Posted on Apr 27, 2023, 4 p.m.
A few years ago researchers from the University of California-San Diego reported that they deciphered some essential mechanisms of the aging process, and after identifying 2 distinct directions cells follow during the process they were able to genetically manipulate these processes to extend the lifespan of cells.
Recent research published in Science expands on the previous work using synthetic biology to engineer a solution that prevents cells from reaching the normal levels of age-related deterioration. Cells from plants, animals, humans and yeast all contain gene regulatory circuits responsible for many physiological functions which includes aging. But, according to the researchers, under the control of a central gene regulatory circuit cells will not necessarily age the same way.
“These gene circuits can operate like our home electric circuits that control devices like appliances and automobiles,” said Professor Nan Hao of the School of Biological Sciences’ Department of Molecular Biology, the senior author of the study and co-director of UC San Diego’s Synthetic Biology Institute.
For this study, the team was envisioning a smart aging process capable of extending longevity by cycling deterioration from one aging mechanism to another. As such they genetically rewired the circuit that controls cell aging from the normal task of functioning like a toggle switch by engineering a negative feedback loop to stall the aging process. It was rewired to operate as a clock-like device (gene oscillator) that drives the cells to periodically alternate between two detrimental aged states while avoiding prolonged engagement with either of them, resulting in the slowing of the cell’s age-related degeneration.
In fact, the anti-aging advances made in this study have resulted in dramatically extending cellular lifespan and is reported to have set a new record for life extension through genetic and chemical interventions.
“This is the first time computationally guided synthetic biology and engineering principles were used to rationally redesign gene circuits and reprogram the aging process to effectively promote longevity,” said Hao.
Initially, computer simulations of how the core aging circuit operates were used which helped the team design and test ideas before engineering or modifying the cell’s circuit. This strategy has advantages in time management as well as resource management to identify effective longevity-extending strategies compared to more traditional genetic methods.
The multidisciplinary team began investigating the mechanisms behind cell aging several years ago, discovering that cells follow a cascade of molecular changes through their lifespan until degenerating and death. They found that cells of the same genetic material within the same environment can travel distinct aging routes, with close to half of the cells aging through a gradual decline in DNA stability, and the rest aging along a path tied to the decline of the mitochondria.
This synthetic biology achievement reveals the potential to delay the aging process. This work provides evidence that slowing the aging clock is possible by actively preventing cells from committing to the predetermined path of decline and eventual death, and these clock-like gene oscillators may be a universal system to help achieve the goal of reconfiguring scientific approaches to delay aging.
“Our results establish a connection between gene network architecture and cellular longevity that could lead to rationally-designed gene circuits that slow aging,” the researchers note in their study.
Saccharomyces cerevisiae yeast cells were used as a model for the aging of human cells for this study, and the team developed as well as employed microfluidics and time-lapse microscopy to track the aging process spanning the cell’s lifespan. Yeast cells that were synthetically rewired and aged under the direction of the oscillator device experienced an 82% increase in longevity compared to the unaltered controls. Which was noted to be “the most pronounced lifespan extension in yeast that we have observed with genetic perturbations.”
“Our oscillator cells live longer than any of the longest-lived strains previously identified by unbiased genetic screens,” said Hao.
“Our work represents a proof-of-concept example, demonstrating the successful application of synthetic biology to reprogram the cellular aging process,” the authors wrote, “and may lay the foundation for designing synthetic gene circuits to effectively promote longevity in more complex organisms.”
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