Scientists’ biosynthetic genetic ‘clock’ can ‘stall the aging process’ and extend lifespan.
Human lifespan is intricately connected to the aging process of individual cells, and this means that scientists have spent decades trying to unravel the mysteries of cellular aging and exploring methods to slow down the ticking of the aging clock.
Longevity.Technology: In 2020, a group of researchers from the University of California San Diego identified two distinct mechanisms of cellular aging and genetically manipulated them to extend cell lifespan . Now, their research has progressed to employ synthetic biology and gene circuits to delay the deterioration associated with cellular aging . The team’s innovative approach could revolutionize scientific methods of aging prevention and contribute to reprogramming aging pathways in various human cell types.
Publishing in Science, the researchers describe how cells in yeast, plants, animals and humans all contain gene regulatory circuits responsible for several physiological functions, including aging. These gene circuits, akin to electric circuits controlling household devices, can operate in different ways, and the UC San Diego team discovered that cells don’t necessarily age the same way – it all depends on their genetic material and environment. The researchers found that cells can age either through DNA stability decline or mitochondrial decline.
“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 .
So, once these functions are understood, can they be varied? In order to promote longevity, the team reprogrammed the circuit that controls cell aging, using synthetic biology to design and build a clock-like gene oscillator that periodically switches cells between two detrimental “aged” states; this avoids prolonged commitment to either, and thereby slows the cell’s degeneration.
The researchers engineered a negative feedback loop to stall the aging process and created a “smart aging process” that extends cellular longevity by cycling deterioration from one aging mechanism to another. This approach led to a dramatically extended cellular lifespan, setting a new record for life extension through genetic and chemical interventions .
Using computational simulations, the researchers tested ideas before modifying the circuit in the cell, which proved advantageous in saving time and resources to identify effective longevity strategies.
“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 .
In their study, the team studied Saccharomyces cerevisiae yeast cells as a model for the aging of human cells. The researchers developed and employed microfluidics and time-lapse microscopy to track the aging processes across the cell’s lifespan. Yeast cells that were synthetically rewired and aged under the direction of the synthetic oscillator device resulted in an 82% increase in lifespan compared with control cells that aged under normal circumstances .
The team’s findings represent a proof-of-concept example that demonstrates the successful application of synthetic biology to reprogram the cellular aging process. The authors note that their results establish a connection between gene network architecture and cellular longevity, which could lead to rationally-designed gene circuits that slow aging . Their approach is distinct from numerous chemical and genetic attempts to force cells into artificial states of “youth,” as it actively prevents cells from committing to a pre-destined path of decline and death.
The potential implications of these findings could be far-reaching, and the researchers note that their method has the potential to reconfigure scientific approaches to age delay . The clock-like gene oscillators could serve as a universal system to promote longevity and could be the foundation for designing synthetic gene circuits to effectively promote longevity in more complex organisms. The team is currently expanding their research to the aging of diverse human cell types, including stem cells and neurons.
The UC San Diego team’s findings represent a significant advancement in the understanding and potential manipulation of the aging process. The researchers’ innovative approach employing synthetic biology and gene circuits represents a promising avenue for reprogramming aging pathways in various human cell types, and if the research can be successfully expanded to more complex organisms, it could pave the way for new strategies to promote longevity and reduce the incidence of age-related diseases