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
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