The de novo design and synthesis of yeast chromosome XIII facilitates investigations on aging

In the era of synthetic biology, design, construction, and utilization of synthetic chromosomes with unique features provide a new strategy to study complex cellular processes such as aging. Herein, we successfully constructed the 884 Kb synXIII of Saccharomyces cerevisiae to investigate replicative aging using this synthetic strains. We verified that up-regulation of a rRNA-related transcriptional factor, RRN9, positively influenced replicative lifespan. Using SCRaMbLE system that enables inducible whole-genome rearrangement on synXIII, we obtained 20 SCRaMbLEd synXIII strains with extended lifespan. Transcriptome analysis revealed the expression of genes involved in global protein synthesis is up-regulated in longer-lived strains. We established causal links between genotypic change and the long-lived phenotype via reconstruction of some key structural variations observed in post-SCRaMbLE strains and further demonstrated combinatorial effects of multiple aging regulators on lifespan extension. Our findings underscored the potential of synthetic yeasts in unveiling the function of aging-related genes.