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

摘要： 衰老的特征是与年龄相关的代谢性疾病的发展和虚弱。最新研究 证明烟酰胺腺嘌呤二核苷酸(NAD)水平的降低是导致 发生与年龄相关的代谢性衰退。NAD+对氧化还原反应和线粒体至关重要 功能。有趣的是，NAD前体的给药，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和寿命。以确定这些机制的日期 导致NAD在衰老过程中下降的原因尚未阐明。普遍的假设是激活 许多DNA修复酶，如聚-ADP-核糖聚合酶(PAPS)，会在衰老过程中消耗NAD 进程。然而，我们最近挑战了这一范式，并表明CD38是主要的NADase 对与老龄化相关的NAD下降负有责任。 我的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 是一种在炎性细胞中高表达的胞外酶。CD38在这些细胞中的表达和活性 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+炎性细胞在脑内的渗透/积聚所介导的 组织，通过其胞外NADase活性消耗NAD及其前体。此外，我们建议 细胞因子来源于“慢性不育炎症的衰老”是CD38的主要诱因。 老化过程。最后，我们认为小分子CD38抑制剂(CD38i)可以保护细胞内的NAD 水平，并增加哺乳动物的代谢健康跨度，CD38i将进一步提高弹性和 长寿。 综上所述，CD38可能在衰老相关炎症细胞NAD下降、 线粒体和代谢功能障碍。此外，小分子CD38i或CD38封闭抗体 单独或与NAD前体联合使用可能会改善老年人的代谢功能和健康寿命。

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.