Slc12a8 is a nicotinamide mononucleotide transporter that counteracts aging

NAD+ levels decline in multiple tissues over age, causing various age-associated pathophysiologies. Nicotinamide mononucleotide (NMN) is a key NAD+ intermediate that promotes NAD+biosynthesis and counteracts age-associated physiological decline. However, how NMN transport is regulated remains unknown. Here we report a novel NMN transporter encoded by the Slc12a8 gene. Slc12a8 is highly expressed and regulated by NAD+ in the small intestine. Knocking down this gene abrogates the transport of NMN in vitro and in vivo. Slc12a8 exhibits specificity to NMN and dependency on the sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, due to decreases in NMN uptake traced by doubly labeled isotopic NMN. Slc12a8 expression is upregulated in the aged ileum, contributing to the maintenance of NAD in aged mice. Thus, this newly identified NMN transporter plays a critical role in counteracting NAD+ decline during aging. To evaluate the effects of NAD depletion induced by FK866 treatment, we conducted microarray analyses and compared global gene expression profiles in control (DMSO 0.1%) and FK866-treated primary hepatocytes/islets.

烟酰胺腺嘌呤二核苷酸（NAD+）水平随年龄增长在多种组织中逐渐下降，进而引发多种与衰老相关的病理生理变化。烟酰胺单核苷酸（Nicotinamide mononucleotide, NMN）是NAD+的关键中间代谢物，可促进NAD+的生物合成，抵消衰老相关的生理功能衰退。然而，目前NMN的转运调控机制仍不明晰。本研究报道了一种由Slc12a8基因编码的新型NMN转运蛋白：Slc12a8在小肠中高表达，且其表达受NAD+调控；敲低该基因可在体外及体内完全阻断NMN的转运过程。Slc12a8对NMN具有转运特异性，且依赖钠离子发挥功能。Slc12a8缺陷会显著降低空肠与回肠中的NAD+水平，这一现象可通过双同位素标记的NMN追踪到的NMN摄取量下降得到证实。衰老小鼠的回肠中Slc12a8的表达会上调，这有助于维持衰老小鼠体内的NAD水平。综上，此次新发现的NMN转运蛋白在对抗衰老过程中NAD+水平下降方面发挥着关键作用。为评估FK866处理诱导的NAD耗竭所产生的影响，本研究开展了微阵列分析，并对比了对照组（0.1%二甲基亚砜（DMSO））与经FK866处理的原代肝细胞/胰岛的全基因表达谱。