Role of CD38 in NAD metabolism: from the basic biology of aging to translation

CD38 在 NAD 代谢中的作用：从衰老的基础生物学到转化

• 批准号: 10116241
• 负责人: Eduardo N Chini
• 金额: $ 16.2万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2021-10-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116241
• 关键词: Age; Age Factors; Aging; Animal Model; Antibodies; Biology of Aging; Blocking Antibodies; Bone Marrow; CD38 molecule; Cells; Chronic; Chronology; Consumption; DNA Repair; DNA Repair Enzymes; Data; Development; Diabetes Mellitus; Disease; Elderly; Elements; Endotoxins; Enzymes; Goals; Homeostasis; Immune; Incidence; Infiltration; Inflammation; Inflammatory; Knowledge; Laboratories; Laboratory Animals; Lead; Link; Longevity; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mus; Muscle function; Muscular Atrophy; NAD+ Nucleosidase; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Nucleotides; Pathway interactions; Pharmacology; Play; Poly(ADP-ribose) Polymerases; Population; Process; Reaction; Regulation; Risk Factors; Role; Signal Transduction; Source; Sterility; Supplementation; TNF gene; Testing; Therapeutic; Tissues; Translations; age related; cytokine; epigenetic regulation; extracellular; frailty; healthspan; human old age (65+); improved; inhibitor/antagonist; mitochondrial dysfunction; nicotinamide-beta-riboside; novel; preservation; resilience; small molecule; therapy development; translational study

ABSTRACT: Aging is characterized by the development of age-related metabolic diseases and frailty. Recent studies demonstrate that a decrease in levels of Nicotinamide adenine dinucleotide (NAD) is key causal factor for the development of age-related metabolic decline. NAD+ is crucial for oxi-reduction reactions and mitochondrial function. Interestingly, administration of NAD precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) is sufficient to improve healthspan and longevity in mice. To date the mechanisms that lead to the NAD decline during aging has not been elucidated. The prevailing hypothesis is that activation of DNA-repair enzymes such as Poly-ADP-ribose polymerases (PARPs) would consume NAD during the aging process. However, we have recently challenged this paradigm and show that CD38 is the main NADase responsible for the aging-related NAD decline. The long term goal of my laboratory is to understand the role of CD38 in NAD metabolism during aging. CD38 is an ecto-enzyme that is highly expresses in inflammatory cells. CD38 expression and activity in these inflammatory cells is induced by cytokines and endotoxins. Thus our main hypothesis is that NAD decline, and metabolic dysfunction during aging is mediated by infiltration/accumulation of CD38+ inflammatory cells in tissues, that consumes NAD and its precursors via its ecto-NADase activity. Furthermore, we propose that cytokines derived from the “chronic sterile inflammation of aging” are the main inducers of CD38 during the aging process. Finally, we propose that small molecule CD38 inhibitors (CD38i) can preserve cellular NAD levels, and augment metabolic health span in mammalians, and that CD38i will further increase resilience and longevity. In conclusion, CD38 may provide a mechanistic link between aging-related inflammation cellular NAD decline, mitochondrial and metabolic dysfunction. Furthermore, small molecule CD38i or CD38 blocking antibodies alone or in combination with NAD precursors may improve metabolic function and health span in the elderly.

摘要： 衰老的特征是与年龄相关的代谢疾病和虚弱的发展。最近的研究 表明烟酰胺腺嘌呤二核苷酸（NAD）水平的降低是导致 与年龄相关的代谢下降。NAD+对氧化还原反应和线粒体 功能有趣的是，给予NAD前体如烟酰胺单核苷酸（NMN）或 烟酰胺核苷（NR）足以改善小鼠的健康寿命和寿命。确定机制的日期 导致衰老过程中NAD下降的原因尚未阐明。流行的假设是， 的DNA修复酶，如聚ADP核糖聚合酶（PARP）将消耗NAD在老化过程中， 过程然而，我们最近挑战了这种模式，并表明CD38是主要的NAD酶。 与衰老相关的NAD下降。 我实验室的长期目标是了解CD38在衰老过程中NAD代谢中的作用。CD38 是一种在炎症细胞中高度表达的胞外酶。CD38表达和活性在这些 炎性细胞由细胞因子和内毒素诱导。因此，我们的主要假设是，NAD下降， 衰老过程中的代谢功能障碍是由CD38+炎性细胞的浸润/积聚介导的， 组织，其通过其外NAD酶活性消耗NAD及其前体。此外，我们建议， 来源于"衰老的慢性无菌性炎症"的细胞因子是CD38在衰老过程中的主要诱导物。 老化过程最后，我们提出小分子CD38抑制剂（CD38i）可以保护细胞NAD 水平，并增加代谢健康的跨度，CD38i将进一步增加弹性， 中心blog 总之，CD38可能提供了衰老相关炎症细胞NAD下降， 线粒体和代谢功能障碍。此外，小分子CD38 i或CD38阻断抗体 单独或与NAD前体组合可改善老年人的代谢功能和健康寿命。