Lautrup Sofie, Zhang Shi-Qi, Funayama Shinichiro, Lirussi Lisa, Visnovska Tina, Cheung Hoi-Hung, Niere Marc, Tian Yuyao, Nilsen Hilde Loge, Selbæk Geir, Saarela Janna, Maezawa Yoshiro, Yokote Koutaro, Nilsson Per, Chan Wai-Yee, Kato Hisaya, Ziegler Mathias, Bohr Vilhelm A, Fang Evandro F
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog 1478, Norway.
Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba 260-0856, Japan.
Aging (Albany NY). 2025 Apr 2;17(4):937-959. doi: 10.18632/aging.206236.
Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER () gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD changes in WS and the impact on WS pathologies were unknown. We show that loss of WRN increases senescence in mesenchymal stem cells (MSCs) likely related to dysregulation of metabolic and aging pathways. In line with this, NAD augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with knockout () and in primary fibroblasts derived from WS patients compared to controls. Moreover, deficiency results in decreased mitochondrial NAD (measured indirectly via mitochondrially-expressed PARP activity), and altered expression of key salvage pathway enzymes, including NMNAT1 and NAMPT; ChIP-seq data analysis unveils a potential co-regulatory axis between WRN and the NMNATs, likely important for chromatin stability and DNA metabolism. However, restoration of mitochondrial or cellular NAD is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of , highlighting an indispensable role of WRN in proliferation even in an NAD affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.
沃纳综合征（WS）由RecQ解旋酶沃纳（WRN）基因突变引起，是一种典型的加速衰老疾病，患者患有多种代谢功能障碍且无法治愈。正如我们之前报道的，NAD耗竭会导致受损线粒体积累，进而导致代谢受损，但WS中线粒体NAD如何变化以及对WS病理的影响尚不清楚。我们发现，WRN缺失会增加间充质干细胞（MSC）的衰老，这可能与代谢和衰老途径的失调有关。与此一致的是，通过补充烟酰胺核糖进行NAD增强，与对照组相比，可减少敲除（KO）的MSC以及源自WS患者的原代成纤维细胞中的衰老，并改善线粒体代谢谱。此外，WRN缺陷导致线粒体NAD降低（通过线粒体表达的PARP活性间接测量），并改变关键补救途径酶的表达，包括NMNAT1和NAMPT；ChIP-seq数据分析揭示了WRN与NMNAT之间潜在的共调节轴，这可能对染色质稳定性和DNA代谢很重要。然而，在用siRNA介导的WRN敲低的永生化细胞中，恢复线粒体或细胞NAD不足以重新恢复细胞增殖，这突出了WRN即使在NAD丰富的环境中对增殖也起着不可或缺的作用。需要进一步的细胞和动物研究来加深我们对潜在机制的理解，促进相关药物的开发。
