More than three decades ago, Thomas Johnson demonstrated that changing a single gene – called age 1 – increased the lifespan of C. elegans worms by up to 60%. Despite the vast evolutionary distance that separates us from these creatures, useful survival mechanisms leap from branch to branch of the tree of life—they are conserved in the genomes of many species, including humans. What works for a worm or a mouse – or even a species of yeast – may not work for us. But the results of manipulating the life expectancy of these distant relatives encourage the search for genetic modifications.
Three years ago, a group of researchers from the University of California at San Diego (UCSD) found an essential mechanism in the aging process of a unicellular fungus that has accompanied us since the dawn of civilization. The yeast species Saccharomyces cerevisiae – from which bread, beer and wine are made – follows one of two directions on its way to death. Half of his cells age as their DNA loses stability; the other half, with the deterioration of the mitochondria, a structure that supplies the cell with energy.
The same UCSD researchers – led by Nan Hao – have now published an article in the journal Science. They explain how they created a kind of switch that reverses cell aging by manipulating two regulators of gene activity. From DNA to the breakdown of mitochondria, a brewer uses a mechanism to keep yeast cells in balance. Similar to a thermostat – where when a higher temperature is reached the refrigerator heats up and when a lower temperature is reached it turns on a heating system – synthetic biology is applied to introduce a similar system. Using what is known as a genetic oscillator, cells alter their aging when they have gone too far in either of two directions. With this weighing game, the scientists have extended the existence of yeast by up to 80% – a new world record in biology. The researchers suggest that this type of oscillator could also serve to slow down the path to death, which begins each time a cell appears in the human body.
The authors intend to “identify the regulatory genetic circuits [beneath] aging in different types of human cells and apply this engineering strategy to modify them and slow down their aging,” explains Nan Hao, lead author of the study and co-director of the Institute of Synthetic Biology at UCSD. “If it works, we will try to do the same thing in cells in live animals like mice,” he adds.
Hao acknowledges that genetic engineering “takes more time in human cells, and the circuits that regulate genes are often more complicated. We will need more time and resources to test these ideas and strategies, but I don’t think anything fundamental is preventing us from doing so,” he concludes.
Carlos López Otín – researcher at the University of Oviedo (Spain) and expert on aging – recognizes the value of the study of these researchers who, like others before them, “have used simple models to try to understand the colossal and fascinating complexity understanding of life.”
“It may seem strange that we can learn lessons from a single-celled organism about the effects of time on our bodies, which are made up of many trillions of cells. But we shouldn’t forget a legendary phrase from the great Jacques Monod (Nobel Prize winner in Medicine), who discovered the first keys to gene regulation in bacteria: “What applies to a bacterium also applies to an elephant.” [That being said]its transmission to human cells and our daily lives seems far away.”
This could help improve our health…something that seems like a more sensible and affordable goal than pursuing improbable dreams of immortality
Carlos López Otín, University of Oviedo
“Protozoa [like the yeast used in this experiment] are selfish by nature: their main goal is division. The dream of a bacterium or yeast is to create others like them,” explains López Otín. This “cellular selfishness is a purpose that our altruistic and supportive cells reject” and only adopt when – through accumulation of molecular damage – they transform and become tumorous.
“Therefore, in humans it is not enough to prevent cell aging at all costs and to extend lifespan. The price of these strategies — so publicized and longed for by some — can be the development of serious pathologies, including malignant tumors, that can significantly shorten human lifespan,” warns López Otín.
The question that arises for the scientist from these results is: if evolution could have created an oscillator similar to the one created by these authors by changing just two genes, why hasn’t this been since the appearance of life more than 3, happened 5 billion years ago? before?
To understand the reason for this gap—while also understanding the cost of extending lifespan—López Otín suggests conducting an experiment in which yeasts carrying the modified genes are allowed to compete with the corresponding normal yeasts “to analyze , whether one of [modified] tribes [influence the untouched ones] over time under different conditions.” Furthermore, he suggests creating other types of oscillators, not to unnecessarily increase lifespan, but to maintain homeostasis – our essential inner balance. “This could help improve our health…something that seems like a more reasonable and affordable goal than chasing unlikely dreams of immortality,” he concludes.
For Jordi García Ojalvo – a researcher at the Universitat Pompeu Fabra in Barcelona and a collaborator of Michael Elowitz, creator of the first synthetic genetic oscillator – he believes that “go beyond the applications that the results of this study could have [many years from now], the interesting thing is that it shows how synthetic biology can be used to understand how organisms work and how they age. It helps us push the boundaries of that knowledge.”
“Aging in human cells or in a whole organism is very complicated. But all cells on Earth have 20 amino acids and the same four nucleic acids,” he adds. “What we learn from these cells can be useful to look for applications.”
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