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: 10372023
• 负责人: Eduardo N Chini
• 金额: $ 34.43万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372023
• 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; 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.

抽象的： 衰老的特征是与年龄有关的代谢疾病和脆弱的发展。最近的研究 证明烟酰胺腺苷二核苷酸（NAD）的水平降低是关键因果因素 与年龄有关的代谢下降的发展。 NAD+对于减少反应和线粒体至关重要 功能。有趣的是，施用NAD前体，例如烟酰胺单核苷酸（NMN）或 烟酰胺核苷（NR）足以改善小鼠的健康状况和寿命。迄今为止的机制 导致衰老期间NAD下降的情况尚未阐明。流行的假设是激活 DNA修复酶（例如多ADP-核糖聚合酶（PARP））在衰老期间会消耗NAD 过程。但是，我们最近挑战了这种范式，并表明CD38是主要的NADase 负责与衰老有关的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外侧酶。 CD38表达和活性 炎性细胞由细胞因子和内毒素诱导。我们的主要假设是NAD的下降和 衰老过程中代谢功能障碍是由CD38+炎症细胞浸润/积累介导的 组织，通过其ecto-nadase活性消耗NAD及其前体。此外，我们建议 源自“慢性无菌炎症”的细胞因子是CD38的主要影响者 衰老过程。最后，我们提出，小分子CD38抑制剂（CD38i）可以保留细胞NAD 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。此外，小分子CD38I或CD38阻断抗体 单独或与NAD前体结合使用可能会改善老年代谢功能和健康跨度。

项目成果

Endogenous metabolism in endothelial and immune cells generates most of the tissue vitamin B3 (nicotinamide).

• DOI: 10.1016/j.isci.2022.105431
• 发表时间: 2022-11-18
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Zeidler, Julianna D.;Chini, Claudia C. S.;Kanamori, Karina S.;Kashyap, Sonu;Espindola-Netto, Jair M.;Thompson, Katie;Warner, Gina;Cabral, Fernanda S.;Peclat, Thais R.;Gomez, Lilian Sales;Lopez, Sierra A.;Wandersee, Miles K.;Schoon, Renee A.;Reid, Kimberly;Menzies, Keir;Beckedorff, Felipe;Reid, Joel M.;Brachs, Sebastian;Meyer, Ralph G.;Meyer-Ficca, Mirella L.;Chini, Eduardo Nunes
• 通讯作者: Chini, Eduardo Nunes

The NADase enzyme CD38: an emerging pharmacological target for systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis.

• DOI: 10.1097/bor.0000000000000737
• 发表时间: 2020-11
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: Peclat TR;Shi B;Varga J;Chini EN
• 通讯作者: Chini EN

NAD metabolism: Role in senescence regulation and aging.

• DOI: 10.1111/acel.13920
• 发表时间: 2024-01
• 期刊: Aging cell
• 影响因子: 7.8

Implications of the NADase CD38 in COVID pathophysiology.

NADase CD38 在 COVID 病理生理学中的意义。

• DOI: 10.1152/physrev.00007.2021
• 发表时间: 2022
• 期刊: Physiological reviews
• 影响因子: 33.6
• 作者: Zeidler,JuliannaD;Kashyap,Sonu;Hogan,KellyA;Chini,EduardoNunes
• 通讯作者: Chini,EduardoNunes

Radiation therapy induces immunosenescence mediated by p90RSK.

• DOI: 10.3389/fcvm.2022.988713
• 发表时间: 2022
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Imanishi, Masaki;Cheng, Haizi;Kotla, Sivareddy;Deswal, Anita;Le, Nhat-Tu;Chini, Eduardo;Ko, Kyung Ae;Samanthapudi, Venkata S. K.;Lee, Ling-Ling;Herrmann, Joerg;Xu, Xiaolei;Reyes-Gibby, Cielito;Yeung, Sai-Ching J.;Schadler, Keri L. L.;Yusuf, Syed Wamique;Liao, Zhongxing;Nurieva, Roza;Amir, El-ad David;Burks, Jared K. K.;Palaskas, Nicolas L. L.;Cooke, John P. P.;Lin, Steven H. H.;Kobayashi, Michihiro;Yoshimoto, Momoko;Abe, Jun-ichi
• 通讯作者: Abe, Jun-ichi