Epigenetic mechanisms determine the structure of nuclear DNA, largely via specific chemical decorations attached to specific locations on the genome or to the histone molecules that act as spindles for nuclear DNA to wrap around. The structure of DNA, which regions are spooled and hidden versus unspooled and exposed, determines which proteins are manufactured from their genetic blueprints, and thus the behavior of the cell. Here, researchers report on a search for genetic interventions that might reduce the magnitude or slow the progression of harmful age-associated epigenetic changes. The researchers found that knockout of TOP2B produces this outcome in yeast, nematode worms, and mice. In mice, reducing TOPB2 expression adds about 10% to life expectancy. While a fair amount is known of the specific functions of TOP2B within the complex processes of managing the structure of DNA, it remains unknown as to how it is that reduced TOP2B expression can produce modestly slowed aging.
In the simple model organism yeast, the lifespans of the nonessential gene knockout mutants have been measured systematically through a multi-year effort and ~200 mutants with extended lifespans were identified. As a significant fraction of the nonessential gene knockout mutants have been profiled transcriptionally, we analyzed the correlation between the gene expression profile and the lifespan of the mutants and identified a number of essential genes whose downregulation strongly correlates with extended lifespan across multiple mutants. Among the top hits is the DNA topoisomerase Top2, with an essential function in managing DNA topology and regulating replication and transcription.
Yeast Top2 has two mammalian homologs, TOP2A and TOP2B. While TOP2A is primarily expressed in proliferating cells and is crucial for DNA replication, TOP2B is expressed in all cell types and plays a more prominent role in DNA replication, chromatin remodeling, and transcriptional regulation that is closely tied to aging. TOP2B is an essential double-stranded DNA topoisomerase, pivotal in identifying DNA topological configurations and relieving DNA torsional strain via cutting, rotating, and reconnecting DNA strands. TOP2B has been much less studied in the context of aging.
In this study, we investigate whether reduction of Top2 or TOP2B confers a longevity phenotype across species and explore the potential mechanisms. We found that knocking down Top2 or TOP2B extends the lifespan of yeast, 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 or TOP2B reduction attenuates the major hallmarks of aging, such as cellular senescence, deregulated nutrient-sensing, epigenetic alterations, and lysosomal dysfunction. We observed that TOP2B reduction alters the epigenetic landscape of various tissues in old mice toward those of the young animals, and differentially downregulates genes with active promoter and high expression. Our observations suggest that Top2 or TOP2B reduction confers longevity effect via remodeling of epigenetic and transcriptional landscapes and suppression of aberrantly expressed genes in old cells.
Link: https://doi.org/10.1111/acel.70010
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