human; In Vitro; Intervention; Investigation; Liver; Mammalian Cell; Mammals; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Methods; Mitochondria; Modeling; Molecular; Mus; Nutrient; Onset of illness; Organism; Oxygen; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphotransferases; Physiological; Population; Predisposition; Process; Research; Role; Severity of illness; Skeletal Muscle; Somatotropin; Sum; Testing; Time; Tissues; Treatment outcome; Werner Syndrome; Work; age effect; age related; aged; base; dihydronicotinamide; genetic approach; in vivo; innovation; intervention effect; metabolomics; mouse model; next generation; novel; pleiotropism; pre-clinical; repaired; response; riboside; self-renewal; senescence; stem cell self renewal; tool; translational study

SUMMARY Aging in mammals is complex, with hallmarks including reduced propensity for stem cell self renewal, deficiencies in DNA repair, reduced responses to growth stimulating hormones and nutrients, metabolic disruption and increased susceptibilities to the onset of diseases. The origins of the deficits in self renewal, self repair, and metabolic homeostasis are central questions in the aging field. Arguably, no single factor can be identified that provides a causative effect. We have focused upon deficits in NAD+ metabolism as a potentially pleiotropic effector leading to downstream dysfunctions in cellular, tissue and organism health. Processes such as senescence, which can more readily arise from genetic factors such as defects in DNA repair genes (e.g. Werner and Bloom Syndromes) present an interesting opportunity to further investigate the role of NAD+ deficiency, given that genetically altered fibroblasts are commercially accessible as potential tools in this regard. We propose to generally characterize how aging affects NAD+ metabolism in progeroid cells, and in aged mice. Specifically, we will characterize NAD+ biosynthetic potential as well as rates of NAD+ turnover. Moreover we will assess how cells respond to pharmacologic interventions that increase NAD+ biosynthesis in order to determine if these interventions mitigate age-dependent phenotypes in these fibroblast cells. These studies will provide a deeper view of how NAD+ decline occurs in cells and tissues, and if some cells and tissues are more susceptible to this decline than others and why. A second part of the application focuses on the discovery of a novel NAD+ enhancer called dihydronicotinamide riboside (NRH), which can raise NAD+ concentrations from 3- 10 fold in mammalian cells. Preliminary data shows that NRH uses a novel mechanism of action,wherein it is converted to NMNH, independent of the known kinases Nrk1 or Nrk2, leading to biosynthesis of NAD+. In mice this compound increases NAD+ concentrations many-fold over control in most tissues. This application investigates its mechanism of action in fibroblasts and in mice to elucidate a novel biosynthetic pathway to NAD+ with translational potential for treatment of disease. Thus, in the latter part of the application, we characterize NRH effects in aged mice and ascertain if it can induce mitochondrial biogenesis. We provide studies to characterize its effects using metabolomics approaches. Finally we test NRH to treat a model of metabolic syndrome and to characterize the effect of age on disease and treatment outcomes. The objectives of the grant are accomplished via 3 specific aims: 1. To characterize NAD+ homeostasis in cells and mice as a function of age. 2. To elucidate effect and metabolic pathway of NRH in fibroblasts and mice. 3. To determine the effect of NRH on aged mice in altering NAD+ metabolism, mitochondrial biogenesis and mitigation of a model of metabolic syndrome. The accomplishment of the objectives will provide new understanding of how NAD+ is a key factor in aging and whether next generation NAD+ precursors can alter phenotypes that are hallmarks of aging.

哺乳动物的摘要衰老很复杂，其标志包括减少干细胞自我更新的倾向， DNA修复的缺陷，对生长刺激激素和营养的反应减少，代谢 疾病发作的破坏和增加的敏感性。自我更新，自我的赤字的起源 维修和代谢稳态是衰老领域的核心问题。可以说，没有一个因素可以 确定提供了一种因果关系。我们专注于NAD+代谢中的缺陷作为潜在的 多效效应子导致细胞，组织和生物体健康的下游功能障碍。这样的过程 作为衰老，它可以更容易源于遗传因素，例如DNA修复基因的缺陷（例如， Werner and Bloom综合征）提供了一个有趣的机会，可以进一步研究NAD+的作用 鉴于在这方面，遗传上改变的成纤维细胞可以作为潜在工具在商业上可以使用。 我们建议通常表征衰老如何影响后代细胞和老年小鼠的NAD+代谢。 具体而言，我们将表征NAD+生物合成电位以及NAD+周转率的速率。而且我们 将评估细胞如何对增加NAD+生物合成的药理干预措施的反应 确定这些干预措施是否减轻了这些成纤维细胞中年龄依赖的表型。这些研究会 对细胞和组织中的NAD+下降的衰落提供了更深入的了解，并且某些细胞和组织是否更多 比其他人容易受到这种衰落的影响，为什么。应用程序的第二部分重点是发现 新颖的NAD+增强剂称为二氢氨基氨酸酰胺核苷（NRH），可以从3-中提高NAD+浓度 哺乳动物细胞中的10倍。初步数据表明，NRH使用一种新型的作用机理，其中它是 转化为NMNH，独立于已知的激酶NRK1或NRK2，导致NAD+的生物合成。在老鼠中 在大多数组织中，这种化合物会增加对照的NAD+浓度。此应用程序 研究其在成纤维细胞和小鼠中的作用机理，以阐明新的生物合成途径到NAD+ 具有疾病治疗的转化潜力。因此，在应用程序的后半部分，我们表征 NRH在老年小鼠中的作用，并确定它是否可以诱导线粒体生物发生。我们为 使用代谢组学方法来表征其效果。最后，我们测试NRH以治疗代谢模型 综合征并表征年龄对疾病和治疗结果的影响。赠款的目标 通过3个特定目的完成：1。表征细胞和小鼠中的NAD+稳态 年龄。 2。阐明成纤维细胞和小鼠中NRH的作用和代谢途径。 3。确定效果 NRH在改变NAD+代谢，线粒体生物发生和缓解代谢模型的NRH上 综合征。目标的实现将为NAD+是如何成为关键因素提供新的了解 衰老以及下一代NAD+前体是否可以改变衰老标志的表型。