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

基本信息

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
项目类别：
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

项目摘要

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.

摘要哺乳动物的衰老是复杂的，其特点包括干细胞自我更新倾向降低、 DNA 修复缺陷、对生长刺激激素和营养物质的反应减弱、代谢破坏和增加对疾病发作的敏感性。自我更新、自我缺陷的根源修复和代谢稳态是衰老领域的核心问题。可以说，任何一个因素都不能确定提供因果效应。我们重点关注 NAD+ 代谢缺陷作为潜在的导致细胞、组织和有机体健康下游功能障碍的多效性效应器。处理这样的衰老，更容易由遗传因素引起，例如 DNA 修复基因缺陷（例如，DNA 修复基因缺陷）。 Werner 和 Bloom 综合征）为进一步研究 NAD+ 的作用提供了一个有趣的机会鉴于转基因成纤维细胞作为这方面的潜在工具可以在商业上获得，因此存在缺陷。我们建议总体描述衰老如何影响早衰细胞和老年小鼠的 NAD+ 代谢。具体来说，我们将表征 NAD+ 生物合成潜力以及 NAD+ 周转率。而且我们将评估细胞如何响应增加 NAD+ 生物合成的药物干预，以便确定这些干预措施是否减轻这些成纤维细胞的年龄依赖性表型。这些研究将更深入地了解细胞和组织中 NAD+ 下降是如何发生的，以及某些细胞和组织是否更多比其他人更容易受到这种下降的影响以及原因。该申请的第二部分侧重于发现新型 NAD+ 增强剂，称为二氢烟酰胺核苷 (NRH)，可将 NAD+ 浓度从 3- 哺乳动物细胞中的10倍。初步数据表明，NRH 采用了一种新颖的作用机制，其中转化为 NMNH，不依赖于已知的激酶 Nrk1 或 Nrk2，导致 NAD+ 的生物合成。在小鼠中在大多数组织中，这种化合物使 NAD+ 浓度比对照增加许多倍。这个应用程序研究其在成纤维细胞和小鼠中的作用机制，以阐明 NAD+ 的新生物合成途径具有治疗疾病的转化潜力。因此，在应用程序的后半部分，我们描述了 NRH 对老年小鼠的影响并确定它是否可以诱导线粒体生物发生。我们提供研究使用代谢组学方法表征其影响。最后我们测试 NRH 来治疗代谢模型综合征并描述年龄对疾病和治疗结果的影响。赠款的目标通过 3 个具体目标来实现： 1. 将细胞和小鼠中的 NAD+ 稳态表征为年龄。 2. 阐明NRH对成纤维细胞和小鼠的作用及代谢途径。 3. 确定效果 NRH 对老年小鼠改变 NAD+ 代谢、线粒体生物合成和缓解代谢模型的作用综合症。这些目标的实现将为 NAD+ 如何成为关键因素提供新的认识。衰老以及下一代 NAD+ 前体是否可以改变衰老标志的表型。