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： 衰老的特点是出现与年龄相关的代谢疾病和虚弱。最近的研究 证明烟酰胺腺嘌呤二核苷酸（NAD）水平的降低是导致该疾病的关键因素 与年龄相关的代谢衰退的发展。 NAD+ 对于氧化还原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) 足以延长小鼠的健康寿命和寿命。迄今为止的机制 导致衰老过程中 NAD 下降的原因尚未阐明。普遍的假设是激活 DNA 修复酶，如聚 ADP 核糖聚合酶 (PARP) 在衰老过程中会消耗 NAD 过程。然而，我们最近挑战了这一范式，并表明 CD38 是主要的 NADase 与衰老相关的 NAD 下降负有责任。 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 的表达和活性 炎症细胞是由细胞因子和内毒素诱导的。因此，我们的主要假设是 NAD 下降，并且 衰老过程中的代谢功能障碍是由 CD38+ 炎症细胞的浸润/积聚介导的 组织，通过其胞外 NAD 酶活性消耗 NAD 及其前体。此外，我们建议 源自“衰老的慢性无菌性炎症”的细胞因子是 CD38 的主要诱导剂。 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，并延长哺乳动物的代谢健康寿命，并且 CD38i 将进一步提高恢复能力和 长寿。 总之，CD38 可能提供衰老相关炎症细胞 NAD 下降之间的机制联系， 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 前体组合可以改善老年人的代谢功能和健康寿命。

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

CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype.

• DOI: 10.15252/emmm.202012860
• 发表时间: 2022-05-09
• 期刊: EMBO molecular medicine
• 影响因子: 11.1

Mitochondrial dysfunction in cell senescence and aging.

• DOI: 10.1172/jci158447
• 发表时间: 2022-07-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Miwa, Satomi;Kashyap, Sonu;Chini, Eduardo;von Zglinicki, Thomas
• 通讯作者: von Zglinicki, Thomas

The CD38 glycohydrolase and the NAD sink: implications for pathological conditions.

• DOI: 10.1152/ajpcell.00451.2021
• 发表时间: 2022-02
• 期刊: American journal of physiology. Cell physiology
• 作者: J. D. Zeidler;K. Hogan;Guilherme Agorrody;Thais R. Peclat;Sonu Kashyap;K. Kanamori;Lilian S. Gomez;Delaram Z Mazdeh;G. Warner;Katie L. Thompson;Claudia C S Chini;E. Chini