Adaptation to a common cell protein gene extends healthy lifespan by 30%

Not only have researchers identified how a common cellular protein affects aging, but they also modified the genes that produce it in fruit flies, extending healthy lifespan by 25% to 30%. The discovery opens the door to healthier aging in people.

The cytoskeleton provides most cells with their shape, structure, and internal organization. The cytoskeleton in turn depends on a type of actin protein called filamentous or F-actin. It forms networks of thin, flexible filaments that influence the shape, stiffness and movement of cells. Studies found that aging alters actin expression, disrupting cytoskeletal functions, which can lead to age-related diseases, including cancer and neurodegenerative diseases.

A new study by UCLA researchers has examined the role of actin in brain aging and found that when F-actin builds up in the brain, it hinders cell clearance and leads to the accumulation of waste that reduces neuronal functioning and contributes to cognitive decline. However, they also found that modifying some genes in fruit flies prevented the build-up of F-actin and extended the flies’ healthy lifespan by about 30%.

“Flies become more forgetful as they age, and their ability to learn and remember declines in middle age, just like humans,” said David Walker, the study’s corresponding author and professor in the Department of Integrative Biology and Physiology at UCLA. “If we prevent the build-up of F-actin, it helps the flies learn and remember when they are older – which tells us that the build-up is not benign.”

Autophagy (from the Ancient Greek for ‘self-eating’) is the body’s cellular recycling system. This vital process breaks down and cleans up old, damaged, or abnormal proteins and other cellular substances. There is increasing evidence that autophagic activity decreases with age, including in the brain.

The researchers experimented with a Drosophila – fruit fly – model, in which the F-actin in the brains of naturally aging animals is examined. They compared the brains of young, middle-aged and late-life flies and observed a significant increase in total F-actin levels in the brain as they aged.

To determine whether the observed F-actin levels reflected age or occurred universally over time, the researchers next examined flies with dietary and/or protein restriction, an approach that has been shown to slow aging and improve promotes longevity. They found that flies fed a low-protein diet had significantly longer lifespans than flies fed a high-protein diet. Furthermore, they saw F-actin in the brains of flies fed a rich diet in middle age, which was not seen in the brains of diet-restricted flies.

Rapamycin, a small molecule shown to extend lifespan, was then given to the flies. Feeding rapamycin to flies significantly increased their lifespan compared to flies fed a control. In addition, old flies given rapamycin had significantly less F-actin in the brain than age-matched controls. Taken together, findings suggested that age-related F-actin reflected healthy aging in fruit flies and could be counteracted by strategies to improve lifespan.

“But that’s a correlation, not a direct demonstration that F-actin is harmful to brain aging,” Walker said. “To figure out causality, we turned to genetics.”

Because the fruit fly genome has been completely mapped, researchers can target aging fly genes known to play a role in actin filament accumulation. They discovered that taking down the Formin homology 2 domain containing ortholog (Phos) gene in fruit fly neurons prevented the accumulation of F-actin in the brain.

“When we reduced Phos expression in aging neurons, it prevented the accumulation of F-actin in the brain,” said Edward (Ted) Schmid, who worked in Walker’s UCLA lab and is the lead author of the study. “This really allowed us to expand our studies because we now had a direct way to target the accumulation of F-actin in the brain and study how this affects the aging process.”

Although the genetic ‘tweak’ only targeted neurons, the researchers saw that it improved the flies’ overall health. They lived 25% to 30% longer and showed signs of improved brain function and markers of improved health in other organs. Preventing the accumulation of F-actin protected cognitive functions, suggesting that the accumulation causes age-related cognitive decline.

Closer examination revealed that the F-actin had disrupted the cell’s recycling system. The researchers found that preventing F-actin accumulation caused more autophagy in the brains of older fruit flies. If they removed F-actin And disabled autophagy, aging was not slowed down. It appeared that the primary mechanism by which F-actin caused brain aging was by interfering with autophagy. The researchers also showed that disrupting F action in older brains restored brain autophagy to the levels seen in youth and reversed certain cellular markers of brain aging.

Of course, these findings need to be translated to humans, which may prove more challenging. But challenges are what researchers are for, right?

“Most of us in the aging field are focused on moving beyond lifespan into what we call healthspan,” Walker says. “We want to help people enjoy good health and a high quality of life while extending their lifespan. Our study improved cognitive and gut function, activity levels and overall health in fruit flies – and offers hope for what we could achieve in humans.”

The research was published in the journal Nature communication.

Source: UCLA