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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的：衰老的特征是与年龄相关的代谢扫描和脆弱的研究证明烟碱腺嘌呤二核苷酸（NAD）的生命中的法令是其关键因果因素与年龄有关的代谢下降的发展。功能。提供烟酰胺核糖剂（NR），以改善小鼠的健康状态和寿命。这导致衰老衰老期间的NAD下降尚未征服。 DNA-Crepair酶的酶，例如Aspoly-ADP-核糖聚合酶（PARPS）在衰老期间会消耗NAD 但是，我们最近挑战了这个范式，并表明CD38是主要的负责与衰老有关的NAD下降。我的实验室的长期目标是了解CD38在NAD代谢中的作用是一种在炎症细胞中高度表达的OCTO酶。炎症细胞由细胞因子和内毒素诱导。在CD38+炎症细胞中介导的代谢功能障碍是介导的组织，通过其ecto-nadase活性消耗NAD及其前体。源自“慢性无菌炎症”的细胞因子是在您期间的主要诱导剂衰老过程。哺乳动物的水平和增强代谢健康跨度，该CD38I将进一步提高弹性和长寿。总之，CD38可以提供与衰老相关的炎症细胞下降之间的机械联系，线粒体和代谢功能障碍。单独或与NAD前体结合使用可以改善老年人的代谢功能和健康跨度。