Not only did researchers identify how a common cellular protein affects aging, they also modified the genes that produce it in fruit flies, extending healthy lifespans by 25 to 30 percent. This discovery opens the door to healthier aging in humans.

The cytoskeleton provides most cells with their shape, structure, and internal organization. In turn, the cytoskeleton relies on a type of actin protein, called filamentous or F-actin. It forms networks of thin, flexible filaments that affect 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 led by UCLA researchers investigated the role of actin in brain aging and found that when F-actin builds up in the brain, it hinders cellular cleaning and leads to accumulation waste that reduces neuronal functioning and contributes to cognitive decline. However, they also found that changing certain genes in fruit flies prevented the accumulation of F-actin and extended the healthy lifespan of the flies by about 30%.

“Flies forget more as they age, and their ability to learn and remember declines in middle age, just like in humans,” said David Walker, corresponding author of the study and professor in the department. in Integrative Biology and Physiology from UCLA. “If we prevent the accumulation of F-actin, it helps the flies learn and remember their age – which tells us that this accumulation is not benign.”

Autophagy (from the ancient Greek meaning “to eat oneself”) is the body’s cellular recycling system. This vital process breaks down and cleans old, damaged, or abnormal proteins and other cellular substances. There is growing evidence that autophagic activity declines with age, including in the brain.

The researchers experimented on a Drosophila – fruit fly – model examining F-actin in the brains of naturally aging animals. 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.

Nature Communications/Edward Schmid

To determine whether the F-actin levels they observed reflected age or occurred universally over time, the researchers next examined flies subjected to dietary and/or protein restriction, an approach that proven effective in slowing aging and promoting longevity. They found that flies fed a low-protein diet had a significantly longer lifespan than those fed a high-protein diet. Additionally, they observed F-actin in the brains of flies fed a high diet at a young middle age, which was not observed in the brains of flies fed a food restriction.

Rapamycin, a small molecule that has been shown to extend lifespan, was then administered to the flies. Feeding flies rapamycin significantly extended their lifespan compared to those fed a control. Additionally, aged flies fed rapamycin had significantly less F-actin in the brain than age-matched controls. All results, taken together, suggest that age-associated F-actin reflects healthy aging in fruit flies and could be counteracted by strategies aimed at improving longevity.

“But this is a correlation, not a direct demonstration that F-actin is detrimental to brain aging,” Walker said. “To determine causality, we turned to genetics.”

With the fruit fly genome completely mapped, researchers could target aging genes in flies known to play a role in the accumulation of actin filaments. They found that by reversing the Formin homology domain 2 containing an ortholog (Fhos) in fruit fly neurons prevented the accumulation of F-actin in the brain.

“When we reduced Fhos expression in aging neurons, it prevented the accumulation of F-actin in the brain,” said Edward (Ted) Schmid, who worked in Walker’s lab at UCLA 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 F-actin accumulation in the brain and study how it affects the aging process.”

Although the genetic “editing” targeted only neurons, the researchers found that it improved the overall health of the flies. They lived 25 to 30 percent longer and showed signs of improved brain function and markers of improved health in other organs. Preventing the accumulation of cognitive function protected by F-actin, suggesting that this accumulation leads to age-related cognitive decline.

A closer look revealed that F-actin had disrupted the cell’s recycling system. The researchers found that preventing F-actin accumulation caused more autophagy in the brains of aged fruit flies. If they removed the F-actin And autophagy disabled, aging was not slowed down. It appeared that the main mechanism by which F-actin causes brain aging is by impairing autophagy. The researchers also showed that disrupting F action in aged brains restored brain autophagy to levels seen in young people and reversed some cellular markers of brain aging.

Of course, these findings need to be translated to humans, which may be more difficult. But researchers are there to meet the challenges, right?

“Most of us in the field of aging strive to move beyond lifespan to what we call lifespan,” Walker said. “We want to help people enjoy good health and a high quality of life while extending their life expectancy. Our study improved cognitive and gut function, activity level and overall health in fruit flies – and offers hope for what we could achieve in humans.

The study was published in the journal Natural communications.

Source: UCLA