Scientists have achieved a significant breakthrough in the effort to slow the aging process with a novel technique that increased the lifespans of yeast cells by a whopping 82 percent, reports a new study.
By programming cells to constantly switch between two aging pathways, researchers were able to prevent them from fully committing to either deteriorative process, a method that nearly doubled the lifespan of the cells. In other words, rather than the entire cell aging at once, the aging process was toggled between different physical parts of the organism, extending its life. This synthetic “toggle switch” offers a potential roadmap toward treatments that could one day extend human longevity, though that future is highly speculative at this time.
We are born, we age, we die—so goes the story of humanity since time immemorial. However, this familiar progression could be shaken up by enormous advances in genetics that have opened new windows into the underlying biological mechanisms that cause us to age, raising the possibility that they could be rewired to extend our lifespans.
Now, a team of scientists at the University of California, San Diego (UCSD), have developed a new solution to this age-old problem that essentially tricks cells into waffling between two common deteriorative processes in cells. Using synthetic biology, the researchers genetically reprogrammed a circuit that chooses between these divergent paths toward death, causing it to constantly oscillate between its fates instead of actually dedicating itself to one.
These “oscillations increased cellular lifespan through the delay of the commitment to aging,” a result that establishes “a connection between gene network architecture and cellular longevity that could lead to rationally designed gene circuits that slow aging,” according to a study published on Thursday in Science.
“The circuit resembles a toggle switch that drives the fate decision and progression toward aging and death,” said Nan Hao, a professor of molecular biology at UCSD and a senior author of the study, in an email to Motherboard.
“Once the fate of a cell is determined, then it will have accelerated damage accumulation and progression to death,” continued Hao, who also serves as co-director of UCSD’s Synthetic Biology Institute. “[I]t became obvious to us that if we could rewire this naturally-occurring toggle switch circuit to an oscillator, it will make the cell to cycle between the two pre-destined aging paths and prevent the cell from making this fate decision toward deterioration and death, and it will make the cell live longer.”
Hao and his colleagues have been working on cellular aging for seven years, focusing on the concept of an oscillator for much of that time. In 2020, the researchers published another study, also in Science, that identified two major fates for budding yeast cells. About half of the cells they observed aged due to the deterioration of structures within the cellular nucleus, a cluster that holds most of an organism’s genome. The other half aged when the energy production units of the cell, known as mitochondria, started to break down over time.
Those observations transformed the oscillator concept from “an abstract idea to an executable idea,” Hao said. To build on the 2020 findings, the researchers used computer simulations of aging-related genetic circuits to develop a synthetic strain that could spark the desired feedback loop between the nucleolar and mitochondrial aging processes. In the new study, they introduced the synthetic oscillator into cells of the yeast species Saccharomyces cerevisiae, a model organism that has already shed light on many of the genetic factors that influence longevity in complex organisms, such as humans.
The approach resulted in an 82 percent increase in the lifespan of cells with the synthetic oscillators, compared with a control sample of cells that aged under normal circumstances, which is “the most pronounced life-span extension in yeast that we have observed with genetic perturbations,” according to the study.
“A major highlight of the work is our approach to achieve longevity: using computers to simulate the natural aging system and guide the design and rational engineering of the system to extend lifespan,” Hao told Motherboard. “This is the first time this computationally-guided engineering-based approach has been used in aging research. Our model simulations actually predicted that an oscillator can double the lifespan of the cell, but we were happily surprised that it actually did in experiments.”
The study is part of a growing corpus of mind-boggling research that may ultimately stave off some of the unpleasant byproducts of aging until later in life, while boosting life expectancy in humans overall. Though countless hurdles have to be cleared before these treatments become a reality, Hao thinks his team’s approach could eventually be applied to humans.
“I don’t see why it cannot be applied to more complex organisms,” Hao said. “If it is to be introduced to humans, then it will be a certain form of gene therapy. Of course it is still a long way ahead and the major concerns are on ethics and safety.”
“The other possibility is that if maintaining oscillations is a universal mechanism to keep cellular homeostasis (making everything in balance in the cell) and promote longevity, we may be able to develop pharmacological or nutritional interventions that can be applied periodically with an optimal timing, which is much safer,” he noted.
To that end, Hao and his colleagues are currently exploring whether the same concept could work in human cells, such as stem cells.
“Our work represents a proof-of-concept, 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 concluded in the study.
Source : VICE