Longevity: Scientists use genetic rewiring to increase cells' lifespan

• Human lifespans have increased throughout the 20th and 21st centuries, but those increases are slowing down, so scientists continue to hunt for ways to improve longevity.
• Healthful diets, hygiene, and medical care have all contributed to the increases in lifespan, and now researchers are looking to genetics.
• In a new proof-of-concept study, researchers almost doubled the lifespan of yeast cells by genetically rewiring the circuit that controls aging.
• Their findings may pave the way to increasing longevity in more complex organisms and, possibly, even in people.

We all strive to live long and healthy lives, but can you lengthen your life? The National Institutes of Health (NIH) tell us that the best way to increase lifespan is to eat well, get quality sleep, exercise regularly, get regular medical checkups, and avoid bad habits such as smoking and drinking excessive alcohol.

Scientists working to combat the aging process have extended the lifespans of worms, mice, and even monkeys. But could they do the same for people?

Now, a team from the University of California, San Diego, has managed to extend the lifespan of a simple organism by around 80% by manipulating the genetic circuit that controls aging.

The proof-of-concept study carried out in yeast is published in Science.

Synthetic biology behind cell aging

The UC San Diego research team has been studying cell aging for several years, discovering that cells follow a cascade of molecular changes throughout their life until they eventually degenerate and die. However, they found that not all cells age in the same way, and this was the focus of their new research.

They first used computer simulations of cell aging to test their ideas before moving on to modifying the aging circuits in the single-celled yeast Saccharomyces cerevisiae.

They discovered that the cells followed one of two aging routes. Around half of the cells underwent a gradual decline in the stability of their DNA (nucleolar aging); for the rest, the aging path was characterized by a decline in their mitochondria – the organelles that provide energy for the cell (mitochondrial aging).

Manipulating gene expression to increase lifespan

To control the aging of the cells, they manipulated the expression of two conserved transcriptional regulators — molecules that determine which genes are active in the cell. Silent information regulator 2 (Sir2) drives nucleolar decline (leading to DNA instability), and heme activator protein 4 (Hap4) is associated with the mitochondrial activity.

When one of these regulators is expressed and therefore active, it stops the other from being expressed, so the researchers engineered a synthetic gene oscillator to re-wire this mechanism. By generating sustained oscillations between the two types of cellular degeneration in individual cells, they prevented the cells from following either of the two aging routes. The lifespan of these cells increased.

Prof. Nan Hao, senior author of the study and co-director of the UC San Diego’s Synthetic Biology Institute, told Medical News Today:

“Our work is a proof-of-concept, showing that, like mechanical engineers can fix and enhance our cars so that they can last longer, we can also use the same engineering approach to modify and enhance our cells to live longer. The highlight is our approach to achieve that: using computers to simulate the natural aging system and guide the design and rational engineering of the system to extend lifespan.”

Lifespan almost doubled after genetic rewiring

By creating the gene oscillator, the scientists made the yeast cells continually switch between the two aging pathways, preventing them from committing to their pre-destined path of decline and death, slowing the cells’ degeneration.

Those yeast cells that were synthetically rewired and aged under the direction of the synthetic oscillator had an 82% increase in lifespan compared with control cells.

And the genetic manipulation did not appear to adversely affect them, according to Prof. Hao, who told MNT: “The yeast cells survive nicely with a fast growth rate.”

Potential application to improve longevity

“This is the first time this computationally-guided engineering-based approach [has been] used in aging research. I can’t see why we cannot apply the same strategy to human cells.”

– Prof. Nan Hao

All cells contain gene regulatory circuits that are responsible for many physiological functions, including aging, so in theory, a similar approach could work in human cells.

The aim may not only be to extend the life of more complex organisms but to extend the life of some cells within organisms to prevent degenerative diseases.

However, Prof. Hao cautioned that they do not know whether increasing longevity might affect the cells in other ways:

“That’s a deep biological question. Our current hypothesis is that the longevity of the cell is not a trait selected through evolution. Cells have to first be able to survive in the rapidly changing, unpredictable stressful environment.”

“There is a possibility that our engineered long-lived cells will be less resistant to certain types of stresses in the environment. So basically, extending longevity might sacrifice some normal functions, but that’s just a hypothesis,” he added.

Implications on increasing healthy life years for people?

Prof. Hao suggested that there may be potential for this approach in people:

“Both of the two regulators have counterparts in humans, so I do believe that the same strategy could be applied to human cells. In fact, that’s our next step in the future.”

And Prof. Howard Salis, Principal Investigator at the Salis Lab, Penn State University, who was not involved in the study, agreed:

“If the collective objective of these interven­tions is to maintain healthier cell states, then the risk and morbidity of age-associated dis­eases will be reduced.”

However, it is very early days, and although this study shows that it is possible to switch off aging mechanisms in a single-celled organism, there are many questions to be answered before the technology might be applied to people.

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