Zhu Man, Ma Meng, Luo Lunan, Li Feiyang, Zheng Jiashun, Pan Yan, Yang Lu, Xiao Ying, Wang Ziyan, Xian Bo, Zheng Yi, Li Hao, Yang Jing
Department of Health Management & Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Laboratory of Aging Research, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Aging Cell. 2025 Jun;24(6):e70010. doi: 10.1111/acel.70010. Epub 2025 Feb 12.
DNA topoisomerases are essential molecular machines that manage DNA topology in the cell and play important roles in DNA replication and transcription. We found that knocking down the enzyme topoisomerase Top2 or its mammalian homolog TOP2B increases the lifespan of S. cerevisiae, C. elegans, and mice. TOP2B reduction also extends the health span of mice and alleviates the pathologies of aging in multiple tissues. At the cellular/molecular level, TOP2B reduction alleviates the major hallmarks of aging, including senescence, DNA damage, and deregulated nutrient sensing. We observed that TOP2B reduction changes the epigenetic landscape of various tissues in old mice toward that of the young animals, and differentially downregulates genes with active promoter and high expression. Our observations suggest that Top2 reduction confers pro-longevity effect across species possibly through a conserved mechanism and may be a promising strategy for longevity intervention.
DNA拓扑异构酶是细胞中调控DNA拓扑结构的重要分子机器，在DNA复制和转录过程中发挥着关键作用。我们发现，敲低拓扑异构酶Top2或其哺乳动物同源物TOP2B可延长酿酒酵母、秀丽隐杆线虫和小鼠的寿命。降低TOP2B水平还能延长小鼠的健康寿命，并减轻多个组织的衰老病理特征。在细胞/分子水平上，降低TOP2B水平可缓解衰老的主要特征，包括细胞衰老、DNA损伤和营养感应失调。我们观察到，降低TOP2B水平可使老年小鼠各种组织的表观遗传格局向年轻动物转变，并差异性地下调具有活跃启动子和高表达的基因。我们的观察结果表明，降低Top2水平可能通过一种保守机制在不同物种中产生促长寿效应，这可能是一种有前景的长寿干预策略。
