How Fruit Flies Stay Young At Heart

Science
سه شنبه 26 تیر 1397 ساعت 16:9
187
Smith sonian mag
The heart is an astounding workhorse of an organ. With every passing minute, the human heart churns out over a gallon of blood that fuels the rest of the body with oxygen and nutrients. In an average person’s lifetime, the heart will beat more than three billion times , pumping enough blood to fill some 1,200 Olympic-sized pools.
After years hard at work, however, muscles tend to wear thin. Like an overstretched elastic, the heart ultimately loses its resilience, steadily increasing the risk of heart failure.
Today, scientists from the University of California, San Diego report that fruit flies engineered to maintain high levels of a heart-remodeling protein enjoy a much longer lifespan. Their findings are the first to tie structural modifications in muscle tissue to metabolic consequences that ultimately affect longevity.
While cardiac cells don’t have the regenerative capacity of other organs like the liver, the heart comes primed with a comprehensive repair kit . A human heart can charge on for decades beyond its expected warranty, deploying a bevy of backup methods to refurbish and remodel old structures even when cells begin to lose their shape. When a heart’s structural integrity is compromised, a suite of proteins quickly sweeps in to mend the cracks in the foundation.
One of most powerful tools at the heart’s disposal is vinculin —a protein akin to the super glue of cells. As cells in the walls of the heart age, they begin to fray away from each other and die, making it more difficult for the heart to execute each rhythmic squeeze. Vinculin anchors cells to each other and into the surrounding matrix that allows the heart to communicate with the outside environment. This protein becomes increasingly necessary after decades of stress on the muscle, and production increases in the heart with age, allowing cells to patch rifts in aged tissue. Both rodents and human patients with broken copies of the vinculin gene are at particularly high risk of heart failure later in life.
Ultimately, however, remodeling only goes so far: In some, the state of disrepair overwhelms even vinculin’s refurbishing power, and the heart can fail. And as the global average life expectancy increases , so do concerns of cardiac complications of the elderly. By 2030, a quarter of Americans will be above the age of 65 . To continue to forestall the onset of heart disease in an older generation, the development of technology must accelerate to keep pace with the human population.
To study the intersection of heart function and longevity, bioengineers Ayla Sessions and Adam Engler decided to leverage the tools evolution has already provided by pushing the heart’s healing capacity to its limits.
Three years ago, senior author Adam Engler’s group demonstrated the importance of vinculin in keeping animal hearts pumping in old age. After showing that the aged hearts of mice and non-human primates manufacture more vinculin, they wondered about the consequences of ramping up vinculin or removing it entirely.
To circumvent the costly and time-consuming pitfalls of genetically manipulating rodents or monkeys, the researchers modeled their experiments in fruit flies. With a lifespan of just over a month, these insects can go from juvenile to geriatric in a matter of weeks. And while we tend to see insects as foreign pests, humans and flies actually have a great deal in common. Fruit fly organs share a surprising amount of structural similarity with mammals like mice and primates, and more than 80 percent of the genes that contain the instructions to build a fly heart are mirrored in people.
“Fruit fly hearts are structurally similar to human cells,” Engler explains. “But their physiology is so simple. It makes them ideal to study.”
And, just like in humans, the hearts of old flies tend to fail .
In their original work , Engler and his team bred a strain of flies to kick the production of vinculin into overdrive in cardiac tissue. As expected, hearts reinforced with more vinculin stayed strong even as the flies aged, mimicking the pumping efficiency of healthy tissue.
To Engler’s surprise, cranking out extra vinculin in the heart also created “superflies” with remarkably enhanced longevity, sometimes more than doubling fly lifespan . But while this supported the idea that vinculin was critical for a heart tissue tune-up, the researchers didn’t understand how or why this was helping the flies live longer.
In an effort to solve the mystery, lead author Ayla Sessions monitored the health and longevity of the same strain of superflies from several different angles. Once again, the superflies outlived their regular peers—but Sessions additionally found that they also exhibited superior athletic ability , using their newfound powers to scuttle across floors and scale sizable walls.
What’s more, like human athletes, the superflies were more efficient at using oxygen and sugar to power their movements. When Sessions fed the flies a labeled form of glucose, she saw that sugars from the flies’ diet were being funneled into hyper-efficient pathways that churned out extra fuel for cells. In fact, these superflies looked eerily like long-lived flies of past works from other groups—except those flies had undergone lifestyle modifications (like caloric restriction), not genetic ones. Somehow, even though vinculin’s extra structural glue was relegated to only a specific part of the body, this change was having robust and far-reaching consequences on overall health.
“Out of millions of cells [in the fly], just 102 cells [in the heart] end up creating this systemic effect,” Engler says. “And that was pretty surprising to us.”
This is the first time that researchers have linked changes in the mechanics of cells to metabolism, and may provide insight into how having a strong heart maintains a healthy metabolism. Sessions and Engler theorize that the increased strength of the superfly heart is what makes all the difference. With more vinculin to bundle them together, the cells of even an older heart need less fuel to contract efficiently—meaning the heart as a whole is better at utilizing energy. This not only frees up sugars for other tissues, but also equips the heart to better distribute that fuel to the rest of the body. And voila: superfly stamina.
“[It’s good to] focus on living longer, but if quality of life is poor, there’s no benefit to that,” Sessions says. “Not only are we increasing lifespan, but we’re increasing metabolism and energy utilization later in life.”
Because the profiles of vinculin-producing flies so closely resemble those of, say, calorically-restricted flies , Engler feels that this work strongly corroborates the findings of other longevity studies. “You’re tweaking the same pathways, just through different mechanisms—but they achieve the same ends,” he explains.
“Ignoring the circulatory system’s role in metabolism is a little one-sided,” adds Sessions. “Metabolism and heart function go hand in hand.”
In future work, Engler’s team plans to continue to suss out the links between tissue structure and metabolism, mindful of the fact that this information may someday contribute to the synthesis of longevity-promoting drugs—some of which may even target proteins like vinculin.
Kristine DeLeon-Pennell , a professor of cardiovascular sciences at the Medical University of South Carolina who was not affiliated with the study, praises the work for opening new doors in future clinical contexts. “With metabolic syndromes on the rise in cardiac patients, it’s really interesting that vinculin could be a link to what we’re actually seeing in the clinic,” she says, adding that this could equip doctors to better monitor elderly patients with low levels of vinculin.
But Engler cautions that much work still needs to be done: We’re a long way from capitalizing on vinculin in the hearts of humans. “We’re not trying to suggest that there’s a pill you can take, or that you need to start modifying your diet so you maintain your metabolism for longer,” he explains. “And it’s certainly not the fountain of youth.”
DeLeon-Pennell also stresses that the work should be confirmed in more complex organisms like mammals before the research can progress.
For now, there’s still good news: Flies can be bred to live longer.
The bad news? Flies can be bred to live longer.
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