The keys to longevity lie in the microbes that give us beer and wine

More than three decades ago, Thomas Johnson demonstrated that modifying a single gene, called age 1, extended the lifespan of C. elegans worms by up to 60%. Despite the vast evolutionary distance that separates us from these creatures, useful survival mechanisms pass from branch to branch of the tree of life—conserved in the genomes of many species, including humans. What works on a worm or a mouse – or even a species of yeast – need not work on us. But the results from manipulating the life expectancy of these distant relatives encourage the search for genetic modification.

Three years ago, a team of researchers from the University of California, San Diego (UCSD) discovered a crucial mechanism in the aging process of a single-celled fungus that has been with us since the dawn of civilization. Saccharomyces cerevisiae, a species of yeast used to make bread, beer and wine, follows one of two paths on its way to death. Half of its cells age when their DNA loses stability; the other half, with the deterioration of the mitochondria, the structure that provides the cells with energy.

The same UCSD researchers, led by Nan Hao, have now published a paper in an academic journal Science. They explain how they have created a kind of switch that reverses cellular aging by manipulating two regulators of gene activity. From DNA to mitochondrial decay, the brewer uses a mechanism to keep yeast cells in balance. Similar to a thermostat – when a higher temperature is reached, the refrigerator increases and when a lower temperature is reached, the heating system is activated – synthetic biology is used to implement a similar system. With so-called genetic oscillators, cells change their way of aging when they have gone too far in one of two directions. With this game of balance, scientists have extended the existence of yeast up to 80% – a new world record in biology. The researchers suggest that these types of oscillators could also slow down the path to death that begins every time a cell appears in the human body.

The authors plan to “identify the regulatory genetic circuits [beneath] aging in different types of human cells and apply this engineering strategy to modify them and slow aging,” explains Nan Hao, lead author of the study and co-director of UCSD’s Institute for Synthetic Biology. “If it works, we’ll try to do the same inside living cells in animals like mice,” he adds.

Hao admits that genetic engineering “takes more time in human cells, and the circuits that regulate genes are often more complex. We will need more time and resources to test these ideas and strategies, but I don’t think there is anything major that would prevent us from doing so,” he concludes.

Carlos López Otín, a researcher and aging expert at the University of Oviedo, Spain, recognizes the value of the study by these researchers, who, like others before them, have used “simple models to try to understand the colossal and fascinating complexity. lifes.”

“It may seem strange that from a single-celled organism we can learn about the effects of time on our body, which consists of many trillions of cells. But we should not forget the legendary line from the great Jacques Monod (Nobel Prize laureate in medicine) about the discovery of the first keys to gene regulation in bacteria: ” What is true of bacteria is true of elephant.” [That being said]its extrapolation to human cells and our daily lives still seems far off.

It could contribute to the improvement of our health… something that seems a more reasonable and accessible goal than the pursuit of improbable dreams of immortality

Carlos López Otin, University of Oviedo

“Unicellular organisms [like the yeast used in this experiment] are naturally selfish: their main purpose is to divide. The dream of a bacterium or a yeast is to create its own kind,” explains López Otin. This “cellular selfishness is a goal that our altruistic and supportive cells reject” and accept only when they accumulate molecular damage and transform into tumors.

“For this reason, it is not enough for humans to prevent cellular aging and prolong longevity at all costs. The price of these strategies, which are so publicized and longed for by some, may be the development of serious pathologies, including malignancies, which can significantly reduce human longevity, ” warns López Otin.

For a scientist, these results raise a question: if evolution could have created an oscillator similar to the one created by these authors by modifying just two genes, why hasn’t this happened since the appearance of life more than 3.5 billion years ago. before?

To understand the reason for this gap, while also understanding the cost of extending longevity, López Otin proposes an experiment in which yeasts containing the modified genes are allowed to compete with the corresponding normal yeasts “to analyze whether any of [modified] strains [influence the untouched ones] over time under different conditions. Furthermore, he suggests creating a different kind of oscillator, not to unnecessarily extend longevity, but in an effort to maintain homeostasis—our essential internal balance. “This could contribute to the improvement of our health … something that seems to be a much more reasonable and accessible goal than the pursuit of improbable dreams of immortality,” he concludes.

Jordi García Ojalvo, a researcher at Barcelona’s Pompeu Fabra University and a collaborator of Michael Elovitz, creator of the first synthetic genetic oscillator, believes that “not only the applications that the results of this research could bring. [many years from now], interestingly, 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 of human cells or the 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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