Researchers not only identified how a common cellular protein affects aging, but also modified the genes that produce it in fruit flies, extending healthy lifespan by 25% to 30%. This discovery opens the door to healthier aging in humans.

The cytoskeleton provides most cells with their shape, structure, and internal organization. In contrast, 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 i found this aging It disrupts the functions of the cytoskeleton by altering actin expression, which can lead to age-related diseases, including cancer and neurodegenerative diseases.

A new study by UCLA researchers investigated actin’s role in brain aging and found that when F-actin accumulates in the brain, it inhibits cellular clearance and leads to waste generation that reduces neuronal functioning and contributes to neuronal function. cognitive decline. But they also found that altering certain genes in fruit flies prevented F-actin formation and extended the flies’ healthy lifespan by about 30%.

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

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

Researchers conducted an experiment Drosophila – fruit fly – model studies F-actin in the brains of naturally aging animals. They compared the brains of young, middle-aged and older flies and observed a significant increase in total F-actin levels in the brains as they aged.

Nature Communication/Edward Schmid

To determine whether the F-actin levels they observed reflected age or occurred universally over time, the researchers examined flies that were subjected to diet and/or protein restriction, an approach that has been shown to slow aging and increase longevity. They found that flies fed a low-protein diet had a significantly longer lifespan than those fed a high-protein diet. What’s more, they saw F-actin in the brains of flies that ate a rich diet in young middle age, which was not seen in the brains of flies that received dietary restriction.

The flies were then given Rapamycin, a small molecule that has been shown to extend lifespan. Feeding flies with rapamycin significantly extended their lifespan compared to those fed control. Additionally, rapamycin-fed aged flies had significantly less F-actin in their brains than age-matched controls. Taken together, all the findings suggested that age-associated F-actin reflects healthy aging in fruit flies and could be prevented by strategies to increase longevity.

“But this is a correlation, not a direct indication that F-actin is detrimental to brain aging,” Walker said. “We turned to genetics to achieve causality.”

Now that the fruit fly genome has been fully mapped, researchers can target senescent fly genes known to play a role in the accumulation of actin filaments. They found this while washing Formin homology 2 domain containing ortholog (Fho’sThe gene in fruit fly neurons prevented F-actin accumulation in the brain.

“When we reduce Fho’s “Expression in aging neurons prevented F-actin from accumulating in the brain,” said Edward (Ted) Schmid, who works in Walker’s UCLA laboratory and is the study’s lead author. “This really allowed us to expand our work because we now have a direct way to target F-actin accumulation in the brain and examine how this affects the aging process.”

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

A closer examination revealed that F-actin disrupted the cell’s recycling system. The researchers found that preventing F-actin accumulation caused greater autophagy in the brains of aged fruit flies. If they removed F-actin And disabled autophagy, aging did not slow down. It turns out that the primary mechanism by which F-actin triggers brain aging is by disrupting autophagy. The researchers also showed that disrupting the F-effect 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 challenging. But researchers are here for the challenges, right?

“Most of us in the field of aging are focused on moving beyond lifespan to what we call healthspan,” Walker said. “We want to help people have a healthy and high quality of life while extending their lives. “Our study improved the cognitive and gut function, activity level and overall healthspan of fruit flies and offers hope for what we can achieve in humans.”

The research was published in the journal Nature Communication.

Source: UCLA