Reduction of <scp>DNA</scp> Topoisomerase Top2 Reprograms the Epigenetic Landscape and Extends Health and Life Span Across Species

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.