Reduction of DNA 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 find that knocking down the enzyme Topoisomerase IIβ (Top2b) increases the lifespan of S. cerevisiae, C. elegans, and mice. TOP2B reduction also extends the health span of mice and alleviates the characteristics and pathologies of aging in multiple tissues. At the cellular/molecular level, TOP2 reduction attenates the major hallmarks of aging, such as cellular senescence, deregulated nutrient-sensing, epigenetic alterations, and lysosomal biogenesis. We observed that TOP2 reduction significantly alters the epigenetic landscape in various mouse tissues toward those of the young animals, and differentially down-regulates genes with active promoter and high expression. Our observations suggest that TOP2 reduction confers longevity effect across species via a conserved mechanism, and may be used as a novel therapeutic strategy for countering aging.