A team of researchers has developed a biosynthetic genetic clock that significantly extends cellular lifespan, as reported in the journal ‘Science’. The study involved genetically rewiring the gene regulatory circuit that controls cell aging, transforming it from a toggle switch to a clock-like device or gene oscillator. This oscillator periodically switches the cell between two detrimental aged states, thereby preventing prolonged commitment to either and slowing cell degeneration. The team used yeast cells in their study and achieved an 82% increase in lifespan compared to control cells. This ground-breaking research, underpinned by computational simulations and synthetic biology, could revolutionize scientific approaches to age delay, going beyond attempts to artificially revert cells to a state of ‘youth’. The team is now expanding its research to human cell types.

The human lifespan is tied to the aging of individual cells, and a group of researchers from the University of California San Diego (UCSD) has been working to decipher the mechanisms behind this process. Three years ago, they identified two distinct directions that cells follow during aging and genetically manipulated these processes to extend cell lifespan. In their recent study, published in the journal Science on April 27, 2023, they used synthetic biology to engineer a solution that keeps cells from reaching their normal levels of deterioration associated with aging.

The researchers discovered that cells follow a cascade of molecular changes through their entire lifespan until they eventually degenerate and die. However, they also found that cells of the same genetic material and within the same environment can follow distinct aging routes. About half of the cells age through a gradual decline in the stability of DNA, while the other half ages along a path tied to the decline of mitochondria, the energy production units of cells.

The University of California San Diego (UCSD) researchers envisioned a "smart aging process" that extends cellular longevity by cycling deterioration from one aging mechanism to another. To achieve this, they genetically rewired the circuit that controls cell aging, engineering a negative feedback loop to stall the aging process. The rewired circuit operates as a clock-like device, called a gene oscillator, that periodically switches the cell between two detrimental "aged" states, avoiding prolonged commitment to either and thereby slowing the cell's degeneration.



The researchers first used computer simulations to design and test their ideas before building or modifying the circuit in the cell. This approach saves time and resources compared to more traditional genetic strategies. The team studied Saccharomyces cerevisiae yeast cells as a model for the aging of human cells and employed microfluidics and time-lapse microscopy to track the aging processes across the cell's lifespan.

In the current study, yeast cells that were synthetically rewired and aged under the direction of the synthetic oscillator device resulted in an 82% increase in lifespan compared to control cells that aged under normal circumstances. This result represents the most pronounced lifespan extension in yeast observed with genetic perturbations. The researchers believe their work represents a proof-of-concept example demonstrating the successful application of synthetic biology to reprogram the cellular aging process and may lay the foundation for designing synthetic gene circuits to effectively promote longevity in more complex organisms.



The team is expanding its research to the aging of diverse human cell types, including stem cells and neurons. Ultimately, their research could reconfigure scientific approaches to age delay by slowing the ticks of the aging clock and actively preventing cells from committing to a pre-destined path of decline and death. The clock-like gene oscillators could be a universal system to achieve this.

References

“Engineering longevity—design of a synthetic gene oscillator to slow cellular aging” by Zhen Zhou, Yuting Liu, Yushen Feng, Stephen Klepin, Lev S. Tsimring, Lorraine Pillus, Jeff Hasty and Nan Hao, 27 April2023, Science. DOI: 10.1126/science.add7631

The research team, Zhen Zhou, Yuting Liu, Yushen Feng, Stephen Klepin, Lev Tsimring, Lorraine Pillus, Jeff Hasty and Nan Hao, are based across UC San Diego, including the Department of Molecular Biology (School of Biological Sciences), Synthetic Biology Institute, Moores Cancer Center (UC San Diego Health) and Shu Chien-Gene Lay Department of Bioengineering (Jacobs School of Engineering).

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