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.

文摘:

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