In yeast, altering genetic circuitry that controls how an aging cell dies enhances longevity

Engineering a synthetic oscillator that cycles between the two deterioration pathways that lead to cell death can slow aging in yeast cells, increasing their longevity by more than 80%, a new study reports. The findings represent a proof-of-concept example of using synthetic biology to reprogram the cellular aging process. Given that the underlying aging pathways are conserved, the findings may one day enable the design of synthetic gene circuits that promote longevity in more complex organisms. Cellular aging is a fundamental and complex biological process and is an underlying driver for many diseases. Although recent advances in synthetic biology have enabled the design of gene networks to control specific cellular functions, the ability to rationally engineer complex traits like cellular longevity remains elusive. Cellular aging in yeast (Saccharomyces cerevisiae) – a single-celled microorganism that has proven to be a genetically tractable model for the aging of mitotic cell types – is controlled by a genetic circuit that guides an aging cell to die in one of two ways: either rDNA instability or mitochondrial dysfunction. Leveraging this mechanism, Zhen Zhou and colleagues controlled aging in yeast cells by manipulating the expression of two conserved transcriptional regulators: silent information regulator 2 (Sir2), which drives nucleolar decline, and heme activator protein 4 (Hap4), which is associated with mitochondrial biogenesis. The expression of Sir2 and Hap4 are linked in that expression of one cross-represses the other. The result is a naturally occurring and widely conserved transcriptional toggle-switch that drives cellular fate decisions. Zhou et al. engineered a synthetic gene oscillator within yeast cells that re-wires this transcriptional toggle switch to generate sustained oscillations between the two states of cellular degeneration in individual cells. By creating a negative feedback loop in the Sir2-HAP circuit, the synthetic oscillator delays the commitment of yeast to one of the two cellular deterioration states. Zhou et al. found that cells containing the synthetic gene oscillator lived considerably longer – exhibiting an 82% increase in lifespan compared to that of wild type cells. In a related Perspective, Howard Salis discusses the study in greater detail.  Reflecting on how the results may inform development of human therapeutics, he writes, “If the collective objective of these interven­tions is to maintain healthier cell states, then the risk and morbidity of age-associated dis­eases will be reduced.”