A “smart aging process” that extends cellular longevity by cycling deterioration from one aging mechanism to another.
Through the study of yeast cells, a team of researchers has successfully constructed a biosynthetic genetic ‘clock’ capable of extending the lifespan of cells. The duration of human life is closely intertwined with the aging process of our individual cells.
Three years ago, a group of esteemed scientists from the University of California San Diego unraveled the fundamental mechanisms driving aging.
By identifying two distinct paths that cells undertake during this process, the researchers were able to genetically manipulate these pathways, resulting in an extension of cell lifespan.
In a groundbreaking study published in Science, the researchers have expanded upon their earlier work by employing synthetic biology to engineer a groundbreaking solution.
This innovative approach prevents cells from succumbing to the usual levels of deterioration typically associated with aging.
It is worth noting that cells, regardless of their origin in yeast, plants, animals, or humans, possess gene regulatory circuits responsible for numerous physiological functions, including the aging process itself. This latest research represents a significant stride forward in our quest to comprehend and potentially counteract the effects of aging at the cellular level.
“These gene circuits can operate like our home electric circuits that control devices like appliances and automobiles,” remarks senior author Professor Nan Hao.
UC San Diego Group Discovers Unique Aging Patterns: Cells Don’t Age Simultaneously
Imagine a car that ages in different ways depending on whether the engine deteriorates or the transmission wears out. That’s exactly what the UC San Diego group found when studying cells under the control of a central gene regulatory circuit. In the study, the researchers uncovered that cells can follow distinct aging mechanisms without aging in tandem.
Inspired by this finding, the UC San Diego team embarked on a quest to develop a “smart aging process” that could prolong cellular longevity. Their latest study introduces a remarkable genetic rewiring of the cell aging control circuit. Transforming its traditional role into a negative feedback loop, the researchers engineered a mechanism to halt the aging process.
The rewired circuit acts as a gene oscillator, akin to a clock-like device, compelling the cell to periodically transition between two detrimental “aged” states. By avoiding prolonged commitment to either state, this innovative approach effectively decelerates the cell’s degeneration, offering new hope for extended cellular health and vitality.
These breakthroughs have led to a remarkable increase in the lifespan of cells, establishing a groundbreaking achievement in extending life through genetic and chemical interventions.
Following a methodology commonly employed by electrical engineers, the team involved in this study initially employed computer simulations to comprehend the functioning of the fundamental aging circuit. This enabled them to design and evaluate concepts before implementing or altering the circuit within the cell. This approach offers significant advantages in terms of time and resource efficiency for identifying effective strategies to promote longevity, surpassing conventional genetic methods.
“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,” adds Hao.
Several years ago, a multidisciplinary research team at the University of California, San Diego began investigating the mechanisms underlying cell aging, a complex biological process underlying human longevity and numerous diseases. They found that during their whole existence, cells undergo a series of chemical modifications before finally deteriorating and dying. But they found that cells with the same genetic information and that live in the same place can age in different ways. The DNA, which is where genetic information is stored, gradually becomes less stable as cells become older, which affects around half of all cells. The other half ages in a manner connected to the deterioration of mitochondria, the parts of cells that produce energy.
The latest breakthrough in synthetic biology has the potential to change how scientists think about age delay.
In contrast to various chemical and genetic interventions aimed at coercing cells into artificial states of “youth,” the latest research presents compelling evidence that the deceleration of the aging process can be achieved by actively impeding cells from following a predetermined trajectory of deterioration and mortality. Moreover, the clock-like gene oscillators discovered in this study hold the potential to serve as a universally applicable system in achieving this goal.
“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 write in their study.
During their investigation, the team examined Saccharomyces cerevisiae yeast cells as a representative model for human cell aging. To monitor the aging processes throughout the lifespan of these cells, the researchers utilized microfluidics and time-lapse microscopy techniques.
In the present study, the researchers subjected yeast cells to synthetic rewiring and guided their aging using a synthetic oscillator device. Remarkably, these manipulated cells exhibited an impressive 82% increase in lifespan compared to control cells that aged naturally. The findings demonstrated the most substantial extension of yeast lifespan achieved through genetic modifications, as emphasized by the researchers.
“Our oscillator cells live longer than any of the longest-lived strains previously identified by unbiased genetic screens,” adds Hao.
“Our work represents a proof-of-concept example, demonstrating the successful application of synthetic biology to reprogram the cellular aging process,” the authors add, “and may lay the foundation for designing synthetic gene circuits to effectively promote longevity in more complex organisms.”
The team is now looking into how different types of human cells, like stem cells and nerves, change as they age.
Source: 10.1126/science.add7631
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