Lu ZuFu, Jiang Liting, Lesani Pooria, Zhang WenJie, Li Ning, Luo Danyang, Li Yusi, Ye Yulin, Bian Ji, Wang Guocheng, Dunstan Colin R, Jiang XinQuan, Zreiqat Hala
Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, the University of Sydney, Sydney, New South Wales, Australia.
ARC Training Centre for Innovative BioEngineering, the University of Sydney, Sydney, New South Wales, Australia.
J Gerontol A Biol Sci Med Sci. 2023 Feb 24;78(2):186-194. doi: 10.1093/gerona/glac175.
Combating the accumulated senescent cells and the healing of osteoporotic bone fractures in the older remains a significant challenge. Nicotinamide mononucleotide (NMN), a precursor of NAD+, is an excellent candidate for mitigating aging-related disorders. However, it is unknown if NMN can alleviate senescent cell induction and enhance osteoporotic bone fracture healing. Here we show that NMN treatment partially reverses the effects of tumor necrosis factor-alpha (TNF-α) on human primary osteoblasts (HOBs): senescent cell induction, diminished osteogenic differentiation ability, and intracellular NAD+ and NADH levels. Mechanistically, NMN restores the mitochondrial dysfunction in HOBs induced by TNF-α evidenced by increased mitochondrial membrane potential and reduced reactive oxidative species and mitochondrial mass. NMN also increases mitophagy activity by down-regulating P62 expression and up-regulating light chain 3B-II protein expression. In addition, the cell senescence protective effects of NMN on HOBs are mitigated by a mitophagy inhibitor (Bafilomycin A1). In vivo, NMN supplementation attenuates senescent cell induction in growth plates, partially prevents osteoporosis in an ovariectomized mouse model, and accelerates bone healing in osteoporotic mice. We conclude that NMN can be a novel and promising therapeutic candidate to enhance bone fracture healing capacity in the older.
对抗老年群体中积累的衰老细胞以及治疗骨质疏松性骨折仍然是一项重大挑战。烟酰胺单核苷酸（NMN）是NAD+的前体，是减轻衰老相关疾病的极佳候选物。然而，NMN是否能减轻衰老细胞诱导并促进骨质疏松性骨折愈合尚不清楚。在此，我们表明NMN处理可部分逆转肿瘤坏死因子-α（TNF-α）对人原代成骨细胞（HOB）的影响：衰老细胞诱导、成骨分化能力减弱以及细胞内NAD+和NADH水平。从机制上讲，NMN可恢复由TNF-α诱导的HOB中的线粒体功能障碍，这表现为线粒体膜电位增加、活性氧和线粒体质量减少。NMN还通过下调P62表达和上调轻链3B-II蛋白表达来增加线粒体自噬活性。此外，线粒体自噬抑制剂（巴弗洛霉素A1）可减轻NMN对HOB的细胞衰老保护作用。在体内，补充NMN可减轻生长板中的衰老细胞诱导，在去卵巢小鼠模型中部分预防骨质疏松，并加速骨质疏松小鼠的骨愈合。我们得出结论，NMN可能是一种新型且有前景的治疗候选物，可增强老年群体的骨折愈合能力。
